Natural and Synthetic Lactones Possessing Antitumor Activities

International Journal of
Molecular Sciences
Review
Natural and Synthetic Lactones Possessing Antitumor Activities
Younghoon Kim 1,2 , Sandip Sengupta 2 and Taebo Sim 1,2, *
1 KU-KIST Graduate School of Converging Science and Technology, Korea University, 145 Anam-ro,
Seongbuk-gu, Seoul 02841, Korea; YHOON9408@yuhs.ac
2 Severance Biomedical Science Institute, Graduate School of Medical Science (Brain Korea 21 Project),
College of Medicine, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea;
SENGSANDIP@yuhs.ac
* Correspondence: TBSIM@yuhs.ac; Tel.: +82-2-2228-0797
Abstract: Cancer is one of the leading causes of death globally, accounting for an estimated 8 million
deaths each year. As a result, there have been urgent unmet medical needs to discover novel oncology
drugs. Natural and synthetic lactones have a broad spectrum of biological uses including anti-
tumor, anti-helminthic, anti-microbial, and anti-inflammatory activities. Particularly, several natural
and synthetic lactones have emerged as anti-cancer agents over the past decades. In this review,
we address natural and synthetic lactones focusing on their anti-tumor activities and synthetic routes.
Moreover, we aim to highlight our journey towards chemical modification and biological evaluation
of a resorcylic acid lactone, L-783277 (4). We anticipate that utilization of the natural and synthetic
lactones as novel scaffolds would benefit the process of oncology drug discovery campaigns based
on natural products.
Keywords: natural lactones; synthetic lactones; anticancer activities; natural product synthesis;
drug discovery

Citation: Kim, Y.; Sengupta, S.; Sim,

T. Natural and Synthetic Lactones
1. Introduction
Possessing Antitumor Activities. Int.
J. Mol. Sci. 2021, 22, 1052. https:// Cancer, the second leading cause of death worldwide, has become one of the greatest
doi.org/10.3390/ijms22031052 challenges to global health. The mortality rate that results from cancer is still unacceptably
high over the last two decades, responsible for about 8 million deaths per year, and it is
Academic Editor: predicted to increase to 13 million by 2030 [1,2]. Hence, there is a consistent and urgent
Czesław Wawrzeńczyk need for the discovery of novel and potential chemotherapeutic agents to combat cancer.
Received: 30 November 2020 Cancer is frequently correlated with disruption in key signaling pathways, which
Accepted: 16 January 2021 involve extracellular ligands, transmembrane receptors, intracellular signaling protein ki-
Published: 21 January 2021 nases, and transcription factors, causing aberrant cell proliferation and defective apoptosis
induction [3,4]. Recently, the targets and molecular mechanisms of natural product-derived
Publisher’s Note: MDPI stays neutral anticancer agents have been extensively investigated [5,6]. Furthermore, the effort has even-
with regard to jurisdictional claims in tually led to the emergence of various natural lactones and their derivatives as potential
published maps and institutional affil- lead compounds for anticancer therapeutics on account of their potent bioactivities, includ-
iations. ing cytotoxicity against cancer cells and anti-neoplastic efficacy in in vivo studies [7–9].
Lactones are basically chemical entities constituted of cyclic carboxylic esters. Nat-
ural and synthetic lactones exhibit a broad spectrum of biological activities such as anti-
helminthic, anti-microbial, anti-inflammatory, and anti-tumor activities. Radicicol (1),
Copyright: © 2021 by the authors. for instance, is a macrocyclic resorcylic acid lactone and its first isolation dates back to
Licensee MDPI, Basel, Switzerland. 1953 [10]. Initial biological activity of resorcylic acid lactones, however, did not draw much
This article is an open access article attention from the researchers until kinase inhibition by cis-enone-containing resorcylic
distributed under the terms and acid lactones is reported in the late 1990s [11].
conditions of the Creative Commons Starting from a series of resorcylic acid lactones (RALs), several classes of natural
Attribution (CC BY) license (https:// lactones including sesquiterpene lactones (SLs), diacylglycerol lactones (DAGLs), and diter-
creativecommons.org/licenses/by/
pene lactones (DLs) received much attention as potential anticancer agents over the past
4.0/).
Int. J. Mol. Sci. 2021, 22, 1052. https://doi.org/10.3390/ijms22031052 https://www.mdpi.com/journal/ijms

Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 2 of 69
Int. J. Mol. Sci. 2021, 22, 1052 diterpene lactones (DLs) received much attention as potential anticancer agents2over of 67
the past few decades [12–16]. Nevertheless, the development of those natural products
into drug discovery programs is still somewhat limited due to complexity in structures
and low pharmacokinetic
few decades profile resulted
[12–16]. Nevertheless, from relatively
the development highnatural
of those lipophilic properties.
products For
into drug
this reason, great efforts were made to complete total syntheses of biologically
discovery programs is still somewhat limited due to complexity in structures and low phar- important
natural lactones
macokinetic andresulted
profile to establish
from synthetic
relatively approaches
high lipophilicto modify
properties.complex natural
For this reason,lactone
great
structures
efforts were[17–19].
made In to the expectation
complete that natural
total syntheses ofproducts-based structures
biologically important would
natural be am-
lactones
ply
and exploited
to establishassynthetic
powerfulapproaches
tools in designing
to modify strategies
complexofnatural
anticancer
lactonedrug discovery
structures pro-
[17–19].
grams, we herein provide
In the expectation a comprehensive
that natural products-based review on the biological
structures would be activities and chem-
amply exploited as
powerful
istry tools in designing
of representative strategies
natural of anticancer
and synthetic lactonesdrug discovery
that are knownprograms, we herein
to exhibit anticancer
provide a comprehensive review on the biological activities and chemistry of representative
activities.
natural and synthetic lactones that are known to exhibit anticancer activities.
2. Biological Activities and Chemistry of Natural and Synthetic Lactones
2. Biological Activities and Chemistry of Natural and Synthetic Lactones
2.1. Reosorcylic Acid Lactones
2.1. Reosorcylic Acid Lactones
The resorcylic acid lactones (RALs) are mucotoxins belonging to a family of benzan-
The resorcylic acid lactones (RALs) are mucotoxins belonging to a family of benzan-
nulated macrolides, which are isolated from various types of fungi. A structural feature
nulated macrolides, which are isolated from various types of fungi. A structural feature
of RALs is characterized by a β-resorcylic acid scaffold annulated to a 12–14 membered
of RALs is characterized by a β-resorcylic acid scaffold annulated to a 12–14 membered
macrolactone [20]. RALs had not been recognized as a significant class of compounds until
macrolactone [20]. RALs had not been recognized as a significant class of compounds
the late 1990s that molecular targets of a few RALs were revealed. Research on RALs was
until the late 1990s that molecular targets of a few RALs were revealed. Research on RALs
delighted with the discovery of radicicol (1) as an Hsp90 inhibitor in conjunction with the
was delighted with the discovery of radicicol (1) as an Hsp90 inhibitor in conjunction
identification of hypothemycin (2) and L783277 (3) as kinase inhibitors [11,21,22]. Espe-
with the identification of hypothemycin (2) and L783277 (3) as kinase inhibitors [11,21,22].
cially, cis-enone moiety containing RALs are prone to undergo 1,4-Michael addition with
Especially, cis-enone moiety containing RALs are prone to undergo 1,4-Michael addition
awith
conserved cysteine
a conserved residue
cysteine in theinATP-binding
residue the ATP-bindingsite ofsite
theofkinases leading
the kinases to covalent
leading to co-
inhibition of the target kinase. The most recognized compounds of
valent inhibition of the target kinase. The most recognized compounds of this type are this type are hypo-
themycin (2), LL-Z1604-2
hypothemycin (3), and
(2), LL-Z1604-2 (3),L783277 (4). (4).
and L783277
2.1.1.
2.1.1. Biological
Biological Activities
Activities ofof Radicicol
Radicicol (1)(1)
Radicicol (1)(1)provided
providedthe thefoundation
foundation forfor research
research on macrocylic
on macrocylic lactones
lactones as anti-
as anticancer
cancer
agents.agents.
In 1953,InRadicicol
1953, Radicicol
(1) was(1) was isolated
isolated from the from the fungus
fungus Monosporium
Monosporium bonordenbonorden
as the
as the first example of RALs [10]. In 1992, radicicol (1) was initially
first example of RALs [10]. In 1992, radicicol (1) was initially reported to act as an reported to act as src
an
src kinase inhibitor, which triggered research interest in RALs and other
kinase inhibitor, which triggered research interest in RALs and other classes of macrocyclic classes of mac-
rocyclic lactones
lactones [23]. [23]. However,
However, radicicol (1)radicicol
was later(1) was later
revealed revealedinhibit
to selectively to selectively inhibit
HSP90 function
HSP90 function
by binding to itsbyN-terminal
binding to ATP
its N-terminal
pocket and ATP thepocket
effectsand the effects(1)
of radicicol ofon
radicicol (1) on
modulating
modulating
protein kinase protein
activitykinase activity
turned out to turned out toas
be indirect bemany
indirect as many
protein protein
kinases kinases
require HSP90 re-
for proper
quire HSP90 folding [24]. folding
for proper Although[24].radicicol
Although (1)radicicol
does not(1)possess
does notdirect kinase
possess inhibitory
direct kinase
activity, it provided
inhibitory activity, itthe foundation
provided for research for
the foundation on macrocylic
research onlactones as anticancer
macrocylic lactones asagents.
anti-
Owing to radicicol (1), there are currently several examples of well-studied
cancer agents. Owing to radicicol (1), there are currently several examples of well-studied RALs, namely:
hypothemycin
RALs, (2), LL-Z1640-2(2),
namely: hypothemycin (3),LL-Z1640-2
and L-783277 (3), (4)
andthat are known
L-783277 to are
(4) that inhibit
knownmitogen-
to in-
activated
hibit protein kinasesprotein
mitogen-activated by the kinases
use of abycis-enone
the usemoiety in an ATP-competitive
of a cis-enone manner
moiety in an ATP-com-
(Figure 1).
petitive manner (Figure 1).
Figure 1. Structures of representative resorcylic acid lactones.

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22, xx FOR
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2.1.2. Chemistry of Radicicol (1)

2.1.2. Chemistry
2.1.2. Chemistry of of Radicicol
Radicicol (1)(1)
Chemistry of
Affirmation of Radicicol
the structure was achieved by the total synthesis accomplished by Lett
Affirmation
Affirmation of
of the
ofthe structure
structure was
was achieved
achieved byby
by thethe
the total
total synthesis
synthesis accomplished by Lett
Lett
Affirmation
and Lampilas in earlythe1992
structure was
and followed achieved
by some total
improvement andaccomplished
synthesis accomplished
modification. by by
Lett’s
and
andLett Lampilas
Lampilas
and in
in
Lampilas early
early
in 1992
1992
early and
and
1992 followed
followed
and by
by
followed some
some
by improvement
improvement
some and
and
improvement modification.
modification.
and Lett’s
Lett’s
modification.
synthetic protocol utilized a key intramolecular Mitsunobu reaction to construct the 14-
synthetic
synthetic protocol
protocol
Lett’s synthetic utilizedutilized
utilized
protocol aa key
key intramolecular
intramolecular Mitsunobu
Mitsunobu
a key intramolecular reactionreaction
reaction to construct
to construct the 14-
the 14-
member macrocycle (Scheme 1). Cyclization precursor 9Mitsunobu
would be synthesized to through
construct a
member
member macrocycle
macrocycle (Scheme(Scheme
(Scheme 1). Cyclization
Cyclization precursorprecursor
99isocoumarin
would be be synthesized through aa
the 14-member
palladium-catalyzed coupling1).reaction
macrocycle precursor
1). ofCyclization
chlorinated would synthesized
9 would 8 and through
bevinyltin
synthesized
sub-
palladium-catalyzed
palladium-catalyzed coupling coupling
reaction reaction
of chlorinated
chlorinated isocoumarin 88 and
and 8vinyltin
vinyltin sub-
through
strate 7. Compound 7 coupling
a palladium-catalyzed
was obtained reaction of
through the addition isocoumarin
of chlorinated isocoumarin
of lithium vinyltin 6 and sub-
vinyltin
to aldehyde
strate
strate 7. Compound
7. Compound 7 was
7 was obtained
7obtained through
through the addition
the addition of lithium
of lithium vinyltin
vinyltin 6 to aldehyde
6vinyltin
to aldehyde
5substrate
already 7. Compound
carrying the epoxidewaswithobtained through
the desired the addition
stereochemistry ofplace.
in lithium involved to
186lin-
55earalready 5carrying
aldehyde
already carrying
already the
the epoxide
carrying
epoxidethe with
epoxide
with thewith
the
steps resulting in a 4.7% overall yield [25].
desired
desiredthe stereochemistry
desired in place.
place.
stereochemistry
stereochemistry in ininvolved
place.
involved 18 lin-
lin-
involved
18
earlinear
18
ear steps steps
steps resulting in aa 4.7%
resulting
resulting in 4.7% overall
in a overall yield yield
4.7% overall
yield [25]. [25].
[25].
Scheme 1. The total synthesis of radicicol (1) according to Lett and Lampilas [25].
Scheme 1.
Scheme 1. The
The total
total synthesis
synthesis of
of radicicol
radicicol (1)
(1) according
according to
to Lett
Lett and
and Lampilas
Lampilas [25].
[25].
In 2000, the Danishefsky group did concise asymmetric syntheses of radicicol (1) and
In 2000,
In 2000, the
the Danishefsky group
group did
did concise
concise asymmetric
asymmetric syntheses
syntheses of radicicol (1) and
monocillin I [26].Danishefsky
Their synthetic strategy relies on a convergent of radicicol
three-stage (1) and
assembly of
monocillin III [26].
monocillin [26]. Their
[26]. Theirsynthetic
Their syntheticstrategy
synthetic strategyrelies
strategy relies on
onon aa convergent
convergent
a convergent three-stage
three-stage assembly
assembly of
of the
the 14-membered lactone which has, as a relies
key transformation, three-stage
a novel assembly
ring-forming of
me-
14-membered
the
the 14-membered
14-membered lactone which
lactone has,
which
lactone awhich as a
has, key
as atransformation,
key a novel
transformation, a ring-forming
novel metathesis
ring-forming me-
tathesis reaction utilizing vinyl has, as a(Figure
epoxide key transformation,
2). a novel ring-forming me-
reactionreaction
tathesis
tathesis utilizingutilizing
reaction a vinyl epoxide
utilizing aa vinyl (Figure 2).
vinyl epoxide
epoxide (Figure 2).
(Figure 2).
Figure
Figure 2.
2. Retrosynthetic
Retrosynthetic analysis
analysis according to Danishefsky
according to Danishefsky et
et al. [26].
al. [26].
Figure
Figure 2.
2. Retrosynthetic
analysis according
according to Danishefsky
to Danishefsky et
et al. [26]..
al. [26]
The synthesis commenced with construction of the chiral homochiral allylic alcohol
The synthesis
The synthesis commenced
commenced with
with construction
construction of of the
the chiral
chiral homochiral
homochiral allylic
allylic alcohol
alcohol
11 from (R)-3-hydroxybutyric
methyl (R)-3-hydroxybutyric acid (13)
acid (13) in
in 88 steps
steps in
in 49%
49% yield
yield (Scheme
(Scheme 2).
2).
11 from methyl (R)-3-hydroxybutyric acid (13) in 8 steps in 49% yield (Scheme
11 from methyl (R)-3-hydroxybutyric acid (13) in 8 steps in 49% yield (Scheme 2). 2).
Scheme 2. Synthesis of intermediate 11 [26].

Scheme 2. Synthesis
Scheme 2. Synthesis of
of intermediate
intermediate 11 [26]..
11 [26]
Int. J. Mol. Sci. 2021, 22, 1052 4 of 67
The
The allylic
allylic dithiane
dithiane 12
12 was
was prepared
prepared in
in one
one step
step from
from commercially
commercially available
available 2,4-
2,4-
hexadienal
The 14 with
allylic 64%
dithiane
dithianeyield
12 (Scheme
was 3).
prepared
hexadienal 14 with 64% yield (Scheme 3). in one step from commercially available
available 2,4-
2,4-
hexadienal 14 with 64% yield (Scheme 3).
Scheme 3. Synthesis of intermediate 12 [26] .

Scheme
Scheme 3.
3. Synthesis
Synthesis of
of intermediate 12 [26]
intermediate 12 [26]..
Formylation
Formylation followed by oxidation and conversion of the alcohol to
to chloride was ef-
Formylation followed
followedby byoxidation
oxidationand andconversion
conversion ofofthethe
alcohol
alcohol chloride
to chloridewaswas ef-
fected
fected with
with 3,5-dimethoxybenzyl
Formylation followed
3,5-dimethoxybenzylby alcohol
oxidation
alcohol 14
and
14 to
to give
give the
conversion
the desired
of the
desired acid
alcohol
acid 15
15 (Scheme
to chloride
(Scheme 4). Inter-
was
4). Inter-ef-
effected with 3,5-dimethoxybenzyl alcohol 14 to give the desired acid 15 (Scheme 4).
mediate
fected 16
16 was
with synthesized
3,5-dimethoxybenzyl in
in 22insteps from
alcohol 14 15
to with
15give 48%
the yield.
desired Ruthenium-based
15 (Scheme 4). olefin
mediate
Intermediate was synthesized
16 was synthesized steps from
2 steps from with
15 with48%
48% yield.acid
yield. Ruthenium-based
Ruthenium-based Inter-
olefin
metathesis
mediate 16 catalyst
was was used
synthesized to
in get
2 the
steps
metathesis catalyst was used to get the desired desired
from 1514-membered
with 48% lactone
yield. 18 stereospecifically
Ruthenium-based
desired 14-membered lactone 18 stereospecifically olefin
in
in 55%
55%yield.
metathesis
55% yield.
yield.Oxidation
catalyst
Oxidationwasand
Oxidation used
and
andcrude
crude getmonosulfoxide
tocrude the
monosulfoxide
monosulfoxide was exposed
desired 14-membered
waswas
exposed to
to the
lactone
exposed toaction
the 18 of
of Ac O, Et
Et332N,
thestereospecifically
action Ac22of
action O,Ac N,
O,
and
in
and H
55% 2O
H2and
Et3 N, to give
yield.
O toHgiveO the
Oxidation
the
to desired
and
desired
give the ketone
crude
ketone
desired dimethyl
dimethyl
ketone monocillin
monosulfoxide was
monocillin
dimethyl I
I (19,
exposed
(19,
monocillin 70%).
to the
70%).
I Regiospecific
action of
Regiospecific
(19, 70%). Ac chlorin-
2O, Et3N,
chlorin-
Regiospecific
2
ation
and Hof2Othe
chlorination
ation of the aromatic
to give
of the
aromatic ring
ring then
thearomatic
desired ring
then produced
ketone then
produced radicicol
dimethyl
produced
radicicol dimethyl
monocillin
radicicolI (19,
dimethyl ether
70%).
dimethyl
ether (20).
Regiospecific
ether
(20). (20). chlorin-
ation of the aromatic ring then produced radicicol dimethyl ether (20).
Scheme
Scheme 4.
4. Synthesis
Synthesis of
of radicicol
radicicol dimethyl
dimethyl ether
ether (20)
(20) [26].
[26].
Scheme 4. Synthesis of radicicol dimethyl ether (20) [26].
However,
However, they
However, they were
were able
able to
to reform
reform the
the natural
natural products
products via
via the
the similar
similar strategy
strategy used
used
before
before except
However,
except the
the modification
they were able
modification of
toof protection
reform the
protection groups
natural
groups in the
products
in the aromatic
via the
aromatic ring
similar
ring
before except the modification of protection groups in the aromatic ring 21 (Scheme 21 (Scheme
strategy
21 (Scheme 5).
used
5).
5).
They
before
They obtained
except
obtained the
the
the final radicicol
modification
final radicicolof(1) by treatment
protection
(1) with
groups in base,
the in 7.5%
aromatic yield
ring over
21 14
(Scheme
They obtained the final radicicol (1) by treatment with base, in 7.5% yield over 14 steps 5).
steps
(longest
(longest linear
linear sequence)
They obtained [27].
the final radicicol
sequence) [27]. (1) by treatment with base, in 7.5% yield over 14 steps
(longest linear sequence) [27].
Synthesis of radicicol
Scheme 5. Synthesis
Scheme radicicol (1) according
according to Danishefsky
Danishefsky et al.
al. [27].
Scheme 5.
5. Synthesis of
of radicicol (1)
(1) according to
to Danishefsky et
et al. [27].
[27].
Scheme 5. Synthesis of radicicol (1) according to Danishefsky et al. [27].
tion of toluate 24 using two equivalents of LDA followed by addition of Weinreb amide
25 afforded cyclization precursor, which after elimination and Grubbs reaction produced
26 with 64% yield in 3 steps. Radicicol (1) was obtained from intermediate 26 in 3 steps
with
Int. J. Mol. Sci. 2021, 22, 43%
x FOR yield.
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Int. J. Mol. Sci. 2021, 22, 1052 5 of 67
Winssinger’s total
Winssinger’s totalsynthesis
synthesisofofradicicol
radicicol(1)(1)was
was reported
reported in in 2005
2005 [28].
[28]. 2-hydroxy
2-hydroxy to-
toluic
luic acid 22 under Mitsunobu condition with 23 and protection gave 24
acid 22 under Mitsunobu condition with 23 and protection gave 24 (Scheme 6). Reaction(Scheme 6). Reac-
tion
of of toluate
toluate 24 using
24 using two two equivalents
equivalents of LDA
of LDA followed
followed by addition
by addition of Weinreb
of Weinreb amide
amide 25
25 afforded
afforded cyclization
cyclization precursor,
precursor, whichwhich after
after elimination
elimination andand Grubbs
Grubbs reaction
reaction produced
produced 26
26 with
with 64%64% yield
yield in 3in 3 steps.
steps. Radicicol
Radicicol (1) was
(1) was obtained
obtained fromfrom intermediate
intermediate 26 in 26 in 3 steps
3 steps with
withyield.
43% 43% yield.
Scheme 6. Synthesis of radicicol (1) according to Winssinger et al. [28].
Later the Danishefsky group decided to “edit” the epoxide and replace it with a cy-
clopropyl group in a highly convergent and efficient three-stage protocol for the syntheses
of radicicol (1) and cycloproparadicicol (32) [29]. The Hsp90 inhibition activity dropped
somewhat from the natural product (IC50 = 20–23 nM for radicicol (1) vs. IC50 = 160 nM for
cycloproparadicicol (32)), yet cycloproparadicicol (32) was still very potent. As with the
epoxide, inversion of the cyclopropane stereochemistry diminishes the activity (Scheme
7). Synthesis of
of radicicol
radicicol (1)
(1) according
according to
Scheme 6.
Scheme 6. Synthesis to Winssinger
Winssinger et
et al.
al. [28].
[28].
The central element of their plan was the building of an “ynolide” intermediate and
its advancement to the benzomacrolide
Later Danishefskyby
the Danishefsky a Diels–Alder
group decidedtotocycloaddition.
“edit”the
the Reformatsky-like
epoxide and replace it with a
Later the group decided “edit” epoxide and replace it with a cy-
condensationcyclopropyl
of propargyl bromide
group 27 with
in a highly 28, followed
convergent by protection
and efficient andprotocol
three-stage subsequentfor the syntheses
clopropyl group in a highly convergent and efficient three-stage protocol for the syntheses
reaction of the lithium alkynide
of radicicol ion, gave them the (32)
(1) and cycloproparadicicol acid[29].
intermediate
The Hsp9029, which under
inhibition activity dropped
of radicicol (1) and cycloproparadicicol (32) [29]. The Hsp90 inhibition activity dropped
Mitsonobu condition,
somewhatfurnished ester 30.
from the natural Cyclopropane-containing
product (IC50 = 20–23 nM forcobalt
radicicolcomplex
(1) vs. of 30= 160 nM for
IC50
somewhat from the natural product (IC50 = 20–23 nM for radicicol (1) vs. IC50 = 160 nM for
cyclized to give 31 in 39% yield, as
cycloproparadicicol a 2:1
(32)), mixture
yet of two diastereomers
cycloproparadicicol (32) wasand stillfinally after 6 As with the
very potent.
cycloproparadicicol (32)), yet cycloproparadicicol (32) was still very potent. As with the
steps providedepoxide, inversion of the cyclopropane
them cycloproparadicicol (32). stereochemistry diminishes the activity (Scheme 7).
epoxide, inversion of the cyclopropane stereochemistry diminishes the activity (Scheme
7).
its advancement to the benzomacrolide by a Diels–Alder cycloaddition. Reformatsky-like
condensation of propargyl bromide 27 with 28, followed by protection and subsequent
reaction of the lithium alkynide ion, gave them the acid intermediate 29, which under
Mitsonobu condition, furnished ester 30. Cyclopropane-containing cobalt complex of 30
cyclized to give 31 in 39% yield, as a 2:1 mixture of two diastereomers and finally after 6
steps provided them cycloproparadicicol (32).
Scheme 7. Synthesis Scheme 7. Synthesis of (32)

of cycloproparadicicol cycloproparadicicol
[29]. (32) [29].
its advancement to the benzomacrolide by a Diels–Alder cycloaddition. Reformatsky-like
condensation of propargyl bromide 27 with 28, followed by protection and subsequent
reaction of the lithium alkynide ion, gave them the acid intermediate 29, which under
Mitsonobu condition, furnished ester 30. Cyclopropane-containing cobalt complex of 30
cyclized to give 31 in 39% yield, as a 2:1 mixture of two diastereomers and finally after
6 steps provided them cycloproparadicicol (32).
Scheme 7. Synthesis of cycloproparadicicol (32) [29].
Int. J. Mol. Sci. 2021, 22, 1052 6 of 67
Unfortunately, radicicol
radicicol(1)
(1)exhibited
exhibitednonoinin vivo
vivo activity,
activity, which
which might
might be due
be due to
to the
the highly
highly sensitive
sensitive functionality
functionality present
present in theinmolecule,
the molecule, including
including an epoxide
an epoxide and a
and a conju-
conjugated
gated dienone,
dienone, both
both of of which
which are readily
are readily metabolized.
metabolized. As a result,
As a result, significant
significant effortsefforts
have
have focused
focused on synthesizing
on synthesizing radicicol
radicicol (1) analogs,
(1) analogs, whichwhich
retainretain the potency,
the potency, but with
but with im-
improved
proved metabolic
metabolic stability
stability (Figure
(Figure 3). 3).
Figure 3. Radicicol
Radicicol (1)
(1) analogs
analogs as
as Hsp90 inhibitors [30].
A series of halohydrin andand oxime

oxime derivatives
derivatives ofof radicicol
radicicol(1)
(1)were
wereprepared
preparedandandevalu-
eval-
ated for their antitumor activities in vitro and in vivo (Figure 3) [31]. Although
uated for their antitumor activities in vitro and in vivo (Figure 3) [31]. Although halohy-halohydrin
derivative
drin 38 was
derivative 38 inactive, oxime
was inactive, derivatives
oxime showed
derivatives in vivo
showed in antitumor activities,
vivo antitumor with
activities,
hydroxime 39 being the most active. KF25706 (39) was further evaluated for its
with hydroxime 39 being the most active. KF25706 (39) was further evaluated for its anti- antitumor
activityactivity
tumor againstagainst
variousvarious
tumor tumor
modelsmodels
by iv (intravenous) injections
by iv (intravenous) (Figure(Figure
injections 4). 4).
Halohydrin and
Figure 4. Halohydrin and oxime
oxime derivatives of radicicol (1) [31].
Triazole derivative
Triazole derivative (35)
(35) was
was synthesized
synthesized byby aa copper-mediated
copper-mediated cycloaddition
cycloaddition between
between
benzyl azide 43 and alkyne 41, prepared from 40 in 8 steps, gave triazole 45 in near in
benzyl azide 43 and alkyne 41, prepared from 40 in 8 steps, gave triazole 45 near
quanti-
quantitative yield. Base-promoted formation of the macrocycle and subsequent
tative yield. Base-promoted formation of the macrocycle and subsequent deprotection af- depro-
tection the
forded afforded the RAL
RAL triazole 35triazole 35 in an
in an efficient efficient
and highlyand highly convergent
convergent synthetic
synthetic route (Schemeroute
8).
(Scheme 8). Despite the additional H-bonding potential, a decrease in Hsp90
Despite the additional H-bonding potential, a decrease in Hsp90 inhibition activity was ob- inhibition
activity(IC
served was observed (IC 35=vs.
50 = 400 nM for 50
50
400 nM for
20–23 vs.radicicol
nM35for 20–23 nM(1)),for radicicolthe
although (1)), althoughdis-
compound the
compound displayed significant in vivo activity. In a similar manner, the
played significant in vivo activity. In a similar manner, the Danishefsky group incorporated Danishefsky
agroup incorporated
triazole ring into RAL a triazole ring
analogs, intoretaining
whilst RAL analogs, whilst retaining
the carbonyl the carbonyl
at the 9-position. None at of the
the
9-position. None of the triazole-containing analogs displayed
triazole-containing analogs displayed significant activity [32]. significant activity [32].
A synthesis of resorcylic acid macrolactam analogs of the natural product radicicol (1)
is described in which the key steps are the acylation and ring opening of a homophthalic
anhydride to give an isocoumarin, followed by a ring-closing metathesis to form the
macrocycle. Synthesis of macrolactam analogs of radicicol reported by Moody group in
2014 [33].
Int. J. Mol. Sci. 2021, 22, 1052 7 of 67
Scheme 8. Synthesis of triazole derivative (35) of radicicol (1) [32].
A synthesis of resorcylic acid macrolactam analogs of the natural product radicicol

(1) is described in which the key steps are the acylation and ring opening of a homoph-
thalic anhydride to give an isocoumarin, followed by a ring-closing metathesis to form the
macrocycle.
Scheme Synthesis
8. Synthesis of macrolactam
of triazole analogs
derivative (35) of radicicol
of radicicol (1) [32]. reported by Moody group in
2014 [33].
Addition
Addition
A synthesis of
of the
the malonate-derived
malonate-derived
of resorcylic acid
acid chloride
acid macrolactam chloride 47 to
47
analogs anhydride
toof
anhydride 46 gave
46
the natural gave the acylated
the radicicol
product acylated
intermediate,
intermediate, which
which spontaneously
spontaneously underwent
underwent a cyclization/retrocyclization,
a cyclization/retrocyclization,
(1) is described in which the key steps are the acylation and ring opening of a homoph- with the loss
with the
of CO
loss of2 ,
CO giving
2
thalic anhydride, the
giving isocoumarin
the isocoumarin 48 in
48 75%
in yield
75% (Scheme
yield (Scheme 9). This
9). was
This wasreadily
readily
to give an isocoumarin, followed by a ring-closing metathesis to form the converted
converted
into
into both
both the
macrocycle. NH
NH and
theSynthesisand ofNMe
NMe macrolactams
macrolactams
macrolactam 49 and
49
analogs and 50, respectively,
50, reported and
respectively,
of radicicol and allowed
allowed
by Moody for
for the
group the
in
incorporation
incorporation
2014 [33]. of
of amide and ester functional groups at C10 (51 and 52, respectively), giving
amide and ester functional groups at C10 (51 and 52, respectively), giving
additional
additional
Addition H-bonding
H-bonding potential.
potential.
of the malonate-derived acid chloride 47 to anhydride 46 gave the acylated
intermediate, which spontaneously underwent a cyclization/retrocyclization, with the
loss of CO2, giving the isocoumarin 48 in 75% yield (Scheme 9). This was readily converted
into both the NH and NMe macrolactams 49 and 50, respectively, and allowed for the
incorporation of amide and ester functional groups at C10 (51 and 52, respectively), giving
additional H-bonding potential.
Scheme 9. Synthesis
of macrolactam
macrolactam analog
analog (49–52)
(49–52) [33].
[33].
The
The macrolactams
macrolactamswere
wereindeed
indeedmore
moremetabolically
metabolicallystable
stable(43%
(43% metabolism forfor
metabolism macro-
mac-
lactam
rolactam 50 vs. 84% for radicicol (1) after 15 min with human liver microsomes and
50 vs. 84% for radicicol (1) after 15 min with human liver microsomes and
NADH/NADPH)
NADH/NADPH) and, and, significantly,
significantly, were
were also
also often
often superior
superior to
to the
the corresponding
corresponding other
other
natural
natural macrolactones
macrolactones in
in terms
terms of
of activity
activity [34].
[34].
Scheme 9. Synthesis of macrolactam analog (49–52) [33].
2.1.3. Biological Activities of Hypothemycin (2) and LL-Z1640-2 (3)
2.1.3.The
Biological Activities
macrolactams of Hypothemycin
were indeed more (2) and LL-Z1640-2
metabolically (3) metabolism for mac-
stable (43%
Hypothemycin (2) is a cis-enone containing natural macrocylic resorcylic acid lactone,
rolactam
which is an50antifungal
vs. 84% for radicicol
metabolite (1) after
isolated from15Hypomyces
min withtrichothecoides.
human liver A microsomes
comprehensiveand
NADH/NADPH) and, significantly, were also often superior to the corresponding
study conducted by groups of Tanaka and Sonoda reported that treatment of hypothemycin other
natural
(2) macrolactones in terms
on v-KRAS-transformed of activity
NIH3T3 [34].dramatically decreased the amount of cyclin
(DT cells)
D1 protein [35,36]. The groups also suggested cyclin D1 as a key molecule involved in
2.1.3.downstream
RAS Biological Activities
signalingofand
Hypothemycin (2) (2)
hypothemycin andmight
LL-Z1640-2
act as a(3)
RAS-signaling pathway
Int. J. Mol. Sci. 2021, 22, 1052 8 of 67
inhibitor by facilitating ubiquitinating process of cyclin D1 in DT cells. Another study

of hypothemycin (2) on its kinase specificity revealed that most kinases inhibited by
hypothemycin (2) contained a conserved cysteine residue at kinase active site, which is
corresponding to the cysteine 166 of ERK1/2 and they were inhibited in a time-dependent
manner suggesting covalent inhibition of the kinases through the formation of a Michael
adduct [37]. Particularly, hypothemycin (2) displayed low nanomolar Ki values against five
kinases (MEK1, MEK2, FLT1, and KDR) and high nanomolar Ki values on TRKB. These
findings furnished explanations of the behavior of hypothemycin (2) as a RAS-signaling
pathway inhibitor [36]. Moreover, it is also of significance that hypothemycin (2) could not
inhibit GSK3β, which possesses a conserved cysteine [37].
LL-Z1640-2 (3), also known as C292 and 5-(Z)-7-oxozeaenol), is a radicicol-related
anti-protozoan isolated from an unidentified fungi source. LL-Z1640-2 (3) can selectively
inhibit transforming growth factor (TGF)-β-activated kinase 1 (TAK1) with high potency
(TAK1, IC50 = 8.1 nM) [38]. TAK1 belongs to the upstream of mitogen-activated protein
kinases (MAPK) called MAPKK-K family. TAK1 is mainly involved in the activation of JNK
and P38 MAPK by activating the following MKKKs: MKK3, MKK4, MKK6, and MKK7.
LL-Z1640-2 (3) strongly inhibited JNK/p38 pathway, however, it did not display any
effect on ERK kinase activation induced by epidermal growth factor (EGF) in Hela cells.
This provided evidence that LL-Z1640-2 (3) does not directly block JNK/p38 pathway,
but rather acts at the upstream of the MAPKK level. The JNK/P38 pathways are important
in biological responses such as inflammation, apoptosis, and cell differentiation and their
aberration might bring about diseases related to inflammatory disease, neurodegenerative
disorder, and cancer progression [39]. Therefore, LL-Z1640-2 (3) is regarded as a potential
therapeutic agent to treat such diseases and can also be used as a great toolbox for signal
transduction research [40].
2.1.4. Chemistry of Hypothemycin (2) and LL-Z1640-2 (3)

The first total synthesis of LL-Z1640-2 (3) was reported by Tatsuta and co-workers in
2001 [41]. Their synthesis commencing from the addition of tris-MOM-protected D-ribose
53 and lithiated TMS-acetylene to propargylic alcohol 54 followed by protection, which
was then undergone a Sonagashira reaction to aromatic iodo 55 to get 56 and after 6 steps
generate propargylic alcohol 57 (Scheme 10). Target structure produced by a Mukaiyama
macrolactonization reaction of a protected seco acid 58 in 3% overall yield for the longest
linear sequence of 19 steps (from D-ribose).
10. Synthesis of LL-Z1640-2

Scheme 10. LL-Z1640-2 by by Tatsuta
Tatsutaet etal.
al.[41].
[41].Reagents
Reagentsand
andconditions:
conditions:(a) TMS-acetylene,n-BuLi,
(a)TMS-acetylene, BF33··Et22O,
n-BuLi,BF
THF, −
THF, −78 ◦ C, rt;
78 °C, rt; (b)
(b) Pd(OAc)
Pd(OAc)22, ,CuI,
CuI,Ph
Ph33P,P,Et
Et33N,
N,22h;h;(c)
(c)ClC(O)OEt,
ClC(O)OEt,pyridine, ◦ C,11h.h.
pyridine,00°C,
An alternative approach to the synthesis of LL-Z1640-2 (3) and hypothemycin (2) has
been reported by Selles and Lett [42]. Here, the macrocyclic framework of hypothemycin
(2) and LL-Z1640-2 (3) would be constructed either through Mitsunobu-based macrolac-
tonization from seco acid 59 or, alternatively, through a Suzuki-type macrocyclization of
ester 60. Both 59 and 60 would be derived from o-bromo benzoic acid 61 and intermediate
62 (Figure 5). The synthesis developed by Selles and Lett provided LL-Z1640-2 (3) and
hypothemycin (2) in overall yields of 1% and 0.17%, respectively, in 26 steps for the long-
est linear sequence.
Scheme 10. Synthesis of LL-Z1640-2 by Tatsuta et al. [41]. Reagents and conditions: (a) TMS-acetylene, n-BuLi, BF3·Et2O,
THF, −78 °C, rt; (b) Pd(OAc)2, CuI, Ph3P, Et3N, 2 h; (c) ClC(O)OEt, pyridine, 0 °C, 1 h.
Int. J. Mol. Sci. 2021, 22, 1052 9 of 67
An alternative approach to the synthesis of LL-Z1640-2 (3) and hypothemycin (2) has
been reported by Selles and Lett [42]. Here, the macrocyclic framework of hypothemycin
(2) and LL-Z1640-2 (3) would be constructed either through Mitsunobu-based
Mitsunobu-based macrolac-
macrolac-
tonization from seco acid
tonization from seco acid 59 or, alternatively, through a Suzuki-type
through a Suzuki-type macrocyclization of
ester 60. Both
Both 59
59 and
and 60
60 would
would bebe derived
derived from
from o-bromo
o-bromo benzoic acid 61 and intermediate
62 (Figure 5). The
The synthesis
synthesis developed
developed byby Selles and Lett provided LL-Z1640-2 (3) and
hypothemycin (2)(2) in
in overall
overall yields
yieldsof
of1%
1%and
and0.17%,
0.17%,respectively,
respectively,inin2626steps
steps
forfor the
the long-
longest
linear
est sequence.
linear sequence.
Figure 5. Retrosynthesis of hypothemycin (2) and LL-Z1640-2 (3) according to Selles and Lett [42].
[42].
In 2007, the Winssinger group developed a concise synthesis of LL-Z1640-2 (3) and
related resorcylic
related resorcylic acid
acid lactones
lactones using
using aa combination
combination ofof fluorous
fluorous tag-isolation
tag-isolation and
and polymer-
polymer-
bound reagents,
bound reagents, thus
thus making
making the
the chemistry
chemistry amenable
amenable to to high
high throughput
throughput synthesis
synthesis [43].
[43].
In the
In the synthetic
synthetic scheme
scheme their
their advanced intermediate 64,
advanced intermediate 64, was
was alkylated
alkylated inin excellent
excellent yield
yield
with aromatic
with aromatic fragments
fragments 63 63 previously
previously deprotonated
deprotonated by by LDA
LDA (Scheme
(Scheme 11).
11). The
The selenide
selenide
was then oxidized and eliminated to afford compounds 65 and purification done by
was then oxidized and eliminated to afford compounds 65 and purification done using
by using
simply loaded on fluorous-silica columns. The PMB group was removed
simply loaded on fluorous-silica columns. The PMB group was removed by DDQ, while by DDQ, while
the TMSE
the TMSE esterester was
was removed
removed with
with TBAF.
TBAF. TheThe hydroxyacids
hydroxyacids thus
thus obtained
obtained were
were engaged
engaged
in Mitsunobu macrocyclisations using fluorous-tagged triphenyl phosphine andand
in Mitsunobu macrocyclisations using fluorous-tagged triphenyl phosphine diazo
diazo di-
dicaboxylate, thus yielding the macrocycles 66 after a fluorous
caboxylate, thus yielding the macrocycles 66 after a fluorous solid-phase solid-phase extraction.
Mol. Sci. 2021, 22, x FOR PEER REVIEW 10 of 69extraction. Fi-
Finally,
nally, deprotection
deprotection andand oxidation
oxidation yielded
yielded a natural
a natural product,
product, LL-Z1640-2
LL-Z1640-2 (3) in(3)
goodin good
yield
yield
[43]. [43].
11. Concise
Schemesynthesis
Scheme 11. Concise synthesis of(3)
of LL-Z1640-2 LL-Z1640-2 (3) by
by Wissinger et Wissinger
al. [43]. et al. [43].
Total synthesisTotal
of synthesis of LL-Z1640-2
LL-Z1640-2 (3) utilizing
(3) utilizing a late-stage
a late-stage intramolecular
intramolecular Nozaki–Hiyama–
Nozaki–
Kishi reaction was reported by Thomas et al. in 2010 [44]. Their
Hiyama–Kishi reaction was reported by Thomas et al. in 2010 [44]. Their route depended route depended on an
aryl selenide nucleophile for a precedented sequence of alkylation,
on an aryl selenide nucleophile for a precedented sequence of alkylation, oxidation, and oxidation, and elimi-
nation to generate the requisite trans-olefin scaffold (Scheme
elimination to generate the requisite trans-olefin scaffold (Scheme 12). Subsequent 12). Subsequent Mitsunobu
esterification
Mitsunobu esterification would
would provide
provide access
access to to
anan advanced
advanced intermediate
intermediate 68 68 and
and 69 69 poised for
poised for macrocyclization with the intramolecular Nozaki–Hiyama–Kishi (NHK) reac-
tion. Finally, oxidation and deprotection completed natural product LL-Z1640-2 (3) syn-
thesis.
Total synthesis of LL-Z1640-2 (3) utilizing a late-stage intramolecular Nozaki–
Hiyama–Kishi reaction was reported by Thomas et al. in 2010 [44]. Their route depended
on an aryl selenide nucleophile for a precedented sequence of alkylation, oxidation, and
Int. J. Mol. Sci. 2021, 22, 1052 elimination to generate the requisite trans-olefin scaffold (Scheme 12). Subsequent
10 of 67
Mitsunobu esterification would provide access to an advanced intermediate 68 and 69
poised for macrocyclization with the intramolecular Nozaki–Hiyama–Kishi (NHK) reac-
macrocyclization with the
tion. Finally, oxidation andintramolecular Nozaki–Hiyama–Kishi
deprotection completed (NHK)
natural product reaction. (3)
LL-Z1640-2 Finally,
syn-
oxidation
thesis. and deprotection completed natural product LL-Z1640-2 (3) synthesis.
Scheme 12. Total

Scheme TotalSynthesis
Synthesisofof
LL-Z1640-2 (3)(3)
LL-Z1640-2 by by
Thomas et al.
Thomas et[44]. Reagents
al. [44]. and conditions:
Reagents (a)
and conditions:
CrCl 2 , NiCl 2 (cat.), DMF; (b) Dess–Martin periodinane, CH 2 Cl 2 , rt; (c) BCl 3, CH 2 Cl
(a) CrCl2 , NiCl2 (cat.), DMF; (b) Dess–Martin periodinane, CH2 Cl2 , rt; (c) BCl3 , CH2 Cl2 .2.
In 2010,
2010, Barrett
Barrettgroup
groupreported
reported total
total synthesis
synthesis of LL-Z1640-2
of LL-Z1640-2 (3)consecutive
(3) via via consecutive
mac-
macrocyclization and transannular aromatization [45]. According to their
rocyclization and transannular aromatization [45]. According to their synthetic protocol synthetic pro-
tocol thermolysis
thermolysis of diketo-dioxinone
of diketo-dioxinone 71 resulted
71 resulted in generation
in generation of ketene
of ketene intermediate,
intermediate, which
which was efficiently
was efficiently trappedtrapped intramolecularly
intramolecularly by theby the alcohol
alcohol to provide
to provide the 18-membered
the 18-membered mac-
macrocyclic lactone
rocyclic lactone 72 (Scheme
72 (Scheme 13). 13). Regioselective
Regioselective methylation,
methylation, followed
followed by deprotection
by deprotection and
and oxidation
oxidation gave gave LLZ1640-2
LLZ1640-2 (3) (3)
in in 51%
51% yield yield
over over
three three steps.
steps. 15-step
15-step biomimetic
biomimetic total total
syn-
Int.
Int.J.J.Mol.
Mol.Sci.
Sci.2021,
2021,22,
22,xxFOR
FORPEER
PEERREVIEW
REVIEW 11
11of
of69
69
synthesis of the
thesis of the TAK-kinase
TAK-kinase inhibitorLL-Z1640-2
inhibitor LL-Z1640-2(3) (3)from
fromcommercially
commercially available
available starting
starting
materials
materials was
was reported.
reported.
Scheme
Scheme13.
Scheme 13.Total
13. Totalsynthesis
Total synthesisof
synthesis ofLL-Z1640-2
of LL-Z1640-2(3)
LL-Z1640-2 (3)by
(3) byBarret
by et
Barretet
Barret al.
etal. [45].
al.[45].
[45].
InIn2007,
In 2007,aaanumber
2007, numberof
number ofsemi-synthetic
semi-syntheticderivatives
semi-synthetic derivativesof
derivatives ofthis
of thisnatural
this naturalproduct
natural producthypothemycin
product hypothemycin
hypothemycin
(2)
(2)and
andtheir
theirbiological assessment
biologicalassessment has
assessmenthas been
hasbeen reported
beenreported [46].
reported[46]. Interestingly,
[46].Interestingly,
Interestingly, derivatives
derivatives
derivatives 74a–
74a–d
74a–
ddshowed
showed
showed similar
similar antiproliferative
antiproliferative
similar antiproliferative activity
activity as
activityas hypothemycin
ashypothemycin
hypothemycin(2) (2) in
(2)in mostcases
inmost casesinvestigated,
investigated,
investigated,
which
whichindicates
which indicatesthatthatsubstituents
that substituentson
substituents on
on C4-O
C4-O
C4-O do
dodonot interfere
not
not with
interfere
interfere with target
with protein
target
target binding
protein
protein and
binding
binding and
may
and thus
may be
thusused
be to modulate
used to the
modulate physico-chemical
the physico-chemicalproperties of
properties hypothemycin
may thus be used to modulate the physico-chemical properties of hypothemycin (2) withof (2)
hypothemycin with-
(2)
out
outimpairing
without
impairing the
impairingthedesired biological
the desired
desired activity
biological
biological (Scheme
activity
activity 14).
(Scheme
(Scheme 14). 14).
Scheme
Scheme14.
14.The
Thesynthesis
synthesisof
ofsemi-synthetic
semi-syntheticderivatives
derivativesof
ofhypothemycin
hypothemycin(2)
(2)[46].
[46].
Herein,
Herein,
Herein,divergent syntheses
divergentsyntheses
synthesesofofresorcylic
resorcylicacid
acidlactones
lactoneswere
werereported,
reported,presenting
presentinganan
effort
effort accessing an alkene, or epoxide at the benzylic
effort on accessing macrocycles bearing an alkene, or epoxide at the benzylic positionfrom
on accessing macrocycles bearing benzylic position from
aacommon
commonbenzylic
benzylicsulfide
sulfideintermediate
intermediatetotoaccess
accessboth
bothLL-Z1640-2
LL-Z1640-2(3)(3)and
andhypothemycin
hypothemycin
(2)
(2)[47].
[47].Starting
Startingfrom
fromresin-bound
resin-boundintermediate
intermediate75,
75,the
thetoluate
toluateposition
positionwaswasalkylated
alkylatedwith
with
iodide 76 to obtain polymer-bound intermediate 77 (Scheme 15). Mitsunobu
iodide 76 to obtain polymer-bound intermediate 77 (Scheme 15). Mitsunobu cyclisation cyclisation
followed
followedby bythe
therelease
releaseofofsulfur
sulfurresin
resinunder
underoxidative
oxidativecondition
conditiongave
gave78 78which
whichwas
wasoxi-
oxi-
dized
dized to the desired cis-enone under slightly more forceful conditions by using DMP in
to the desired cis-enone under slightly more forceful conditions by using DMP in
Scheme 14. The synthesis of semi-synthetic derivatives of hypothemycin (2) [46].
Int. J. Mol. Sci. 2021, 22, 1052 11 of 67
Herein, divergent syntheses of resorcylic acid lactones were reported, presenting an
effort on accessing macrocycles bearing an alkene, or epoxide at the benzylic position from
a common benzylic sulfide intermediate to access both LL-Z1640-2 (3) and hypothemycin
Starting from
(2) [47]. Starting from resin-bound
resin-bound intermediate 75, the toluate position was alkylated with
iodide 76 to obtain
obtain polymer-bound
polymer-bound intermediate
intermediate 77 (Scheme
(Scheme 15).
15). Mitsunobu
Mitsunobu cyclisation
cyclisation
followed by by the
therelease
releaseofofsulfur
sulfurresin
resin under
under oxidative
oxidative condition
condition gavegave 78 which
78 which was was
oxi-
oxidized
dized to the
to the desired
desired cis-enone
cis-enone underslightly
under slightlymore
moreforceful
forcefulconditions
conditionsby
by using
using DMP in
CH22ClCl22under
underreflux
reflux and
and led
ledto
tofinal
finalcompounds
compounds both
both natural
natural products
products LL-Z1640-2 (3) and
hypothemycin (2).
Scheme 15. Divergent synthesis of hypothemycin (2) and LL-Z1640-2 (3) [47].
In 2009, aa serum
In serumandandplasma-stable
plasma-stableresorcylic
resorcylicacid analog
acid analog of ER-803064
of ER-803064 (79)(79)
waswas
dis-
covered [48].
discovered The
[48]. Theaddition
additionofof
the
the(S)-Me
(S)-Megroup
groupatatC4C4has
hasresulted
resulted in
in aa dramatic improve-
dramatic improve-
ment in
ment in metabolic
metabolic stability
stability with
with retention
retention of
ofbioactivity
bioactivity(Scheme
(Scheme16).16). Aromatic
Aromatic ester
ester 80
80
andaliphatic
and aliphaticiodo
iodo81 81were
werecoupled
coupledandandfurther
further steps
steps were
were employed
employed to get
to get aldehyde
aldehyde 82
82 in
in 5 steps which after 8 synthetic steps gave final ER-803064
5 steps which after 8 synthetic steps gave final ER-803064 (79). (79).
Scheme16.
Scheme 16. Synthesis
Synthesis of
of ER-803064
ER-803064 (79)
(79)[48].
[48].
In
In2010,
2010,the
theWang
Wang group
group reported
reporteda potent
a potentin vitro leadlead
in vitro compound,
compound,83 and andfully
83 84, syn-
84, fully
thetic analogs of natural product LL-Z1640-2 (3). The analog 84 maintained
synthetic analogs of natural product LL-Z1640-2 (3). The analog 84 maintained the meta- the metabolic
stability, regained
bolic stability, full in
regained vitro
full potency
in vitro similar
potency to natural
similar to naturalproduct,
product,and
andhad
hadsignificant
significant
improvement
improvement in in in
invivo
vivopotency
potency(Scheme
(Scheme17).17). Their
Their synthesis
synthesis started
started from
fromcommercially
commercially
available
availablemethyl
methylorsellinate
orsellinate(85)
(85)and
andafter
after 55 steps
steps afforded
affordedaromatic
aromaticselenide
selenideintermediate
intermediate
86 which was then coupled with acyclic iodide in the presence of LiHMDS followed
86 which was then coupled with acyclic iodide in the presence of LiHMDS followed byby
mCPBA
mCPBA oxidation, TBAF deprotection, and lactone cyclization under the influence of
oxidation, TBAF deprotection, and lactone cyclization under the influence of
Mukaiyama’s
Mukaiyama’s reagent
reagent to to provide
providelactone 87.Deprotection
lactone87. Deprotectionfollowed
followedby byC14
C14substitutions
substitutions
was
was done
done through
through Mitsunobu
Mitsunobu reaction
reaction and
and benzoyl
benzoyl group
group waswas then
thendeprotected
deprotected under
under
basic conditions to produce allylic alcohol 11. Finally, oxidation followed by deprotection
led to final analog 83 and 84 [49].
bolic stability, regained full in vitro potency similar to natural product, and had significant
improvement in in vivo potency (Scheme 17). Their synthesis started from commercially
available methyl orsellinate (85) and after 5 steps afforded aromatic selenide intermediate
86 which was then coupled with acyclic iodide in the presence of LiHMDS followed by
Int. J. Mol. Sci. 2021, 22, 1052 mCPBA oxidation, TBAF deprotection, and lactone cyclization under the influence of
12 of 67
Mukaiyama’s reagent to provide lactone 87. Deprotection followed by C14 substitutions
was done through Mitsunobu reaction and benzoyl group was then deprotected under
basic conditions to produce allylic alcohol 11. Finally, oxidation
oxidation followed
deprotection
led to final analog 83 and
and 84
84 [49].
[49].
Scheme 17.
Scheme 17. Synthesis of LL-Z1650-2
LL-Z1650-2 (3) (3) analogs
analogs (83
(83 and
and 84)
84) [49].
[49]. Reagents and conditions:
conditions: (a). (i). LiHMDS, acyclic iodide,
(ii). mCPBA, Et3 N, (iii). TBAF, (iv). 2-Cl-1-Me pyridinium iodide; (b). (i). TBAF, (ii).(ii).
(ii). mCPBA, Et3N, (iii). TBAF, (iv). 2-Cl-1-Me pyridinium iodide; (b). (i). TBAF, Mitsunobu
Mitsunobu reaction,
reaction, (iii).(iii).
NaOH;NaOH;
(c). (c).
(i).
(i). PCC/Swern reaction, (ii).
PCC/Swern reaction, (ii). HCl. HCl.
In 2014, synthesis and biological studies of a triazole analogue (90) of LL-Z1640-2 (3)
were reported by the the Chen
Chen group
group inin 66 linear
linear steps
steps in
in 18%
18% overall
overall yield
yield [50].
[50]. The
The triazole
triazole
analog (90)
(90)showed
showedgoodgoodactivity (IC(IC
activity 50 =507.2
= μM) against
7.2 µM) MNK2
against kinase,
MNK2 which which
kinase, is an emerg-
is an
ing target target
emerging for cancer chemotherapy
for cancer chemotherapy(Scheme 18). Azido
(Scheme intermediate
18). Azido 91 which
intermediate was syn-
91 which was
thesized from
synthesized 2-deoxy
from d-ribose
2-deoxy acetonide
d-ribose acetonideand and
phloroglucinol carboxylic
phloroglucinol acid treated
carboxylic with
acid treated
with excess (S)-pent-4-yn-ol, under the standard CuSO4 /sodium ascorbate conditions,
excess (S)-pent-4-yn-ol, under the standard CuSO4/sodium ascorbate conditions, led to a
led to a smooth click reaction to afford the desired triazole 92 followed by successful
smooth click reaction to afford the desired triazole 92 followed by successful macrocy-
macrocyclization and intramolecular transesterification with NaH. Final deprotection of
clization and intramolecular transesterification with NaH. Final deprotection of the ace-
the acetonide 93 concluded a conciseofsynthesis
tonide 93 concluded a concise synthesis of analog
the triazole the triazole
90. analog 90.
Scheme 18.
Scheme 18.Synthesis
Synthesisof of
triazole derivative
triazole (90) of
derivative LL-Z1650-2
(90) (3) [50].
of LL-Z1650-2 (3)Reagents and conditions:
[50]. Reagents and conditions: (a).
(a). (i). CuSO4·H2O, t-BuOH/H2O, sodium ascorbate; (b). NaH, THF; (c). 1 N HCl, MeOH/THF.
(i). CuSO4 ·H2 O, t-BuOH/H2 O, sodium ascorbate; (b). NaH, THF; (c). 1 N HCl, MeOH/THF.
In 2016, an efficient synthesis of an exo-enone analog (94) of LL-Z1640-2 and evalua-
In 2016, an efficient synthesis of an exo-enone analog (94) of LL-Z1640-2 and eval-
tion of its protein kinase inhibitory activities were reported by the Chen Group [51]. The
uation of its protein kinase inhibitory activities were reported by the Chen Group [51].
synthesis has been achieved using a Ni-catalyzed regioselective reductive coupling mac-
The synthesis
rocyclization of has been achieved using
an alkyne–aldehyde as a keya step
Ni-catalyzed regioselective
(Scheme 19). The synthesisreductive
of 94 com-coupling
macrocyclization of an alkyne–aldehyde as a key step (Scheme 19). The
menced with the reported intermediate alkene 95 which after protection and transesteri- synthesis of 94
commenced with the reported intermediate alkene 95 which after protection
fication in the presence of NaH gave intermediate 96 in nearly quantitative yield. Alkyne– and trans-
esterification
aldehyde 97 was inreadily
the presence of NaH
synthesized gavefrom
in 3 steps intermediate 96 in nearly
96. As per reported quantitative
condition 97 un- yield.
der moderate dilution (0.013 M), gratifyingly provided the desired macrocyclization prod-
uct 98 in 57% isolated yield. This reaction proceeds via an alkenylnickel species formed
by a regioselective hydronickelation of the alkyne. Finally, oxidation and deprotection
furnished the required exo-enone analog 94.
In 2016, an efficient synthesis of an exo-enone analog (94) of LL-Z1640-2 and evalua-
tion of its protein kinase inhibitory activities were reported by the Chen Group [51]. The
synthesis has been achieved using a Ni-catalyzed regioselective reductive coupling mac-
Int. J. Mol. Sci. 2021, 22, 1052 rocyclization of an alkyne–aldehyde as a key step (Scheme 19). The synthesis of 9413com- of 67
menced with the reported intermediate alkene 95 which after protection and transesteri-
fication in the presence of NaH gave intermediate 96 in nearly quantitative yield. Alkyne–
aldehyde 97 was readily
Alkyne–aldehyde 97 was synthesized in 3 steps
readily synthesized in from 96.from
3 steps As per
96. reported condition
As per reported 97 un-
condition
97 under
der moderate
moderate dilution
dilution (0.013(0.013 M), gratifyingly
M), gratifyingly providedprovided the desired
the desired macrocyclization
macrocyclization prod-
product
uct in 57%
98 in9857% isolated
isolated yield.
yield. ThisThis reaction
reaction proceeds
proceeds viaananalkenylnickel
via alkenylnickelspecies
species formed
by a regioselective hydronickelation of the alkyne. Finally, oxidation and deprotection
furnished the required exo-enone analog 94.
[51]. Reagents and conditions: (a). (i). TBSCl, imidazole,

Scheme 19. Synthesis of exo-enone analog (94) of LL-Z1640-2 (3) [51]. imidazole,
(ii). NaH, THF; (b). (i). MOMCl, NaH, (ii). TBAF, THF,
THF, (iii).
(iii). DMP,
DMP,DCM;
DCM;(c).(c).NiCl
NiCl22,, CrCl
CrCl22, PPh33, H22O,
O, DMF;
DMF; (d).
(d). (i).
(i). DMP,
DMP,
DCM, (ii).
DCM, (ii). HCl,
HCl, MeOH.
MeOH.
2.1.5. Biological Activities of L-783277 (4)

L-783277 (4) is a naturally occurring 14-membered resorcylic acid lactone isolated
from Helvella acetababulum, a species of fungus in the family Helvellaceae. L-783277 (4)
is especially known for its highly potent inhibitory activity against MEK (IC50 of 4 nM).
The unexceptional binding affinity of L783277 (4) to kinases is mainly due to the presence
of the electrophilic cis-enone moiety that forms Michael adducts with conserved cysteine
residue residing near the DFG motif of the kinases. As a good comparison, a C70 -C80
trans-enone analog of L-783277 (4), exhibited 75-fold decreased activity against MEK (IC50
of 300 nM). Moreover, L-783277 (4) was reported to possess potent inhibitory activities
against several kinases including VEGFR2/3, FLT1/3/4, MEK1/2, KDR, and PDGFRα but
with low kinome selectivity [47,52].
We investigated the effects of a structural nature of L-783277 (4) on kinase inhibitory
activities in three subsequent researches [52–54]. In an effort to expand our MEK kinase
program and to conduct a detailed SAR study with L-783277 (4) derivatives, we devel-
oped an efficient synthetic route toward L-783277 (4) [54]. With this effective synthetic
approach distinctive from those reported in precedent literature at the time, we were able
to obtain tens of milligrams of L-783277 (4) by simple purification method using flash silica
chromatography [47,55].
We noticed an observation that hypothemycin (2) could not inhibit GSK3β possessing
a conserved cysteine while it could inhibit kinases without conserved cysteines (Src, TrkA,
and Trk) [37]. Accordingly, we further investigated the structure of L-783277 (4), based
on our postulation that the reversible binding of RALs might also play a key role in
determining the inhibitory activities and overall selectivity toward kinases. To test the
hypothesis, we synthesized a reversible version of L-783277 (4), 99, in which the alkene
moiety of the cis-enone of L-783277 (4) was saturated and a number of analogs derived from
99 (Figure 6). Kinome-wide selectivity profiling and biochemical assays were conducted
with 99 and results showed that 99 inhibits activin A-like kinase 1 (ALK1) more potently
than its parent compound, L-783277 (4), does and it displayed a better kinase selectivity
against a panel of 342 kinases. ALK1 is a serine threonine kinase expressed predominantly
in endothelial cells and it functions as a receptor for bone morphologic protein 9 (BMP9).
Binding of the ligand to ALK1 activates Smad4 by phosphorylating Smad1/5/8, which
Int. J. Mol. Sci. 2021, 22, 1052 14 of 67
upregulates transcription of various target genes involved in angiogenesis [56,57]. Due to

the significance of ALK1 in regulation of tumor angiogenesis, it has been regarded as
a potential therapeutic target for the development of anticancer agents [58]. Although
dorsomorphin and LDN193189 showed inhibitory activities against BMP type I receptor
kinase and could inhibit BMP-related Smad and non-Smad signaling, inhibitory activities
displayed by the two were so broad that it also inhibited other signaling pathways, inducing
adverse events brought by off-target effects. In this study, we reported that 99 is a potent
and selective ALK1 inhibitor, which acts by selectively blocking BMP9-induced ALK1
signaling in C2C12 cells [52]. It is also highly noteworthy that ALK1 is one of the kinases
that has no conserved cysteine residue equivalent to Cys168 of ERK2. Therefore, the
selectivity of 99 is achieved by its inability to form a Michael adduct with the most kinases.
Moreover, greater conformational flexibility of 99 enables it to adopt superior binding
mode, which is the reason that the 99 shows higher activity relative to L-783277 (4) against
ALK1 (IC50 ALK1 = 62 nM and 126 nM for 99 and L-783277 (4), respectively).
Figure 6.
Figure Structures of
6. Structures of L-783277
L-783277 (4)
(4) derivatives
derivatives (99
(99 and
and 100).
100).
Our experience in discovering the first reversible version of L-783277 (4) as a potent
Our experience in discovering the first reversible version of L-783277 (4) as a potent
and selective ALK1 inhibitor encouraged us to focus on further development of L-783277 (4)
and selective ALK1 inhibitor encouraged us to focus on further development of L-783277
analogs with increased kinome-wide selectivity. We previously observed that L-783277 (4)
(4) analogs with increased kinome-wide selectivity. We previously observed that L-783277
strongly inhibited VEGFR3/2 and FLT3 but it displayed poor kinome-wide selectivity. The
(4) strongly inhibited VEGFR3/2 and FLT3 but it displayed poor kinome-wide selectivity.
tyrosine kinase vascular endothelial growth factor receptor3 (VEGFR3) and its homolog,
The tyrosine kinase vascular endothelial growth factor receptor3 (VEGFR3) and its hom-
VEGFR2, take part in tumor lymphangiogenesis [59] and angiogenesis [60], respectively.
olog, VEGFR2, take part in tumor lymphangiogenesis [59] and angiogenesis [60], respec-
Because inhibiting both angiogenesis and lymphangiogenesis is claimed to be a reasonable
tively. Because inhibiting both angiogenesis and lymphangiogenesis is claimed to be a
strategy to treat cancer [61,62], we aimed to discover novel L-783277 (4) derivatives that
reasonable strategyVEGFR2/3
selectively inhibit to treat cancer
and [61,62], we high
FLT3 with aimed to discover
potency. Our novel
strategy L-783277 (4) deriv-
implemented in
atives that selectively inhibit VEGFR2/3 and FLT3 with high potency. Our
order to achieve this goal was to rigidify the structure of 14-membered lactone scaffold strategy imple-
of
mented
L-783277in(4),order to achievethat
anticipating thisstructural
goal was rigidity
to rigidify the potentially
could structure ofenhance
14-membered lactone
kinome-wide
scaffold
selectivityof of
L-783277
L-783277(4),(4).
anticipating that structural
We synthesized 11 novelrigidity could
L-783277 (4) potentially
derivativesenhance
containing ki-
nome-wide selectivity of L-783277 (4). We synthesized 11 novel L-783277
a phenyl ring incorporated in the 14-membered chiral resorcylic acid lactone ring system (4) derivatives
containing
to assess this a phenyl ring incorporated
hypothesis. Among theseinderivatives,
the 14-membered chiral resorcylic
100 exhibited the highest acid lactone
potencies
ring system to assess this hypothesis. Among these derivatives, 100 exhibited
against VEGFR3, VEGFR2, and FLT3 and excellent kinome-wide selectivity [54]. Moreover, the highest
potencies
results of against
cornealVEGFR3, VEGFR2,with
assay conducted and 100
FLT3 and excellenteffective
demonstrated kinome-wide selectivity
suppression [54].
of both
Moreover, results of corneal assay conducted with 100 demonstrated effective
lymphangiogenesis and angiogenesis, indicating that 100 is a potential and unique template suppres-
sion
to beof both
used in lymphangiogenesis and angiogenesis,
the development of therapeutically indicating
active that 100
and selective is a potential
compound, and
targeting
unique template to be used
both lymphangiogenesis and in the development
angiogenesis [54]. of therapeutically active and selective
compound, targeting
Most natural both lymphangiogenesis
macrocyclic and angiogenesis
lactones exert physiological [54].
effects by covalently binding
to various biological targets. This, however, is often regarded as aby
Most natural macrocyclic lactones exert physiological effects covalently
major reasonbinding
behind
to
poor selectivity among substrates and undesired dose-dependent toxicities.reason
various biological targets. This, however, is often regarded as a major behind
Our findings
poor selectivity
obtained duringamong substrates
the course and undesired
of structural dose-dependent
modification and biologicaltoxicities.
evaluationOur findings
of L-783277
obtained
(4) indicateduring the course
that simple of structural
transformation mademodification and biological
on a macrocyclic lactone canevaluation of L-
dramatically
783277
increase(4) indicatespecificity
substrate that simpleand transformation made
potency against on a macrocyclic
a certain protein of lactone
interest.can
It isdramat-
also of
ically increase substrate specificity and potency against a certain protein of interest. It is
also of significance that exploration of such an effort was firstly demonstrated by our
group [52,54]. Furthermore, we anticipate that our works on L-783277 (4) and its deriva-
tives (99 and 100) provide a promising basis for further developments of natural and syn-
thetic lactones, along with other natural products, as potential anticancer agents.
Int. J. Mol. Sci. 2021, 22, 1052 15 of 67
significance that exploration of such an effort was firstly demonstrated by our group [52,54].
Furthermore, we anticipate that our works on L-783277 (4) and its derivatives (99 and 100)
provide a promising basis for further developments of natural and synthetic lactones, along
with other natural products, as potential anticancer agents.
2.1.6. Chemistry of L-783277 (4)

The first synthesis of L-783277 (4) was achieved by Altmann et al. in 2008, through the
successful exploration of Suzuki coupling and a late-stage macrolactonization reaction [55].
Int. J.J. Mol.
Mol. Sci.
Sci. 2021,
2021, 22,
22, xx FOR
FOR PEER Their
PEER REVIEW
REVIEW synthesis commenced from isopropylidene-D-erythrono-1,4-lactone 101 as a 16 chiral
of 69
69
Int. 16 of
starting material to intermediate 102 in 10 steps with 27% yield (Scheme 20). TMS-ethyl
ester was obtained from the corresponding methyl ester 103 via ester cleavage with TMSOK
under microwave conditions followed by Suzuki coupling with 102 gave 104 in 60% yield.
acids 105
acids 105 in
in good
Hydrogenation good yield.
ofyield. Cyclization
Cyclization
104 under under
Lindlarunder Mitsunobu
Mitsunobu
condition conditionsgave
conditions
and deprotection followed
followed by deprotec-
by
the seco deprotec-
acids 105
tion
tion and oxidation
and oxidation
in good with polymer-bound
with polymer-bound
yield. Cyclization IBX led to a mixture
IBX ledconditions
under Mitsunobu to a mixture of L-783277
of L-783277
followed (4) and aa second
(4) and
by deprotection second
and
mono-oxidized
mono-oxidized
oxidation product whose
product whose exact
with polymer-bound exact structure
structure
IBX led was uncertain,
was
to a mixture uncertain, separated
separated
of L-783277 by
(4) andby flash chroma-
flash
a second chroma-
mono-
tography.product whose exact structure was uncertain, separated by flash chromatography.
oxidized
tography.
Scheme 20.
Scheme First total
20. First total synthesis
synthesis of
of L-783277
L-783277 (4)
(4) by
by Altmann
Altmann et
et al. [55]..
al. [55]
[55].
In 2009,
In 2009, the
the Winssinger
Winssinger Group
Group reported
Group reported the
the synthesis
reported the synthesis of
synthesis of
of L-783277
L-783277 (4)
(4) together
L-783277 (4) together with
together with
with
the synthesis
synthesis of LL-Z1640-2
LL-Z1640-2 (3),
(3), and hypothemycin
hypothemycin (2)
(2) as
as a part of their divergent synthetic
synthetic
the synthesis of LL-Z1640-2 (3), and hypothemycin (2) as a part of their divergent synthetic
approach towards
approach towards resorcylic
towards resorcylic acid
resorcylic acid lactones
acid lactones [47].
lactones [47]. According
[47]. According
According to to their
to their synthetic
their synthetic route,
route, vinyl
synthetic route, vinyl
approach vinyl
bromide
bromide 107
107 could
could be
be obtained
obtained inin44steps
stepsfrom
fromthe
theless expensive
less expensive methyl
methyl3-hydroxybutyrate
3-hydroxybutyr-
bromide 107 could be obtained in 4 steps from the less expensive methyl 3-hydroxybutyr-
106 (Scheme
ate 106
106 21). 21).
(Scheme Another commercially
Another commercially available protected
available deoxyribose
protected 108 was
deoxyribose 108converted
was con-
con-
ate (Scheme 21). Another commercially available protected deoxyribose 108 was
to protected
verted to aldehyde
protected 109
aldehydein 3 steps
109 in which
3 steps was
whichfurther
was converted
further to intermediate
converted to 110 in
intermediate
verted to protected aldehyde 109 in 3 steps which was further converted to intermediate
4110
synthetic steps with
in 44 synthetic
synthetic steps72% yield.
with 72% yield.
yield.
110 in steps with 72%
Scheme 21.
21. Synthesis of
Synthesis of intermediates
of intermediates of
intermediates of L783277
of L783277 (4)
L783277 (4) by
(4) by Winssinger
by Winssinger et
Winssinger et al.
et al. [47].
al. [47].
[47].
Scheme
Toluate position
Toluate position of
of resin-bound
resin-bound 111
111 was
was alkylated
alkylated with
with iodide
iodide 110
110 to
to obtain
obtain polymer-
polymer-
bound intermediate 112 followed by removal of the PMB and the TMSE. Macrolactoniza-
bound intermediate 112 followed by removal of the PMB and the TMSE. Macrolactoniza-
tion under
tion under Mitsunobu
Mitsunobu conditions
conditions followed
followed by
by reductive
reductive conditions
conditions to
to get
get macrocycle
macrocycle 113
113
after benzoate hydrolysis (Scheme 22). The natural products L-783277 (4) could
after benzoate hydrolysis (Scheme 22). The natural products L-783277 (4) could be ob- be ob-
tained by straightforward diazomethane treatment of compounds 114 (>90%
tained by straightforward diazomethane treatment of compounds 114 (>90% conversion conversion
Int. J. Mol. Sci. 2021, 22, 1052 16 of 67
Toluate position of resin-bound 111 was alkylated with iodide 110 to obtain polymer-
bound intermediate 112 followed by removal of the PMB and the TMSE. Macrolactonization
under Mitsunobu conditions followed by reductive conditions to get macrocycle 113 after
benzoate hydrolysis (Scheme 22). The natural products L-783277 (4) could be obtained by
straightforward diazomethane treatment of compounds 114 (>90% conversion based on
LC/MS, 63–74% isolated yield after HPLC purification). It should be noted that their
Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 17final
of 69
Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW
product isolated by HPLC were typically contaminated with small amounts (>5%) of 17 of 69
a side
product that is tentatively ascribed to the trans-enone isomer.
Scheme 22. Synthesis of L783277 (4) by Winssinger et al. [47].

of L783277
L783277 (4)
(4) by
by Winssinger
Winssinger et
et al.
al. [47].
[47].
In
In 2010, our
our group
group successfully
successfully accomplished
accomplished efficient
efficient and
and enantioselective
enantioselective total total syn-
thesisInof2010,
2010, our
L-783277 group
(4), successfully
based on accomplished
convergent assembly efficient
of oneand enantioselective
aromatic unit and total
two
syn-
syn-
chiral
thesis
thesis of L-783277
of blocks
L-783277 (4), based
based on
(4),efficienton convergent
convergent assembly
assembly of of one
one aromatic
aromatic unit and
and two
unit[53]. two chiral
chiral
building
building blocks with
with efficient orthogonal
orthogonal protection-deprotection
protection-deprotection strategy
strategy [53]. Three
Three key
key
building
steps blocks
composed with
of efficient
olefin crossorthogonal
metathesis, protection-deprotection
addition of acetylene strategy
derivative [53].
to Three
aldehyde, key
steps
steps composed
composed of
of olefin
olefin cross
cross metathesis,
metathesis, addition
addition of
of acetylene
acetylene derivative
derivative to
to aldehyde,
aldehyde,
and
and Yamaguchi
Yamaguchi macrolactonization
macrolactonization were were subsequently
subsequently employed
employed to to construct
construct thethe frame-
frame-
and Yamaguchi
work of L-783277 macrolactonization
(4) (Scheme 23). werefragment
The subsequently
118 employed
was prepared to construct
from the frame-
commercially
work of L-783277 (4) (Scheme 23). The fragment 118 was prepared from commercially
work of L-783277 (4) (Scheme 23).
available The fragment 118 was23% prepared from commercially
available 2,4,6-trihydroxybenzoic
2,4,6-trihydroxybenzoic acid acid 115
115 in
in 44 steps
steps with yield. Trihydroxybenzoic
with 23% yield. Trihydroxybenzoic
availablewas
acid 2,4,6-trihydroxybenzoic acid 115
in in 4 stepsto with 23%theyield. Trihydroxybenzoic
acid 115
115 wastreated
treated with
withTFATFAand TFAA
and TFAA acetone
in acetone afford
to afford corresponding
the corresponding acetonide
ace-
acid
116 115
on thewas treated with TFA and TFAA in acetone to afford the corresponding acetonide
tonide 116 basis
on theofbasis
modified Danishefsky’s
of modified methodmethod
Danishefsky’s which after
whichtwo-step protection
after two-step deliv-
protection
116 on
ered 117the basis of modified
and Danishefsky’s method which after118
two-step protection deliv-
delivered 117finally Stille Stille
and finally coupling reaction
coupling to furnish
reaction styrene
to furnish styrenewas 118 obtained.
was obtained.
ered 117 and finally Stille coupling reaction to furnish styrene 118 was obtained.
Scheme 23.
Scheme Synthesis of
23. Synthesis of fragment
fragment 118 by Sim
118 by Sim et
et al.
al. [53].
[53].
Scheme 23. Synthesis of fragment 118 by Sim et al. [53].
D-(R)-glyceraldehyde acetonide
D-(R)-glyceraldehyde acetonide 120 was prepared
120 was prepared from
from D-mannitol
D-mannitol 119 in two
119 in two steps
steps
according to the literature method [63]. The asymmetric Brown allylation of aldehydesteps
D-(R)-glyceraldehyde
according to the literature acetonide
method 120
[63]. Thewas prepared
asymmetric from
BrownD-mannitol
allylation 119
of in two
aldehyde 120
120
according
using ( − to
)-Ipcthe
using (−)-Ipc2BOMe2 literature
BOMe method
yielded the [63]. The
desired asymmetric
allylic alcohol Brown
121 in allylation
high of aldehyde 120
diastereoselectivity
yielded the desired allylic alcohol 121 in high diastereoselectivity
(92:8) (Scheme
using (Scheme
(92:8) (−)-Ipc2BOMe24). The
24). The deprotection
yielded of
the desired
deprotection the acetonide
of theallylic group
alcohol
acetonide group generated
121generated 122 and protection
in high diastereoselectivity
122 and protection
of TBDPS
(92:8) (Schemeand acetonide
24). The then produced
deprotection of fragment
the 123
acetonide in 38%
group
of TBDPS and acetonide then produced fragment 123 in 38% yield from yield from122
generated glyceraldehyde.
and protection
glyceraldehyde.
The preparation
of TBDPS and acetonide of the
thenthird alkynefragment
produced fragment 124,
123 commenced
in 38% yield from with commercially
glyceraldehyde.
available (S)-(−)-propylene oxide 125, which underwent ready conversion into secondary
alcohol 126 upon treatment with lithium trimethylsilylacetylene (Scheme 25). Protection
and deprotection gave us alkyne fragment 124 with a 93% yield in 2 steps.
D-(R)-glyceraldehyde acetonide 120 was prepared from D-mannitol 119 in two steps
according to the literature method [63]. The asymmetric Brown allylation of aldehyde 120
using (−)-Ipc2BOMe yielded the desired allylic alcohol 121 in high diastereoselectivity
Int. J. Mol. Sci. 2021, 22, 1052 (92:8) (Scheme 24). The deprotection of the acetonide group generated 122 and protection
17 of 67
of TBDPS and acetonide then produced fragment 123 in 38% yield from glyceraldehyde.

The preparation of the third alkyne fragment 124, commenced with commercially
The preparation
available of theoxide
(S)-(−)-propylene third125,
alkyne fragment
which 124, ready
underwent commenced withinto
conversion commercially
secondary
available (S)-(−)-propylene oxide 125, which underwent ready conversion into
alcohol 126 upon treatment with lithium trimethylsilylacetylene (Scheme 25). Protectionsecondary
alcohol 126 upon treatment
and deprotection with fragment
gave us alkyne lithium trimethylsilylacetylene
124 with a 93% yield in(Scheme
2 steps.25). Protection
Scheme
Scheme 24.
24. Synthesis of fragment 123 by Sim
Sim et
et al.
al. [53].
[53].
and deprotection gave us alkyne fragment 124 with a 93% yield in 2 steps.
Scheme 25.
Synthesis of
of fragment
fragment 124
124 by
by Sim
Sim et
et al.
al. [53].
[53].
Olefin cross
Olefin cross metathesis
metathesis strategy
strategy between
between fragments
fragments 118 118 and
and 123
123 using
using Grubbs
Grubbs 2nd
2nd
Olefin catalyst
generation
generation cross metathesis
catalyst furnishedstrategy
furnished the between
the styrene
styrene fragments
127 (cis:trans
127 (cis:trans 118 which
== 3:7)
3:7) and 123
which using Grubbs
hydrogenated
hydrogenated to2nd
to get
get
generation
128 (Scheme
128 (Scheme catalyst
26). furnished
The the styrene
transesterification 127
of (cis:trans
the compound = 3:7)
waswhich hydrogenated
conducted
The transesterification of the compound was conducted with NaOMe to with to
NaOMe get
128
to (Scheme
provide
provide 26).ester
methyl
methyl The transesterification
ester 129,
129, which
which after
after ofprotection
the compound
protection andand was conducted
deprotection
deprotection withprimary
NaOMe
generated
generated primary to
al-
provide
alcohol methyl
130
cohol 130 ester
with17%
with 129, in
17%yield
yield which after protection and deprotection generated primary al-
in5 5steps.
steps.
cohol 130 with 17% yield in 5 steps.

of fragment 130 by
fragment 130 by Sim
Sim et
et al.
al. [53].
[53].
The
The primary
primary alcohol 130 was
alcohol 130 was smoothly
smoothly oxidized
oxidized toto the
the corresponding
corresponding aldehyde
aldehyde and
and
attacked
attacked by
by lithium
The primary acetylide
alcohol
lithium to
to afford
130 was
acetylide allylic
smoothly
afford alcohol
oxidized
allylic alcohol the in
to131
131 in 42%
42% yield
yield over
corresponding two
two steps
aldehyde
over and
steps
(Scheme
(Scheme 27).
attacked 27). Hydrogenation
by lithium
Hydrogenation reaction
acetylidereaction
to afford using Lindlar
allylic
using alcohol
Lindlar catalyst
131 in
catalyst to to
42%give
give the over
yield
the corresponding
two steps
corresponding cis-
cis-olefin
(Scheme 132,
27). which after
Hydrogenation protection
reaction and deprotection generate 133 with 86% yieldcis-in
olefin 132, which after protection and using Lindlar generate
deprotection catalyst to133give the86%
with corresponding
yield in 3 steps.
3olefin
steps.132,
Saponification
whichfollowed followed
after protection by cyclization under
and deprotection Mukaiyama
generate 133 condition
with 86% generated 134
yield in 3 134
steps.
Saponification by cyclization under Mukaiyama condition generated in
in moderate yield.
Saponification Finally,
cyclization followed
under by oxidation
Mukaiyama and global
condition deprotection
generated 134 in
moderate yield. Finally, deprotection followed by oxidation and global deprotection fur-
furnished yield.
moderate naturalFinally,
product L-783277 (4)followed
deprotection with 63% byyield in 3 steps.
oxidation and global deprotection fur-
nished natural product L-783277 (4) with 63% yield in 3 steps.
nished natural product L-783277 (4) with 63% yield in 3 steps.
Int.
Int. J.J. Mol.
Mol. Sci.
Sci. 2021,
2021, 22,
22, xx FOR
FOR PEER
PEER REVIEW
REVIEW 19
19 of
of 69
69
Int. J.J. Mol.
Int. Mol. Sci.
Sci. 2021,
2021, 22,
22, 1052
x FOR PEER REVIEW 19of
18 of67
69
Scheme
Scheme 27.
27. Synthesis
Synthesis of
of L-783277
L-783277 (4)
(4) by
by Sim
Sim et
et al.
al. [53].
[53].
of L-783277
L-783277 (4)
(4) by
by Sim
Sim et
et al.
al. [53].
[53].
Recently,
Recently, The Nanda Group reported an asymmetric total synthesis of L-783277 (4)
Recently, The
The Nanda
Nanda Group
Group reported
reported an an asymmetric
asymmetric total synthesis of
total synthesis L-783277 (4)
of L-783277 (4)
through
through
through intramolecular
intramolecular base-mediated
base-mediated macrolactonization
macrolactonization reaction
[64].[64].
reaction TheThe
[64]. The synthesis
synthesis
throughintramolecular
intramolecularbase-mediated
base-mediated macrolactonization
macrolactonization reaction
reaction [64]. synthesis
The was
synthesis
was
was initiated
withwith DD-galactose
136,136, which after 77 synthetic steps gave 137 in40%
40% yield
yield and
was initiated
initiated
initiated with
with -galactose
D-galactose
D-galactose
136, which
which
136, which after
after 7 synthetic
7 synthetic
after steps
steps
synthetic steps gave
gave 137
137inin
gave137 in 40%
40% yield and
yieldand
and
further
further reduction generate 138 in 80% yield (Scheme 28). Their desired sulfone 139 for
further reduction generate 138 in 80% yield (Scheme 28). Their desired sulfone 139 for
reduction
reduction generate
generate 138
138 in in
80%80% yield
yield (Scheme
(Scheme 28).28).
TheirTheir desired
desired sulfone
sulfone 139 139
for Julia
for
Julia
Julia precursor
precursor
precursor can can
can
be be
be obtained
obtained
obtained from from
from
138 138
in138
2 in
in
steps2
2 steps
steps
with with
with
85% 85%
85%
yield. yield.
yield.
Julia precursor can be obtained from 138 in 2 steps with 85% yield.
Scheme
Scheme 28.
28. Synthesis
Synthesis of
of fragment
fragment 139
139 by
by Nanda
Nanda et al. [64]
et al. [64]..
[64].
Scheme 28. Synthesis of fragment 139 by Nanda et al. [64].
The aromatic
The
The aromatic fragment
aromatic fragment
fragment can be
140 can
140
140 be prepared
prepared in
in 44 steps
steps starting
starting from
from 2,4,6-trihydroxy
2,4,6-trihydroxy
Theacid
benzoic aromatic
141 asfragment
starting 140 can
can be
material be prepared
prepared
(Scheme 29).
in
in 44 steps
steps starting
starting from
from 2,4,6-trihydroxy
2,4,6-trihydroxy
benzoic
benzoic acid 141 as starting material (Scheme 29).
benzoic acid
acid 141
141 as
as starting
starting material
material (Scheme
(Scheme 29).
29).
Synthesis of fragment
Scheme fragment 140 by
by Nanda et
et al. [64]
[64].
Scheme 29.
29. Synthesis of
of fragment 140
140 by Nanda
Nanda et al.
al. [64]..
Scheme 29. Synthesis of fragment 140 by Nanda et al. [64].
J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 20 of 69
Int. J. Mol. Sci. 2021, 22, 1052 19 of 67
Sulfone 139Sulfone
and aromatic
Sulfone and
139 and
139 aldehyde
aromatic140
aromatic was then
aldehyde
aldehyde subjected
140 was then
was tosubjected
then JK olefination
subjected JKto
to JK furnish to furnish
olefination
olefination furnish
the ‘E’-olefin 142
the in 78%
the ‘E’-olefin yield
‘E’-olefin 142
142 in which
in78% after
78%yield 3 steps
yieldwhich
which gave
after aldehyde
3 steps
after gave
3 steps intermediate
aldehyde
gave 143 with
intermediate
aldehyde 143 with
intermediate 73%
143 with
73% yield (Scheme
73% 30).
yieldyield
(Scheme 30). 30).
(Scheme
Sulfone 139 and aromatic aldehyde 140 was then subjected to JK olefination to furnish
the ‘E’-olefin 142 in 78% yield which after 3 steps gave aldehyde intermediate 143 with
73% yield (Scheme 30).
Scheme 30. Synthesis of intermediate

Scheme 30.
Synthesis 143 by Nanda
of intermediate
intermediate et by
143
143 al. [64]
by Nanda. et
Nanda et al.
al. [64]
[64]..
Alkyne
Alkyne 144Alkyne
which was144 which was
144 which
obtained was obtained
through
obtained through nucleophilic
nucleophilic nucleophilic addition
addition reaction reaction
of reaction
143 of 143
withof 143 with
Scheme 30. Synthesis of intermediate 143 by through
Nanda et al. [64]. addition with
alkyne
alkyne 145,alkyne 145,
after 5 145, after
gave55 146
stepsafter steps gave
with within
146yield
45% 45%
5 yield Deprotection
steps. in 5 steps. Deprotection
and and oxidation
oxidation
steps gave 146 with 45% yield in 5 steps. Deprotection and oxidation
thenAlkyne
then furnished furnished natural product L-783277 (4) with 47% yield in reaction
3 steps (Scheme 31).
thennatural product
furnished whichL-783277
144 natural was (4)L-783277
obtained
product with 47%
through yield
within47%3 steps
nucleophilic
(4) yield(Scheme
addition 31).
in 3 steps of 143 with
(Scheme 31).
alkyne 145, after 5 steps gave 146 with 45% yield in 5 steps. Deprotection and oxidation
then furnished natural product L-783277 (4) with 47% yield in 3 steps (Scheme 31).
Complete
Scheme 31.synthesis
Scheme 31. Complete of synthesis
L-783277 of L-783277
(4) by Nanda(4)etby
al.Nanda
[64]. etetal. [64].
Scheme 31.Complete
Scheme 31. Complete synthesis
synthesis of L-783277
of L-783277 (4)
(4) by by
NandaNanda . [64].
et al. [64]al.
A trans-isomer
A trans-isomer of L-783277 of L-783277
(4) was also (4) was also
isolated butisolated
RALs but RALs
bearing thebearing
cis-enonethe cis-enone moiety
such Aas
A trans-isomer
trans-isomer ofof
hypothemycin L-783277
L-783277
(2), (4) (4)
was
LL-Z1640-2was
alsoalso isolated
isolated
(3), and but RALs
but RALs
L-783277 bearing
(4) bearing themoi-
the cis-enone
are more cis-enone
moi-
potent moi-
than the
ety such as ety
hypothemycin
ety such
such as
as (2), LL-Z1640-2
hypothemycin
hypothemycin (2),(2), (3),
LL-Z1640-2and
LL-Z1640-2 L-783277
(3), and
(3), (4)
L-783277
and are more
(4)
L-783277 are potent
more
(4) are than
potent
more the
than the
potent than the
trans-enone
trans-enonetrans-enone
L-783290 (147) L-783290
(Figure (147)
7). (Figure 7).
Banwell’s Banwell’s
group reported group
the reported
first the first synthesis of
trans-enone L-783290
L-783290 (147) (Figure
(147) (Figure7). Banwell’s
7).L-783277
Banwell’sgroupgroup
reported the synthesis
reported firstthe ofsynthesis
synthesis
first L-
of L- of L-
L-783290 (147, the E-counterpart of (4), Figure 6) through the exploitation of
783290 (147,783290
the E-counterpart
783290 (147,
(147, the
the of L-783277
E-counterpart
E-counterpart (4),
of Figure
of L-783277
L-783277(4), 6) through
Figure
(4), the
6) through
Figure 6) exploitation
the exploitation
through the of Heck
of Heck of Heck
exploitation
Heck coupling
coupling and intramolecular
and intramolecular Weinreb ketone synthesis followed by other synthetic
coupling and intramolecular
coupling Weinreb Weinreb
and intramolecular ketone
Weinreb
ketone synthesis
synthesis
ketonefollowed
followed by other
synthesisbyfollowed
other synthetic ma-
synthetic
by otherma- synthetic ma-
manipulation
nipulation [65]. [65].
nipulation [65].
nipulation [65].
Figure Structure
Figure 7.7.Structure of of L-783290
L-783290 (147).
(147).
Figure 7. Structure
Figureof
7. L-783290
Structure(147).
of L-783290 (147).
Int. J.Int.
Mol. Sci.Sci.
J. Mol. 2021, 22,22,
2021, 1052
x FOR PEER REVIEW 21 of 69 20 of 67
A chemoenzymatic pathway was employed where they used enantiomerically pure
and commercially available cis-1,2-dihydrocatechol 148 derived from the whole-cell 21 of 69
bio-
transformation of chlorobenzene
A chemoenzymatic
chemoenzymatic pathway to get Weinreb amide fragment 149 in 7 steps (Scheme
A pathway waswas employed
employed wherewhere theyenantiomerically
they used used enantiomerically
pure pure
32).
and commerciallyavailable
available cis-1,2-dihydrocatechol 148 derived from the whole-cell bio-
and commercially cis-1,2-dihydrocatechol 148 derived from the whole-cell bio-
A chemoenzymatic
transformation
transformation of pathway
ofchlorobenzene
chlorobenzene toto was
get
get employed
Weinreb
Weinreb where
amide
amide they149
fragment
fragment used enantiomerically
in 7in
149 7 steps
steps (Scheme pure
(Scheme 32).
and
32). commercially
The reaction ofavailable cis-1,2-dihydrocatechol
commercially 148 derived
available dimethoxyaniline 150 from the whole-cell
to a Sandmeyer bio-
reaction
transformation of chlorobenzene
followed by Vilsmeier–Haack to get Weinreb
conditions affordedamide fragment 152
benzaldehyde 149inin27steps
stepswith
(Scheme
44%
32). (Scheme 33).
yield
Scheme 32. Synthesis of fragment 149 by Banwell et al. [65].

Scheme 32. Synthesis of fragment 149 by Banwell et al. [65].
The reaction of commercially available dimethoxyaniline 150 to a Sandmeyer reac-
tion The
followed byofVilsmeier–Haack
reaction conditions
commercially available afforded benzaldehyde
dimethoxyaniline 152 inreac-
150 to a Sandmeyer 2 steps with
44% yield
32. (Scheme
tion followed
Scheme
Scheme 32. Synthesis 33).
of fragment
fragment 149
by Vilsmeier–Haack
Synthesis of by
by Banwell
conditions
149 et
et al.
al. [65].
afforded
Banwell benzaldehyde 152 in 2 steps with
[65].
The reaction of commercially available dimethoxyaniline 150 to a Sandmeyer reac-
tion followed by Vilsmeier–Haack conditions afforded benzaldehyde 152 in 2 steps with
Scheme
33.Synthesis
Scheme 33. Synthesisof of
of Fragment
152 152
Fragment
Fragment 152 by
by Banwell
et al. et
Banwell
by Banwell et al.
al. [65].
[65]. [65].
The Heck
The Heck coupling reaction of aryl iodide 152 and terminal alkene 153,gave
149 153,
The Heckcoupling
coupling reaction of aryl
reaction iodide
of aryl 152 and
iodide 152terminal alkene alkene
and terminal 149 gave149 gave 153,
which after
which after 2 steps produced 154 for a Mitsunobu reaction with 155 to give ester/amide
which after22steps
stepsproduced
produced 154154
for afor
Mitsunobu
a Mitsunobureaction with 155
reaction to give
with ester/amide
155 to give ester/amide
156,
156, whichwas
which wastreated
treated with
with Grignard
Grignard reagent
reagent to to157.
get getFinally,
157. Finally,
Grubbs Grubbs metathesis
metathesis and and
156, which
Scheme was treated
33. Synthesis with Grignard
oftarget
Fragment 152 by147 reagentetto
Banwell al.get 157. Finally, Grubbs metathesis
[65]. and
deprotection
deprotection furnished
furnished target macrolide
macrolide 147 in 10%
in 10% yield yield (Scheme
(Scheme 34). 34).
deprotection furnished target macrolide 147 in 10% yield (Scheme 34).
The Heck coupling reaction of aryl iodide 152 and terminal alkene 149 gave 153,
which after 2 steps produced 154 for a Mitsunobu reaction with 155 to give ester/amide
156, which was treated with Grignard reagent to get 157. Finally, Grubbs metathesis and
deprotection furnished target macrolide 147 in 10% yield (Scheme 34).
Scheme 34.
Scheme Synthesis
34.Synthesis of of L-783290
L-783290 (147)
(147) by Banwell
by Banwell et al. [65].
et al. [65].
50 -Deoxy analog (158) of L-783277 (4) was synthesized stereoselectively in 2011 by

Scheme 34.group
Altmann Synthesis
[66].of L-783290 (147)retains
This analog by Banwell et al.the
almost [65].full kinase inhibitory potential of
natural L-783277 (4), with low nanomolar IC50 values against the most sensitive kinases,
and it exhibits essentially the same selectivity profile (within the panel of 39 kinases
investigated). In contrast, removal of both the 40 - and the 50 -hydroxyl groups leads to a
more significant
Scheme reduction
34. Synthesis in kinase
of L-783290 inhibitory
(147) by Banwell etactivity.
al. [65].
5′-Deoxy analog (158) of L-783277 (4) was synthesized stereoselectively in 2011 by
5′-Deoxy analog (158) of L-783277 (4) was synthesized stereoselectively in 2011 by
Altmann group [66]. This analog retains almost the full kinase inhibitory potential of nat-
Altmann group [66]. This analog retains almost the full kinase inhibitory potential of nat-
ural L-783277 (4), with low nanomolar IC50 values against the most sensitive kinases, and
ural L-783277 (4), with low nanomolar IC50 values against the most sensitive kinases, and
it exhibits essentially the same selectivity profile (within the panel of 39 kinases investi-
it exhibits essentially the same selectivity profile (within the panel of 39 kinases investi-
gated). In contrast, removal of both the 4′- and the 5′-hydroxyl groups leads to a more
Int. J. Mol. Sci. 2021, 22, 1052 gated). In contrast, removal of both the 4′- and the 5′-hydroxyl groups leads to a21more of 67
significant reduction in kinase inhibitory activity.
significant reduction in kinase inhibitory activity.
Intermediate 160 was prepared from TBS-protected 3-hydroxy propanal 159 in a
Intermediate 160 was prepared from TBS-protected 3-hydroxy propanal 159 in a
high-yielding
Intermediatefour-step
160 wassequence
prepared(69%
fromoverall yield) involving
TBS-protected 3-hydroxyKeck allylation
propanal 159 in(Scheme
a high-
high-yielding four-step sequence (69% overall yield) involving Keck allylation (Scheme
35). After
yielding some synthetic steps, intermediate 160 was converted to 161, which was coupled
35). Afterfour-step sequence
some synthetic (69%intermediate
steps, overall yield)160
involving Keck allylation
was converted (Scheme
to 161, which was35). After
coupled
with aromatic
some syntheticfragment 162 by Suzuki
steps, intermediate 160coupling to get 163.
was converted to Mitsunobu
161, which cyclization,
was coupled protec-
with
with aromatic fragment 162 by Suzuki coupling to get 163. Mitsunobu cyclization, protec-
tion, deprotection
aromatic fragment steps
162 were
by usedcoupling
Suzuki to furnished
to get5′-deoxy
163. analog (158)
Mitsunobu of L-783277
cyclization, (4) in 4
protection,
tion, deprotection steps were used to furnished 5′-deoxy analog (158) of L-783277 (4) in 4
steps.
deprotection
steps. steps were used to furnished 50 -deoxy analog (158) of L-783277 (4) in 4 steps.
Scheme 35.
35. 5′-deoxy [66].
0 -deoxy analogue (158) by Altmann et al. [66].
Scheme Synthesis of
of 55′-deoxy analogue (158) by Altmann et al. [66].
Our group
group synthesized
synthesized aa saturated
saturated analog
analog (99)
(99) of
of L-783277
L-783277 (4)(4) [52].
[52]. Our
Our synthetic
synthetic
Our group synthesized a saturated analog (99) of L-783277 (4) [52]. Our synthetic
route comprises
comprises three key
key steps
steps involving
involving aa Suzuki
Suzuki cross-coupling
cross-coupling reaction
reaction between
between an
an
route comprises three key steps involving a Suzuki cross-coupling reaction between an
aromatic triflate and olefin,
olefin, the
the addition
addition of
of an
an acetylene
acetylene toto an
an aldehyde,
aldehyde, and and Mitsunobu
Mitsunobu
aromatic triflate and olefin, the addition of an acetylene to an aldehyde, and Mitsunobu
macrolactonization (Scheme 36). Triflate 164 and olefin 165, 165, prepared
prepared fromfrom commercially
commercially
macrolactonization (Scheme 36). Triflate 164 and olefin 165, prepared from commercially
available 2,4,6-trihydroxybenzoic acid and 1,2,5,6-bis-O-(1-methylethylidene)-
available 2,4,6-trihydroxybenzoic acid and 1,2,5,6-bis-O-(1-methylethylidene)- D -mannitol,
D-manni-
available 2,4,6-trihydroxybenzoic acid and 1,2,5,6-bis-O-(1-methylethylidene)-D-manni-
respectively (structures
tol, respectively not shown),
(structures wouldwould
not shown), be joined by the use
be joined of a use
by the Suzuki
of across-coupling
Suzuki cross-
tol, respectively (structures not shown), would be joined by the use of a Suzuki cross-
reaction
couplingtoreaction
producetothe key intermediate
produce 166.
the key intermediate 166.
coupling reaction to produce the key intermediate 166.
Scheme 36. Synthesis of key intermediate 166

Scheme 36. 166 by
by Sim
Sim et
et al.
al. [52].
[52].
Scheme 36. Synthesis of key intermediate 166 by Sim et al. [52].
The propargylic alcohol
The propargylic alcohol 167 wasprepared
167was preparedfromfrom166 using
166using thethe same
same sequence
sequence of
of re-
The propargylic
reactions described inalcohol
our 167 wasreport
previous prepared from
[53]. 166 using
Lindlar the same sequence
hydrogenation, of re-
deprotection,
actions described in our previous report [53]. Lindlar hydrogenation, deprotection, and
actions
and described in
saponification our previous
generated report [53]. Lindlar hydrogenation, deprotection, and
saponification generated secoseco
acidacid
168,168, which
which waswas cyclized
cyclized under
under Mitsunobu
Mitsunobu condition
condition to
saponification
to deliver generated
a diastereomeric seco acid
mixture 168, which was cyclized under Mitsunobu condition to
deliver a diastereomeric mixture of of
169169 (Scheme
(Scheme 37).
37).
deliver a diastereomeric mixture of 169 (Scheme 37).
Oxidation of a mixture 169 gave pure keto derivative which after final deprotection
furnished target lactone 99 (Scheme 38). It is noteworthy to mention that advanced inter-
mediates 169 and 170 in the route for synthesis of 99 were also used for preparation of
the trihydroxy analogs of L-783277 (4), 171, 172, and external olefin containing analog 173
(Scheme 38).
Next, we synthesized phenyl ring incorporated derivatives of L-783277 (4) in ex-
pectation that these derivatives would improve kinome-wide selectivity of the parent
compound 4 [54]. The key reactions employed in the synthetic sequences are Suzuki
coupling, Sharpless asymmetric dihydroxylation, alkyne addition to an aldehyde, Lindlar
reduction, and Mitsunobu cyclization.
Int. J. Mol. Sci. 2021, 22, 1052 22 of 67
Scheme 37. Synthesis of intermediates 169A and 169B by Sim et al. [52].
mediates 169 and 170 in the route for synthesis of 99 were also used for preparation of the
trihydroxy analogs of L-783277 (4), 171, 172, and external olefin containing analog 173
Synthesis of intermediates 169A and 169B by Sim et al. [52].
(Scheme37.38).
Scheme
mediates 169 and 170 in the route for synthesis of 99 were also used for preparation of the
trihydroxy analogs of L-783277 (4), 171, 172, and external olefin containing analog 173
(Scheme 38).
Scheme 38. Synthesis of analogs (99, 172–173) from

Scheme 38. from intermediates 169A and
intermediates 169A 169B by
and 169B by Sim
Sim et
et al.
al. [52].
[52].
Our
Next,route began withphenyl
we synthesized Suzukiring coupling between
incorporated triflate 174
derivatives of and boronic
L-783277 acid
(4) in 175
expec-
to produce biphenyl derivative 176 firstly (Scheme 39). Oxidation
tation that these derivatives would improve kinome-wide selectivity of the parent com- followed by Wittig
olefination
pound 4 [54]. formed
The key trans form ofemployed
reactions 177. Sharplessin theasymmetric dihydroxylation
synthetic sequences are Suzuki followed
coupling, by
protection and trans-esterification produced 178 in 4 steps which
Sharpless asymmetric dihydroxylation, alkyne addition to an aldehyde, Lindlar reduc- after 4 synthetic steps
produced
Scheme
tion, and 179. PMB-ether
38.Mitsunobu
Synthesis protection
ofcyclization.
analogs followed
(99, 172–173) by TBS-ether169A
from intermediates deprotection
and 169B by then
Simgenerated
et al. [52].
180 inOur
2 steps, the important cyclization precursor.
route began with Suzuki coupling between triflate 174 and boronic acid 175 to
Subsequently,
Next,
produce biphenyl 180
we synthesized underwent
derivative 176 saponification
phenyl firstly (Schemefollowed
ring incorporated by cyclization
39).derivatives
Oxidation of under
L-783277
followed Mitsunobu
by(4) in expec-
Wittig ole-
condition
tation that and
thesedeprotection
derivatives to get
would 181 in 3 synthetic steps with
fination formed trans form of 177. Sharpless asymmetric dihydroxylation followed bycom-
improve kinome-wide good
selectivity yield
of the (Scheme
parent 40).
pro-
Oxidation
pound 4 of
[54]. 181
The formed
key the
reactions corresponding
employed in ketones
the 182
synthetic as a single
sequences
tection and trans-esterification produced 178 in 4 steps which after 4 synthetic steps pro- stereoisomer,
are Suzuki which
coupling,
was
ducedfinally
Sharpless deprotected
179.asymmetric to form target
dihydroxylation,
PMB-ether protection followed Other
100.alkyne derivatives
addition
by TBS-ether to also we synthesized
an aldehyde,
deprotection thenLindlar byreduc-
generated using
180
a similar
tion, and synthetic
Mitsunobu strategy to
cyclization. expand the scope of the SAR study.
in 2 steps, the important cyclization precursor.
Our route began with Suzuki coupling between triflate 174 and boronic acid 175 to
2.2. Sesquiterpene
produce biphenylLactones
derivative 176 firstly (Scheme 39). Oxidation followed by Wittig ole-
Sesquiterpene
fination formed translactones
form of(SLs) are a sub-class
177. Sharpless of sesquiterpenoids,
asymmetric dihydroxylation which are natural
followed by pro-
products synthesized in several organs of plants such as leaves,
tection and trans-esterification produced 178 in 4 steps which after 4 synthetic steps shoots, and roots [67,68].
pro-
In addition, SLs comprise a large and diverse group of secondary
duced 179. PMB-ether protection followed by TBS-ether deprotection then generated 180 metabolites isolated
from
in diverse
2 steps, the plant families
important [69,70] precursor.
cyclization with the greatest number occurring in members of
Asteraceae [69–71]. Extracts of SLs, like other natural products, have been broadly used in
folk medical practices for fever, headache, rheumatoid arthritis, and menstrual irregular-
ities [72]. SLs are usually characterized by the presence of α-methylene-γ-lactone group
Int. Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW
J. Mol. Sci. 2021, 22, 1052 24 of 69
23 of 67
(αMγL), which mainly contributes to the underlying biological activity of SLs through
irreversibly forming a Michael adduct with nucleophilic amino acid residues in proteins,
causing
Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEWalterations in protein activity [73]. This is regarded as the primary mechanism
24 of 69 of
cytotoxicity induced by SLs (Figure 8).
Scheme 39. Synthesis of the cyclization precursor 180 by Sim et al. [54].
Subsequently, 180 underwent saponification followed by cyclization under

Mitsunobu condition and deprotection to get 181 in 3 synthetic steps with good yield
(Scheme 40). Oxidation of 181 formed the corresponding ketones 182 as a single stereoi-
somer, which was finally deprotected to form target 100. Other derivatives also we syn-
Scheme
Scheme
thesized Synthesis
39.39.
by
Synthesisofofthe
using a similarcyclization precursorto
the cyclization precursor
synthetic strategy
180
180byby Sim
Sim
expand theetscope
et al. al. [54].
[54].
of the SAR study.
Subsequently, 180 underwent saponification followed by cyclization under
Mitsunobu condition and deprotection to get 181 in 3 synthetic steps with good yield
(Scheme 40). Oxidation of 181 formed the corresponding ketones 182 as a single stereoi-
somer, which was finally deprotected to form target 100. Other derivatives also we syn-
thesized by using a similar synthetic strategy to expand the scope of the SAR study.

Scheme
Scheme40.
40.Synthesis
Synthesisof rigidified analogue
of rigidified of L-783277
analogue (100) by
of L-783277 Simby
(100) et al.
Sim [54].
et al. [54].
2.2. Sesquiterpene Lactones

Sesquiterpene lactones (SLs) are a sub-class of sesquiterpenoids, which are natural
products synthesized in several organs of plants such as leaves, shoots, and roots [67,68].
In addition, SLs comprise a large and diverse group of secondary metabolites isolated
Scheme 40. Synthesis of rigidified analogue of L-783277 (100) by Sim et al. [54].
from diverse plant families [69,70] with the greatest number occurring in members of
Asteraceae [69–71]. Extracts
2.2. Sesquiterpene Lactones of SLs, like other natural products, have been broadly used
in folk medical practices for fever, headache, rheumatoid arthritis, and menstrual irregu-
Sesquiterpene lactones (SLs) are a sub-class of sesquiterpenoids, which are natural
larities [72]. SLs are usually characterized by the presence of α-methylene-γ-lactone group
products synthesized in several organs of plants such as leaves, shoots, and roots [67,68].
In addition, SLs comprise a large and diverse group of secondary metabolites isolated
from diverse plant families [69,70] with the greatest number occurring in members of
causing alterations in protein activity [73]. This is regarded as the primary mechanism of
Asteraceae [69–71]. Extracts of SLs, like other natural products, have been broadly used
in folk medical practices for fever, headache, rheumatoid arthritis, and menstrual irregu-
larities [72]. SLs are usually characterized by the presence of α-methylene-γ-lactone group
Figure 8.8. Structures
Structuresofofrepresentative
representativesesquiterpene
sesquiterpene lactones.
lactones.
causing
2.2.1. alterations
Biological in protein
Activities activity [73]. This is regarded as the primary mechanism of
2.2.1. Biological Activities ofofParthenolide
Parthenolide (183)
(183)
Parthenolide (183) isisa anaturally
Parthenolide naturallyoccurring sesquiterpene
occurring sesquiterpene lactone derived
lactone from
derived Tanace-
from
tum parthenium,
Tanacetum also known
parthenium, as feverfew
also known [74]. It[74].
as feverfew is regarded as a recognized
It is regarded candidate
as a recognized can- for
drug
didatedevelopment due to notable
for drug development anti-cancer
due to and anti-inflammatory
notable anti-cancer properties.
and anti-inflammatory Partheno-
proper-
lide
ties. (183) contains(183)
Parthenolide an α-methylene-γ-butyrolactone group and group
contains an α-methylene-γ-butyrolactone an epoxide
and angroup,
epoxidewhich
participate
group, which inparticipate
interactions with protein
in interactions targets
with proteinto exert
targetsmultiple therapeutic
to exert multiple effects [75].
therapeutic
effects
To date,[75]. To date, parthenolide
parthenolide (183) reported
(183) has been has been to
reported
vitiatetocancer
vitiatepathogenicity
cancer pathogenicity
in various
types of cancer including myeloma, colorectal, liver prostate, pancreatic,pancreatic,
in various types of cancer including myeloma, colorectal, liver prostate, thyroid, andthy-
breast
roid, and breast cancers [76–79]. Especially, parthenolide (183) showed effects on suppres-
sion of MDA-MB-231 breast cancer cells and reduction in tumor size in a mouse xenograft
model, when it was used in combination with docetaxel [80]. Interested by cytotoxicitiy
of parthenolide (183) across a wide range of human cancers and its high tolerability in
humans [81], several researches focused on the identification of molecular targets of par-
Parthenolide (183) is a naturally occurring sesquiterpene lactone derived from
Tanacetum parthenium, also known as feverfew [74]. It is regarded as a recognized can-
didate for drug development due to notable anti-cancer and anti-inflammatory proper-
ties. Parthenolide (183) contains an α-methylene-γ-butyrolactone group and an epoxide
group, which participate in interactions with protein targets to exert multiple therapeutic
Int. J. Mol. Sci. 2021, 22, 1052 24 of 67
effects [75]. To date, parthenolide (183) has been reported to vitiate cancer pathogenicity
in various types of cancer including myeloma, colorectal, liver prostate, pancreatic, thy-
roid, and[76–79].
cancers breast cancers
Especially,[76–79]. Especially,(183)
parthenolide parthenolide (183) showed
showed effects effects onof
on suppression suppres-
MDA-
sion of MDA-MB-231 breast cancer cells and reduction in tumor
MB-231 breast cancer cells and reduction in tumor size in a mouse xenograft model, when size in a mouse xenograft
model,
it was usedwhen initcombination
was used inwith combination
docetaxelwith [80].docetaxel
Interested [80].
by Interested
cytotoxicitiy by ofcytotoxicitiy
partheno-
of parthenolide (183) across a wide range of human cancers
lide (183) across a wide range of human cancers and its high tolerability in humans [81], and its high tolerability in
humans [81], several researches focused on the identification
several researches focused on the identification of molecular targets of parthenolide (8).of molecular targets of par-
thenolide
Kwok (8).inKwok
et al., et al., in 2001,
2001, reported reported
that one of the that
primaryone targets
of the primary
that inducestargets thethat induces
anti-cancer
the anti-cancer
activity activity
is IκB kinase is IκB kinase
β (IKK-β) wherein β both
(IKK-β)IKK-β wherein both IKK-β
and nuclear factorand nuclear signaling
κB (NF-κB) factor κB
(NF-κB)
are signaling
impaired due to aremodified
impairedcysteine
due to modified
179 [82]. In cysteine 179 more
addition, [82]. In addition,
findings more find-
indicate that
ings indicate that parthenolide affects additional cell signaling
parthenolide affects additional cell signaling pathways such as induction of oxidative pathways such as induc-
tion ofand
stress oxidative
apoptosis,stress andadhesion
focal apoptosis, focal1adhesion
kinase kinase 1 (FAK1)
(FAK1) signaling, signaling, mitogen-
mitogen-activated protein
activated
kinase protein kinase
signaling, signaling, and
and mitochondrial mitochondrial
function [82–86].function
Recently, [82–86].
BerdanRecently, Berdan
et al. reported
et al.parthenolide
that reported that(183) parthenolide (183) shows
shows inhibitory activity inhibitory
on FAK1activity
signalingon pathway
FAK1 signaling path-
by targeting
way by targeting
cysteine 427 of FAK1 cysteine
[87]. 427 of FAK1 [87].
However, parthenolide
parthenolide (183) (183)isisquite
quitelipophilic
lipophilic in in nature
nature and, and, accordingly,
accordingly, poorpoor bio-
bioavailability
availability caused caused by by
lowlow solubility
solubility hashas risen
risen as as a critical
a critical issue.
issue. Therefore,
Therefore, a dimethy-
a dimethyla-
lamino
mino group groupcontaining
containing derivative
derivative of of parthenolide,
parthenolide, DMAPT
DMAPT (190)
(190) (Figure
(Figure 9), 9),
waswas de-
devel-
veloped to overcome
oped to overcome poorpoor solubility
solubility of parthenolide
of parthenolide (183)(183)
withoutwithoutlosinglosing the original
the original anti-
anti-tumor
tumor activity activity
[88].[88].
TheThe hydrophilic
hydrophilic parthenolide
parthenolide analog,(190),
analog, (190),diddidnotnot only increase
increase
pharmacokinetic
pharmacokinetic properties compared to the parent compound, but it was was also
also able
able toto
selectively eliminate acute myeloid leukemia (AML) stem cells,
selectively eliminate acute myeloid leukemia (AML) stem cells, which led to the initiation which led to the initiation
of
of aa clinical
clinical trial
trial for
for its
its use
use in in hematologic
hematologic cancer
cancer [89].
[89].
9. Structure of dimethylamino
Figure 9. dimethylamino parthenolide,
parthenolide, DMAPT
DMAPT (190).
(190).
2.2.2. Chemistry of Parthenolide (183)

The first total synthesis of parthenolide (183) and its analogs was reported by Long
and co-workers in 2014 [90]. In their initial retro-synthetic analysis of parthenolide (183)
(Scheme 41), it was anticipated that parthenolide (183) could be obtained by the known
compound 191 through three key intermediates. The crucial reaction step conceived by
Long et al. for the target molecule included intramolecular Barbier-type cyclization of B to
form A [91], which then undergoes lactonization to generate parthenolide (183).
The primary attempt of the group to synthesize parthenolide (183) is summarized
in Scheme 42. The synthesis was initiated with known compound 191, which was ob-
tained from farnesol in three steps [92]. 191 was treated with methyl acrylate and 1,4-
diazabicyclo[2.2.2]octane (DABCO) to produce substituted acrylate 192. This was followed
by chlorination with simultaneous double bond isomerization to provide only (Z)-193
and TBDPS was deprotected by using HF-pyridine. It should be noted that TDBPDS
deprotection of 193 did not proceed under standard TBAF or TFA conditions [90]. The pri-
mary alcohol of 193 underwent Sharpless asymmetric oxidation (SAE) reaction to yield
compound 194, which was subsequently oxidized to give corresponding aldehyde 195.
Authors have investigated the cyclization of 195 by means of reductive Barbier-type cou-
pling conditions to form the desired 10-membered ring. Under CrCl2 in degassed DMF,
amongst other conditions, such as Zn0 , In0 , and SmI2 , only gave out the cyclized product
196. Unfortunately, the lactone 196 was revealed to be the C-7 epimer of parthenolide (183)
after an analysis of X-ray co-crystal data [90].
The first total synthesis of parthenolide (183) and its analogs was reported by Long
and co-workers in 2014 [90]. In their initial retro-synthetic analysis of parthenolide (183)
(Scheme 41), it was anticipated that parthenolide (183) could be obtained by the known
compound 191 through three key intermediates. The crucial reaction step conceived by
Int. J. Mol. Sci. 2021, 22, 1052 Long et al. for the target molecule included intramolecular Barbier-type cyclization 25 of B
of 67
Scheme 41. Retrosynthesis of parthenolide (183) according to Long et al. [90].
to form A [91], which then undergoes lactonization to generate parthenolide (183).
The primary attempt of the group to synthesize parthenolide (183) is summarized in

Scheme 42. The synthesis was initiated with known compound 191, which was obtained
from farnesol in three steps [92]. 191 was treated with methyl acrylate and 1,4-diazabicy-
clo[2.2.2]octane (DABCO) to produce substituted acrylate 192. This was followed by chlo-
rination with simultaneous double bond isomerization to provide only (Z)-193 and
TBDPS was deprotected by using HF-pyridine. It should be noted that TDBPDS deprotec-
tion of 193 did not proceed under standard TBAF or TFA conditions [90]. The primary
alcohol of 193 underwent Sharpless asymmetric oxidation (SAE) reaction to yield com-
pound 194, which was subsequently oxidized to give corresponding aldehyde 195. Au-
thors have investigated the cyclization of 195 by means of reductive Barbier-type coupling
conditions to form the desired 10-membered ring. Under CrCl2 in degassed DMF,
amongst other conditions, such as Zn0, In0, and SmI2, only gave out the cyclized product
196. Unfortunately, the lactone 196 was revealed to be the C-7 epimer of parthenolide (183)
Scheme
after an41. Retrosynthesis
analysis of X-rayofco-crystal
parthenolide (183)
data according
according to
[90]. to Long
Long et
et al.
al. [90].
[90].
The primary attempt of the group to synthesize parthenolide (183) is summarized in

Scheme 42. The synthesis was initiated with known compound 191, which was obtained
from farnesol in three steps [92]. 191 was treated with methyl acrylate and 1,4-diazabicy-
clo[2.2.2]octane (DABCO) to produce substituted acrylate 192. This was followed by chlo-
rination with simultaneous double bond isomerization to provide only (Z)-193 and
TBDPS was deprotected by using HF-pyridine. It should be noted that TDBPDS deprotec-
tion of 193 did not proceed under standard TBAF or TFA conditions [90]. The primary
alcohol of 193 underwent Sharpless asymmetric oxidation (SAE) reaction to yield com-
pound 194, which was subsequently oxidized to give corresponding aldehyde 195. Au-
thors have investigated the cyclization of 195 by means of reductive Barbier-type coupling
conditions to form the desired 10-membered ring. Under CrCl2 in degassed DMF,
amongst other conditions, such as Zn0, In0, and SmI2, only gave out the cyclized product
Scheme 42. Synthesis the
42.
196. Unfortunately, of intermediate
lactone 196 196
intermediate wasby
by Long
Long et
revealed al.
etto [90].
al.be theReagents
[90]. Reagents and conditions:
andof
C-7 epimer conditions: (a)
(a) methyl
parthenolide methyl
(183)
acrylate, DABCO, RT,
RT, 77%;
77%; (b)
(b) CCl
CCl 4 3P, 83%; (c) HF-pyridine, THF,
4, n-Bu3
after an analysis of X-ray co-crystal data [90]. THF, 91%;
91%; (d)
(d) 4
4 Å
Å MS,
MS, Ti(OiPr)
Ti(OiPr)44
(0.1 equiv), (–)-DIPT (0.12 equiv),
equiv), TBHP
TBHP (1.5
(1.5 equiv),
equiv), CH
CH22Cl −40°C◦ C
Cl2,2 ,−40 toto
−18 °C,◦ 93%,
−18 C, 93%,ee =ee92%; (e)
= 92%;
Dess–Martin
(e) periodinane,
Dess–Martin NaHCO
periodinane, NaHCO3, CH,2CH
3
Cl 2, 92%;
Cl
2 2 , (f)
92%;CrCl
(f) , DMF;
2CrCl
2 , (g)
DMF;DBU,
(g) CH 2ClCH
DBU, 2, 41%Cl
2 2
over
, 41%2 steps.
over
2 steps.
Long et al. have designed and synthesized cyclization precursors 197a and 197b
via 8 steps, based on their speculation that the configuration of the two new stereogenic
centers might be highly affected by the geometric configuration of 1,10-double bond
(Scheme 43) [90]. From nerol, compound 198 was obtained in 5 steps [93,94]. After pro-
tecting alcohol of 198 with TBDPS, C10-C11 double bond was cleaved to afford aldehyde
199, which underwent Baylis–Hillman reaction, then chlorination to produce 200a and
200b in 3:1 ratio. Lastly, 200a and 200b were used to obtain the cyclization precursors
197a and 197b. A reaction condition of an umpolung allylation optimized by Baran et al.
was utilized in the transformation of 197a to 6,7-cis 201 and the desired 6,7-trans 202 in a
ratio
Schemeof 42.
2.8:1 in 16% of
Synthesis yield [95]. Surprisingly,
intermediate 196 by Longthe ratio
et al. ofReagents
[90]. 6,7-transand reaction yield
202conditions: was
(a) methyl
much improved when the relatively low reactive allylic chloride was converted into
acrylate, DABCO, RT, 77%; (b) CCl4, n-Bu3P, 83%; (c) HF-pyridine, THF, 91%; (d) 4 Å MS, Ti(OiPr)4 allylic
iodide prior(–)-DIPT
(0.1 equiv), to Barbier reaction
(0.12 equiv), using
TBHP CrCl 2 in THF.
(1.5 equiv), CHThis
2Cl2, two-steps procedure
−40 °C to −18 °C, 93%,produced
ee = 92%; an
(e)
increased
Dess–Martin ratio of 6,7-trans
periodinane, 202 (1:1)
NaHCO 3, CHand
2Cl2, a moderate
92%; (f) CrCl2yield
, DMF;(52%) [90].CH2Cl2, 41% over 2 steps.
(g) DBU,
Scheme 44 provided the target compound parthenolide (183). Hydrolysis of 201 and
202 by using basic hydrogen peroxide produced compounds 203, 204, and 205 (Scheme 44).
Lactone 206 was obtained by refluxing compound 203 in benzene with DBU. Moreover,
another side product 204 could be converted to the desired intermediate 205 upon stirring
with DBU in CH2 Cl2 . The target molecule 183 was successfully obtained upon irradiating
205 with UV light (254 nM) in 58% conversion and 77% yield [90].
A reaction condition of an umpolung allylation optimized by Baran et al. was utilized in
the transformation of 197a to 6,7-cis 201 and the desired 6,7-trans 202 in a ratio of 2.8:1 in
16% yield [95]. Surprisingly, the ratio of 6,7-trans 202 reaction yield was much improved
when the relatively low reactive allylic chloride was converted into allylic iodide prior to
Int. J. Mol. Sci. 2021, 22, 1052 Barbier reaction using CrCl2 in THF. This two-steps procedure produced an increased 26 ofra-
67
tio of 6,7-trans 202 (1:1) and a moderate yield (52%) [90].
Scheme 43. Synthesis of trans-intermediate 202 by Long et al. Reagents and conditions: (a) TBDPSCl,
imidazole; (b) NBS, THF/H2O, then K2CO3, MeOH; (c) H5IO6, NaIO4, 63% over 3 steps; (d) acryloni-
trile, DABCO, RT; (e) CCl4, n-Bu3P, 73% over 2 steps, 27a/b = 3:1; (f) HF-Pyridine, THF; (g) 4 Å MS,
Ti(OiPr)4 (0.1 equiv), (–)-DIPT (0.12 equiv), TBHP (1.5 equiv), CH2Cl2, −40 °C to −18 °C; (h) Dess–
Martin periodinane, NaHCO3, CH2Cl2, for 28a 3 steps, 81%, ee = 97%, for 28b 3 steps, 76%, ee = 95%;
(i) NaI, acetone (b) CrCl2, THF, rt [90].
Scheme 43. 43. Synthesis trans-intermediate
Synthesisofoftrans-intermediate 202202by by
LongLong etReagents
et al. al. Reagents and conditions:
and conditions: (a) TB-
(a) TBDPSCl,
Scheme
imidazole;
DPSCl, imidazole;
44 provided
(b) NBS,(b)THF/H
NBS,2O,
the
THF/H
targetCO
then K2 2O,
compound
3, MeOH;
then K2 CO(c)
parthenolide
, H IO
MeOH;
5 6 , NaIO
(c) H 4
(183).
, 63%
IO ,
Hydrolysis
over
NaIO 3 steps;
, 63%
of acryloni-
(d)
over
201
3
and
steps;
3 5 6 4
202
trile,by using
DABCO, RT; basic hydrogen
(e) CCl4RT;
, n-Bu peroxide
(e)3P, 73% produced
over3 P,2 73%
steps,over compounds
27a/b = 3:1; 27a/b 203,
(f) HF-Pyridine,204, and 205 (Scheme
THF; (g) 4 ÅTHF;
MS,
(d) acrylonitrile, DABCO, CCl 4 , n-Bu 2 steps, = 3:1; (f) HF-Pyridine,
44). Lactone
Ti(OiPr) (0.1 206 was
equiv), obtained
(–)-DIPT by
(0.12 refluxing
equiv), TBHP compound
(1.5 equiv), 203
CH in Clbenzene
, −40
(g) 4 Å MS, Ti(OiPr)4 (0.1 equiv), (–)-DIPT (0.12 equiv), TBHP (1.5 equiv), CH2 Cl2 , −40 C to −18 ◦ C;
4 2 2 °C with
to DBU.
−18 °C;
◦ Moreo-
(h) Dess–
ver,
Martin
(h)
another side
periodinane,
Dess–Martin
product
NaHCO3204
periodinane, , CHcould
NaHCO 2Cl2, forbe28aconverted
3 steps, 81%, to ee
the= 97%,
desired for 28b intermediate
3 steps, 76%,205 ee =upon
95%;
3 , CH2 Cl2 , for 28a 3 steps, 81%, ee = 97%, for 28b 3 steps, 76%,
stirring with
(i) NaI, acetone DBU in
(b) CrCl CH 2Cl2rt
2, THF, . The
[90].target molecule 183 was successfully obtained upon ir-
ee = 95%; (i) NaI, acetone (b) CrCl2 , THF, rt [90].
radiating 205 with UV light (254 nM) in 58% conversion and 77% yield [90].
Scheme 44 provided the target compound parthenolide (183). Hydrolysis of 201 and
202 by using basic hydrogen peroxide produced compounds 203, 204, and 205 (Scheme
44). Lactone 206 was obtained by refluxing compound 203 in benzene with DBU. Moreo-
ver, another side product 204 could be converted to the desired intermediate 205 upon
stirring with DBU in CH2Cl2. The target molecule 183 was successfully obtained upon ir-
radiating 205 with UV light (254 nM) in 58% conversion and 77% yield [90].
Scheme 44. Synthesis parthenolide (183) and its its analog

analog (206).
(206). Reagents
Reagents and
and conditions:
conditions: (a)
(a) K
K22CO33,
H
H2 O2 , DMSO/THF, 86%; (b) DBU, CH2 Cl2 , rt, 92%; (c) DBU, benzene, reflux, 91%; (d) hv (254 nm),
2 O 2 , DMSO/THF, 86%; (b) DBU, CH 2Cl 2 , rt, 92%; (c) DBU, benzene, reflux, 91%; (d) hv (254 nm),
benzene,
benzene, conversion:
conversion: 58%,
58%, yield:
yield: 77%
77% based
based on on recovered
recovered starting
starting material
material [90].
[90].
Overall, Long et al. have demonstrated the first effective synthetic route, which can be
used to synthesize parthenolide (183) and its analogs. Moreover, insights acquired from
this investigation
Scheme onparthenolide
44. Synthesis synthetic routes
(183) of
and parthenolide (183)
its analog (206). may provide
Reagents general strategies
and conditions: (a) K2CO3,
to2O
H synthesize trans-germacronolide
2, DMSO/THF, 86%; (b) DBU, CH2Clanalogs with
2, rt, 92%; (c) high
DBU,medical
benzene,relevance.
reflux, 91%; (d) hv (254 nm),
benzene, conversion:
In an 58%, yield: poor
effort to overcome 77% based
wateronsolubility
recoveredofstarting material(183)
parthenolide [90]. without compro-
mising its anti-leukemic activity, Neelakantan and coworkers carried out the synthesis
and structure-activity relationship studies of a series of aminoparthenolide analogs deriv-
ied from various aliphatic primary and secondary amines [88]. It is of significance that
R-configuration at the newly formed C-11 chiral center was conserved after the Michael-
type addition of parthenolide (183) with aliphatic amines (Scheme 45). Authors have
concluded that the protonation of the enolate formed during the reaction, which occurs
from the exo face of the molecule, causes the conservation of R-conformation at C-11 in the
product. During the course of investigation, dimethylamino analog (190) was identified
as the representative compound exhibiting significant anti-leukemic activity in the AML
assay [88]. However, aminoparthenolide analogs showed low metabolic and chemical
stability. Especially, it was prone to the cytochrome P450 (CYP450)-catalyzed oxidation,
which significantly decreases the bioactivity of the compound [96]. Therefore, additional
research to reduce the effect of CYP450-catalyzed oxidation was necessitated.
product.
product. During
During the
the course
course of
of investigation,
investigation, dimethylamino
dimethylamino analog
analog (190)
(190) was
was identified
identified
as
as the representative compound exhibiting significant anti-leukemic activity in
the representative compound exhibiting significant anti-leukemic activity in the
the AML
AML
assay
assay [88]. However, aminoparthenolide analogs showed low metabolic and chemical sta-
[88]. However, aminoparthenolide analogs showed low metabolic and chemical sta-
bility.
bility. Especially,
Especially, itit was
was prone
prone toto the
the cytochrome
cytochrome P450 P450 (CYP450)-catalyzed
(CYP450)-catalyzed oxidation,
oxidation,
Int. J. Mol. Sci. 2021, 22, 1052 which
which significantly
significantly decreases
decreases the
the bioactivity
bioactivity of
of the
the compound
compound [96].
[96]. Therefore,
Therefore, additional
additional
27 of 67
Scheme
Scheme 45.
45. Synthesis
Synthesis
Synthesis of dimethylamino-parthenolide
ofof dimethylamino-parthenolide
dimethylamino-parthenolide analog (190).
analog
analog Reagents
(190).
(190). and
and conditions:
Reagents
Reagents (a)
and conditions:
conditions: (a)
dimethylamine,
dimethylamine,
(a) MeOH,
MeOH,
dimethylamine, MeOH, rt;
rt; (b)
(b) Fumaric
Fumaric
rt; (b) acid,
acid,
Fumaric diethyl
diethyl
acid, ether.
ether.
diethyl [88].
[88].
ether [88].
In
In addition,
addition, Yang
Yang et al.
et al.
al. reported
reported the asymmetric
the asymmetric
asymmetric total total synthesis
synthesis of germacrane
of germacrane
germacrane ringring
207, inspired by the biosynthetic route of sesquiterpene lactones (Figure
207, inspired by the biosynthetic route of sesquiterpene lactones (Figure 10) [97]. A more 10) [97]. A more
detailed descriptionon
detailed description
description onthe
on thesynthetic
the syntheticroute
synthetic routeused
route usedto
used totoafford
afford
afford the
the
the germacrane
germacrane
germacrane ring
ring
ring 207207
207 will
will
will be
be
be provided
provided in in
the the chemistry
chemistry of of costunolide
costunolide (186)(186)
sectionsection
(see (see Section
Section 2.2.8).
2.2.8).
provided in the chemistry of costunolide (186) section (see Section 2.2.8). The key inter- The The
key key
inter-
intermediate
mediate
mediate 207
207 can
can canserved
207be
be be served
served as as a great
as aa great
great starting
starting
starting pointpoint
point to to prepare
to prepare
prepare the the natural
the natural
natural lactones
lactones
lactones par-
par-
parthenlide
thenlide
thenlide (183)(183)
(183) and and costunolide
and costunolide
costunolide (186). (186).
(186).
Figure
Figure 10. Preparation
10.
Figure 10. Preparation of
of parthenolide
parthenolide (183)
(183) and
and costunolide
costunolide (186)
(186) from 207 [97].
from 207
207 [97].
Moreover, trifluoromethylated
Moreover, germacrane skeleton
skeleton 208 can be used to synthesize
Moreover, trifluoromethylated
trifluoromethylated germacrane
germacrane skeleton 208 208 can
can be
be used
used toto synthesize
synthesize
analogs
analogs of the aforementioned lactones, such as trifluoromethylated analogs (209 and
and 210)
analogs of the aforementioned lactones, such as trifluoromethylated analogs (209 and 210)
of the aforementioned lactones, such as trifluoromethylated analogs (209 210)
(Scheme 46). Based on literature findings [98–100], authors expected that replacing 14-
(Scheme
(Scheme 46).
46). Based
Based on on literature
literature findings
findings [98–100],
[98–100], authors
authors expected
expected that
that replacing
replacing 14-
14-
methyl group with an electron-withdrawing group such as a trifluoromethyl moiety would
methyl
methyl group
group with
with an
an electron-withdrawing
electron-withdrawing group
group such
such as
as aa trifluoromethyl
trifluoromethyl moiety
moiety
protect against oxidation by CYP450 oxidases. Both analogues showed a comparable anti-
would
would protect
protect against
against oxidation by by CYP450 oxidases.
oxidases. Both
Both analogues showed aa compara-
cancer activity to theiroxidation
natural product CYP450
counterparts, analogues
parthenolide showed
(183) compara-
and costunolide
ble anti-cancer
ble anti-cancer activity
activity to their
to their natural
natural product counterparts,
product counterparts, parthenolide
parthenolide (183) and
29 of 69
(186), respectively. Moreover, 210 was less acid-labile than parthenolide (183) and (183) and
exhibited
costunolide
costunolide (186), respectively.
(186), respectively. Moreover, 210 was less acid-labile than parthenolide (183)
metabolic stability equivalent toMoreover, 210 was less
that of parthenolide acid-labile
(183) [97]. than parthenolide (183)
and
and exhibited
exhibited metabolic
metabolic stability
stability equivalent
equivalent to to that
that ofof parthenolide
parthenolide (183)
(183) [97].
[97].
Scheme 46.
Scheme Synthesis of
46. Synthesis of trifluoromethylated
trifluoromethylatedanalogs
analogs(209
(209and
and210) from208.
210)from Reagentsand
208.Reagents andcondi-
condi-
tions: (a) MnO , CH Cl , r.t., 8 h, 25% over 3 steps; (b) m-CPBA, CH Cl , 25 ◦ C, 3 h, 91%. [97].
tions: (a) MnO22, CH22Cl2,2 r.t., 8 h, 25% over 3 steps; (b) m-CPBA, CH2Cl 2 2,225 °C, 3 h, 91%. [97].
2.2.3. Biological Activities of Alantolactone (184)

2.2.3. Biological Activities of Alantolactone (184)
Alantolactone (184) is a potent anticancer compound for various tumor cells, which is
Alantolactone (184) is a potent anticancer compound for various tumor cells, which
mainly obtained from the medical herb Inula helenium [101–103]. However, the underlying
is mainly obtained
mechanism from theactivity
of anti-cancer medicalofherb Inula helenium
alantolactone (184)[101–103].
is still notHowever, the under-
clearly determined.
lying mechanism of anti-cancer activity of alantolactone (184) is still not
Liu et al. investigated antiangiogenic effect alantolactone and its molecular mechanism.clearly deter-
mined. Liu et al. investigated antiangiogenic effect alantolactone and its molecular
Alantolactone (184) exhibits an IC50 value of 40 µM against MDA-MB-231 cells and 14.2 µM mech-
anism.
againstAlantolactone
human umbilical (184)vein
exhibits an IC50 value
endothelial cells of 40 μM against
(HUVEC) MDA-MB-231
cells. This cells and
indicates selective
14.2
nature of alantollactone (184) on active endothelial cells. VEGFR2 phosphorylation playsse-
μM against human umbilical vein endothelial cells (HUVEC) cells. This indicates a
lective nature of alantollactone (184) on active endothelial cells. VEGFR2 phosphorylation
plays a key role in tumor angiogenesis and authors demonstrated alantolactone (184) sup-
presses VEGFR2 phosphorylation and its downstream signals, including PLCγ1, FAK,
Src, and AKT [104]. Hence, alantolactone (184) can work as a VEGFR2 inhibitor and ex-
hibit antiangiogenic activity. Xing Kang et al. suggested in their study of alantolactone
Int. J. Mol. Sci. 2021, 22, 1052 28 of 67
key role in tumor angiogenesis and authors demonstrated alantolactone (184) suppresses
VEGFR2 phosphorylation and its downstream signals, including PLCγ1, FAK, Src, and
AKT [104]. Hence, alantolactone (184) can work as a VEGFR2 inhibitor and exhibit an-
tiangiogenic activity. Xing Kang et al. suggested in their study of alantolactone (184) on
HepG2 (description) that ROS-AKT pathway might participate in apoptosis induced by
alantolactone (184) [105]. In addition, alantolactone (184) can penetrate the blood brain
barrier (BBB) and act as a therapeutic agent for CNS neoplasm. Alantolactone (184) induces
apoptosis in glioblastoma cells by inhibiting NFkB/COX-2 signaling pathway. Expression
of COX-2 in glioblastoma cells was suppressed mainly due to inhibition of IKKβ by binding
of alantolactone (184) to the ATP-site [106].
2.2.4. Chemistry of Alantolactone (184)

The stereoselective total synthesis of racemic alantolactone (184) was reported in 1965
by Marshall et al. [107]. To the best of our knowledge, there were no other reports illustrat-
ing the enhanced synthetic approaches to alantolactone (184), but a number of groups have
reported semi-synthetic derivatives of the natural product and their biological evaluation.
Probably, this is because there are abundant available sources of alantolactone in nature,
including Inula helenium L., Inula japonica, Aucklandia lappa, Inula racemosa, and so on, where
it can be isolated at ease by means of different chromatographic techniques [108–111].
Three key reaction steps categorized by Marshall and coworkers are as follows: first,
the construction of the carboxylic scaffold by cationic olefin cyclization (212 to 213), sec-
ondly, modification of the carbon framework to afford 222, and lastly, formation of α-
methylene-γ-butyrolactone (222 to 184). The actual synthesis of Alantolactone (184) is
summarized in Scheme 47, commencing with unsaturated ketone 211 afforded from 4-
bromobutene in two steps [107]. Ketone 211 then was reacted with ethereal methylithium
to give alcohol 212, which was cyclized to generate formate 213 according to a procedure
previously developed by Johnson and co-workers for analogous compounds [112]. Alcohol
214 produced from saponification of the resulting formate 213 was oxidized with chromic
acid reagent giving octalone 215 [113]. Upon treatment of ethyl bromacetate to 215 via Stork
enamine procedure and saponification of the crude mixture, keto acid 216 was afforded
in 53% overall yield [107]. It should be noted that steric effects around C-9 rendered the
alkylation difficult and thus formed ∆7 -isomer more predominantly than ∆7 -isomer, which
eventually led to the formation of C-alkylation product 216 in high yield [114]. Keto acid
216 underwent esterification to furnish, after reduction with methanolic potassium boro-
hydride, unsaturated lactone 219. Photo-oxygenation of 219 as stated in the procedure by
Nickon and Bagli gave hydroperoxide 220 [115], which was directly reduced to alcohol 221
due to stability issue [107]. The key intermediate 222 was obtained by unsaturation of the
alcohol 221 upon treatment with thionyl chloride in pyridine according to the procedure
described by Benesova et al. [116]. Lactone 222 was converted to lactone ester 223 via
carbomethoxylation with sodium hydride in dimethyl carbonate. 223 was then reduced
without further purification to yield diol 224. Finally, diol 224 was subjected to oxidation
with manganese dioxide in benzene to afford racemic alantolactone (184). The stereoselec-
tive total synthesis of racemic alantolactone (184) elucidated by Marshall and co-workers
provided an approach to related sesquiterpene lactones [107].
Kaur and co-workers have recently reported a number of semi-synthetic derivatives
(225–228) of the natural product and their biological evaluation [117]. Alantolactone (184),
upon reaction with diazomethane, afforded pyrazoline derivative 228 as a major product
(Scheme 48). Alantolactone (184) underwent epoxidation reaction with trifluoroacetic acid
in dichloromethane as a solvent to generate compound 229 [118]. Moreover, alantolactone
(184), like other α-methylene-γ-lactone moiety containing sesquiterpene lactones, was read-
ily reacted with various amines to yield amine adduct 230 in a stereoselective manner [119].
Shul’ts et al. investigated the pharmacological properties caused by an arylidene fragment
in the lactone ring [120]. Thus, aromatic substituents at position C-13 was introduced via
Heck reaction with aryl iodides. Compound 231 having (E)-configuration was afforded by
borohydride, unsaturated lactone 219. Photo-oxygenation of 219 as stated in the proce-
dure by Nickon and Bagli gave hydroperoxide 220 [115], which was directly reduced to
alcohol 221 due to stability issue [107]. The key intermediate 222 was obtained by unsat-
uration of the alcohol 221 upon treatment with thionyl chloride in pyridine according to
Int. J. Mol. Sci. 2021, 22, 1052 the procedure described by Benesova et al. [116]. Lactone 222 was converted to lactone 29 of 67
ester 223 via carbomethoxylation with sodium hydride in dimethyl carbonate. 223 was
then reduced without further purification to yield diol 224. Finally, diol 224 was subjected
arylation
to withwith
oxidation iodoarenes in the
manganese presence
dioxide in of Pd(OAc)
benzene /(2-MeC
to 2afford 6 H4 )3 and
racemic trimethylamine
alantolactone (184).
in DMF.
The The configuration
stereoselective of the of
total synthesis C(11)=C(13) double bond
racemic alantolactone of 231
(184) was determined
elucidated by Marshallby
analysis
and of 13 C NMR
co-workers spectrum.
provided an approach to related sesquiterpene lactones [107].

Scheme 47.
Scheme Total synthesis
47. Total synthesis of
of alantolactone
alantolactone (184)
(184) according
according to
to Marshall
Marshall et
et al.
al. [107].
[107].
Kaur and co-workers have recently reported a number of semi-synthetic derivatives

(225–228) of the natural product and their biological evaluation [117]. Alantolactone (184),
upon reaction with diazomethane, afforded pyrazoline derivative 228 as a major product
(Scheme 48). Alantolactone (184) underwent epoxidation reaction with trifluoroacetic acid
in dichloromethane as a solvent to generate compound 229 [118]. Moreover, alantolactone
(184), like other α-methylene-γ-lactone moiety containing sesquiterpene lactones, was
readily reacted with various amines to yield amine adduct 230 in a stereoselective manner
[119]. Shul’ts et al. investigated the pharmacological properties caused by an arylidene
fragment in the lactone ring [120]. Thus, aromatic substituents at position C-13 was intro-
duced via Heck reaction with aryl iodides. Compound 231 having (E)-configuration was
afforded by arylation with iodoarenes in the presence of Pd(OAc)2/(2-MeC6H4)3 and tri-
methylamine in DMF. The configuration of the C(11)=C(13) double bond of 231 was de-
termined by analysis of 13C NMR spectrum.
48. Synthetic
Scheme 48. Synthetictransformations
transformationsofof alantolatone
alantolatone (184). Reagents
(184). andand
Reagents conditions:
conditions: (a) CHBr 3 , 50%
(a) CHBr 3,
50% aq. KOH,

aq. KOH, TEBAC,
TEBAC, 5 h;NaBH
5 h; (b) (b) NaBH 4, MeOH,
4 , MeOH, 25 min;
25 min; (c) Mg, (c) dry
Mg,MeOH,
dry MeOH, 3 h;
3 h; (d) TEA, (d) TEA, diazome-
diazomethane,
thane, overnight;
overnight; (e) CF(e)
3 COCF 3CO
3 H, Na3H,CO
2 Na32,CO
DCM, 0 ◦ C;
3, DCM, 0 °C;
(f); (f);
(g) (g) Pd(OAc)
Pd(OAc) 2/(2-MeCH
2 /(2-MeC 6 6H
4 )4)33,, trimethylamine,
DMF [117,119,120].
DMF [117,119,120].
2.2.5. Biological Activities of Deoxyelephantopin (185)

Deoxyelephantophin (DET)
Deoxyelephantophin (DET)(185)
(185)is is
thethe major
major sesquiterpene
sesquiterpene lactone
lactone component
component pre-
present in extracts of medicinal herb Elephantopus scaber, which has long been used
sent in extracts of medicinal herb Elephantopus scaber, which has long been used as as aa rem-
rem-
edy for various types of diseases such as hepatitis, arthritis, asthma, and cancer [121,122].
Recent studies showed that DET exhibits a broad spectrum of antitumor activities includ-
ing nasopharyngeal [123], cervical [124], colorectal [125], lung [126], skin [127], and par-
ticularly in breast cancer [128]. Characteristic structural feature of DET is a functionalized
germacranolide skeleton, which is a 10-membered ring with a trans-fused α-methylene-
Int. J. Mol. Sci. 2021, 22, 1052 30 of 67
edy for various types of diseases such as hepatitis, arthritis, asthma, and cancer [121,122].
Recent studies showed that DET exhibits a broad spectrum of antitumor activities including
nasopharyngeal [123], cervical [124], colorectal [125], lung [126], skin [127], and particularly
in breast cancer [128]. Characteristic structural feature of DET is a functionalized germacra-
nolide skeleton, which is a 10-membered ring with a trans-fused α-methylene-γ-lactone.
It is widely accepted that an α, β-unsaturated ketones, and an α-methylene-γ-lactone group
of this natural product attribute to a variety of biological effects by acting as a Michael
acceptor for nucleophilic amino residues like a cysteine [129].
Although inhibitory activities of DET (185) on NK-κB pathways and partial agonistic
inhibition of PPARγ were previously described [130,131], covalent targets of DET (185)
were not clearly assessed. Lagoutte et al. sought to find out direct cellular targets of DET
(185) with the use of a proteome-wide identification technique. During the investigation,
they were able to identify several cellular targets of DET (185) (RBP4, GSTA2, SLC26A3,
LIPA, and ANXA1) and reported DET (185) as the first example of a small molecule that
modulates a pharmacologically important nuclear receptor, PPARγ [132,133], activity by
engaging a zinc finger through Michael addition [134].
In addition, Nakagawa-Goto et al. reported the design and synthesis of deoxyelephan-
tophin derivatives (DETDs) and conducted a comprehensive structural-activity relationship
study of DETDs on triple-negative breast cancer (TNBC) cell lines. TNBC accounts for
around 15% of breast cancers and notorious for having a poor prognosis [135,136]. TNBC,
as its name implies, lacks conventional molecular targets usually found in breast cancers
namely: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth
receptor2 (HER2). This makes effective treatment for TNBC extremely challenging. Among
all derivatives synthesized, DETD-35 (232) containing a naphthyl group attached to the
cytotoxic
ketone by drug, paclitaxel,
a methylene linkershowed
showedsynergistic effectsactivity
the most potent on MDA-MB-231 cells,
and no toxicity suggesting
towards nor-
that cells
mal DETD-35
in vitro(232) could
(GI50 be further
of DETD-35 developed
(232) as a potential compound
against MDA-MB-231, a TNBC celltoline
complement
= 3.5 µM,
chemotherapeutic
Figure 11). Moreover, drugs
theused for of
effects TNBC [137].
DET-35 (232) on inhibiting cell migration, invasion,
Besides,ofinMDA-MB-231
and motility another studycells
carried
wereout by thetogroup,
shown it was
be better thandemonstrated that DETD-
that of the parental com-
35 (232)DET
pound also(185).
shows synergism
Lastly, with other
a combination of BRAF
DETD-35 inhibitors,
V600E (232) with avemurafenib (PLX4032),
cytotoxic drug, to
paclitaxel,
showed synergistic effects on MDA-MB-231
overcome acquired vemurafenib resistant BRAF cells, suggesting
V600E that DETD-35 (232)
mutant melanoma in a mouse model could be
further developed
[127]. These as afurther
findings potential compound
reinforce to complement
the significance chemotherapeutic
of DETD-35 drugschem-
(232) as a novel used
for
icalTNBC
entity [137].
for anti-cancer drug discovery campaign.
Figure 11.
Figure 11. Structure
Structure of
of DETD-35
DETD-35 (232).
(232).
2.2.6.Besides, in another
Chemistry study carried out
of Deoxyelephantopin by the group, it was demonstrated that DETD-
(185)
35 (232) also shows synergism with other BRAFV600E inhibitors, vemurafenib (PLX4032),
Deoxyelephantopin has received much interest because of its impressive in vitro and
to overcome acquired vemurafenib resistant BRAFV600E mutant melanoma in a mouse
in vivo activities. However, total synthesis of deoxyelephantopin (185) has not been re-
model [127]. These findings further reinforce the significance of DETD-35 (232) as a novel
ported up-to-date, probably for the same reason as in the case of alantolactone (184).
chemical entity for anti-cancer drug discovery campaign.
Lagoutte et al. profoundly explored the synthesis in regard to deoxyelephantopin (185) as
part of
2.2.6. their endeavor
Chemistry to develop synthetic
of Deoxyelephantopin (185)methodologies to provide analogs of the nat-
ural compound, including alkyne tagged probes to be used in target identification [134].
Deoxyelephantopin has received much interest because of its impressive in vitro
According to the retrosynthetic analysis provided by the group (Figure 12), deoxy-
and in vivo activities. However, total synthesis of deoxyelephantopin (185) has not been
elephantopin (185) and its analogs were envisioned to be obtained via Barbier-type allyla-
reported up-to-date, probably for the same reason as in the case of alantolactone (184).
tion of fragment 234 and bromolactone 235, followed by a late-stage ring-closing metath-
Lagoutte et al. profoundly explored the synthesis in regard to deoxyelephantopin (185)
esis (RCM) on substrate 233. Barbier-type allylation, which serves as the key reaction step
in the synthetic route, enables the diastereoselective coupling of the intermediate 235 with
diverse aldehydes [19].
Figure 11. Structure of DETD-35 (232).
2.2.6. Chemistry of Deoxyelephantopin (185)

Deoxyelephantopin has received much interest because of its impressive in vitro and
Int. J. Mol. Sci. 2021, 22, 1052 in vivo activities. However, total synthesis of deoxyelephantopin (185) has not been 31 ofre-
67
ported up-to-date, probably for the same reason as in the case of alantolactone (184).
Lagoutte et al. profoundly explored the synthesis in regard to deoxyelephantopin (185) as
as part
part of their
of their endeavor
endeavor to develop
to develop synthetic
synthetic methodologies
methodologies to provide
to provide analogs
analogs of nat-
of the the
natural compound,
ural compound, including
including alkyne
alkyne tagged
tagged probestotobebeused
probes usedinintarget
targetidentification
identification [134].
According
According totothetheretrosynthetic
retrosyntheticanalysis provided
analysis by the
provided bygroup (Figure(Figure
the group 12), deoxyelephan-
12), deoxy-
topin (185) and
elephantopin its and
(185) analogs were envisioned
its analogs to be to
were envisioned obtained via Barbier-type
be obtained allylation
via Barbier-type allyla-
of fragment
tion 234 and
of fragment bromolactone
234 and bromolactone followed
235, 235, by aby
followed late-stage ring-closing
a late-stage metathesis
ring-closing metath-
(RCM) on substrate
esis (RCM) Barbier-type
233.233.
on substrate allylation,
Barbier-type which
allylation, whichserves as the
serves keykey
as the reaction step
reaction in
step
the synthetic route, enables the diastereoselective coupling of the intermediate
in the synthetic route, enables the diastereoselective coupling of the intermediate 235 with 235 with
diverse
diverse aldehydes
aldehydes [19].
[19].
Figure 12. Retrosynthetic analysis of Deoxyelephantopin (185)

(185) [19].
[19].
The
The synthesis
synthesis commenced
commencedwith withthe
theesterification
esterificationofof
alcohol
alcohol providing
236236 providing thethe
acrylate
acry-
237, which is subsequently converted to allylic alcohol 238 under Morita-Baylis-Hillman
late 237, which is subsequently converted to allylic alcohol 238 under Morita-Baylis-Hill-
conditions (Scheme
man conditions 49). RCM
(Scheme 49). of
RCMtriene
of 238 mediated
triene by Grubbs
238 mediated II as catalyst
by Grubbs II as generated endo-
catalyst gener-
butenolide 239, which is then converted to key intermediate 235 under
ated endo-butenolide 239, which is then converted to key intermediate 235 under Appel Appel conditions.
It should be Itnoted
conditions. thatbethe
should allylic
noted alcohol
that of 238alcohol
the allylic needs toof be
238conserved
needs to tobeaccomplish RCM
conserved33to
Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW ofac-
69
at an appreciable rate [19]. The second fragments (234, 242) required
complish RCM at an appreciable rate [19]. The second fragments (234, 242) required for for Barbier-type
allylation were
Barbier-type prepared
allylation in 5prepared
were steps from in240 and from
5 steps 241, respectively.
240 and 241, respectively.
Scheme 49.
Scheme (a) Synthesis
49. (a) Synthesis of
of bromolactone
bromolactone 235; (b) synthesis
235; (b) synthesis of
of fragment 234 [19].
fragment 234 [19].
As expected,
As expected,the
thezinc-mediated
zinc-mediated Barbier-type
Barbier-type allylation
allylation of fragments
of fragments 234 and
234 and 235
235 pro-
provided secondary alcohol 243 in moderate yield [138]. However, the resulting alcohol
vided secondary alcohol 243 in moderate yield [138]. However, the resulting alcohol 243
243 did not undergo RCM to produce the cyclized product (Scheme 50). Authors assumed
did not undergo RCM to produce the cyclized product (Scheme 50). Authors assumed
that presence of free alcohol might interfere with the intermediate ruthenium carbene,
hindering formation of the desired RCM product 244. Therefore, alcohol 243 was esterified
hindering formation of the desired RCM product 244. Therefore, alcohol 243 was esteri-
to give methacrylate 233, which, however, also did not provide the product 246 upon
fied to give methacrylate 233, which, however, also did not provide the product 246 upon
submission to various RCM conditions [19]. RCM was not proceeded with the silyated
compound 245 as well, suggesting the presence of free alcohol might not be responsible
for this failure.
As expected, the zinc-mediated Barbier-type allylation of fragments 234 and 235 pro-
vided secondary alcohol 243 in moderate yield [138]. However, the resulting alcohol 243
did not undergo RCM to produce the cyclized product (Scheme 50). Authors assumed
Int. J. Mol. Sci. 2021, 22, 1052
hindering formation of the desired RCM product 244. Therefore, alcohol 243 was 32 esteri-
of 67
fied to give methacrylate 233, which, however, also did not provide the product 246 upon
compound
compound 245 245 as
as well,
well,suggesting
suggestingthe
thepresence
presenceofof free
free alcohol
alcohol might
might notnot be responsible
be responsible for
for this failure.
this failure.
Scheme 50.
Scheme RCM attempts
50. RCM attempts by
by Lagoutte
Lagoutte et
et al.
al. [19].
[19].
Formation of
Formation of aa medium-sized
medium-sized tri-substituted
tri-substituted olefin
olefin under
under RCMRCM conditions
conditions is is known
known
to be
to be particularly
particularly difficult
difficult [139,140].
[139,140]. Authors
Authors attempted
attempted to to investigate
investigate whether
whether the
the failure
failure
resulted from
resulted from the
the presence
presence ofof the
the methyl
methyl group
groupor
or the
the ring
ring tension.
tension. For
For this
this purpose,
purpose, RCM
RCM
precursor 248,
precursor 248, which
which lacks
lacks aa methyl
methyl group,
group, was
was used
used inin the
the reaction
reaction (Scheme
(Scheme51).51). Upon
Upon
treatment with Grubbs
Grubbs IIininrefluxing
refluxingdichloromethane,
dichloromethane,248 248waswassuccessfully
successfully converted
converted to
thethe
to ring closed
ring product
closed as aassingle
product diastereomer,
a single nordeoxyelephantophin
diastereomer, nordeoxyelephantophin 249.249.
Lastly, 249
Lastly,
waswas
249 treated withwith
treated meta-chloroperbenzoic
meta-chloroperbenzoic acidacid
(mCPBA)
(mCPBA) to generate norelephantopin
to generate norelephantopin 250.
Further
250. investigation
Further to cyclize
investigation the carbon
to cyclize skeleton
the carbon of deoxyelephantopin
skeleton of deoxyelephantopinis welliselabo-
well
rated in theinreference
elaborated [19]. [19].
the reference
Scheme
51.Synthesis of nordeoxyelephantophin
of nordeoxyelephantophin (249)
(249) and and norelephantophin
norelephantophin (250) et
(250) by Lagoutte by
Lagoutte
al. [19]. et al. [19].
In
In addition,
addition, Lagoutte
Lagoutte et
et al.
al. synthesized
synthesized deoxyelephantopin-related
deoxyelephantopin-related probes probes 254–256
254–256
and simplified analogs 258 and 260, which were utilized to indirectly demonstrate
and simplified analogs 258 and 260, which were utilized to indirectly demonstrate inter- in-
teraction between deoxyelephantopin and PPARγ [134]. Although synthetic
action between deoxyelephantopin and PPARγ [134]. Although synthetic access to deox- access to
deoxyelephantopin (185) could not be elucidated despite their efforts, preparation
yelephantopin (185) could not be elucidated despite their efforts, preparation of deoxy- of
deoxyelephantopin-related
elephantopin-related analogsanalogs
and and probes,
probes, by by means
means of of
a ashort
shortand
anddivergent
divergent synthetic
synthetic
design, was comprehensively described during the journey towards deoxylelephantopin
design, was comprehensively described during the journey towards deoxylelephantopin
(Scheme
(Scheme 52).
52).
In addition, Lagoutte et al. synthesized deoxyelephantopin-related probes 254–256
and simplified analogs 258 and 260, which were utilized to indirectly demonstrate inter-
action between deoxyelephantopin and PPARγ [134]. Although synthetic access to deox-
yelephantopin (185) could not be elucidated despite their efforts, preparation of deoxy-
elephantopin-related analogs and probes, by means of a short and divergent synthetic
Int. J. Mol. Sci. 2021, 22, 1052 design, was comprehensively described during the journey towards deoxylelephantopin 33 of 67
(Scheme 52).
Scheme52.
Scheme Synthesis
52.Synthesis of of DET-related
DET-related probes
probes (254–256)
(254–256) and analogs
and analogs (258,
(258, 260) 260) [134].
[134].
Nakagawa-Goto
Nakagawa-Goto et et
al. al. reported
reported a number
a number of semi-synthetic
of semi-synthetic derivatives
derivatives of the natural
of the natural
product
product and andtheir
their biological
biological assessment
assessment [137]. [137]. The synthesis
The synthesis commenced commenced with hydrol-
with hydrolysis
of deoxyelephantopin
ysis of deoxyelephantopin (185) with NaOH
(185) withfollowed by acidic treatment
NaOH followed by acidic(Scheme
treatment53). (Scheme
Ac- 53).
cording to ato
According previous report
a previous on cnicin
report [141], [141],
on cnicin the group expected
the group C-8 alcohol
expected C-8 263 to be263 to be
alcohol
generated.
generated.However,
Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW However, C-7-C-8
C-7-C-8lactonization of carboxylic
lactonization acid 261 solely
of carboxylic provided
acid 261 solelyless
35 ste-
of 69
provided less
rically hindered C-6 alcohol
sterically hindered C-6 alcohol 262. 262.
Scheme
Scheme 53. Synthesis 53. Synthesis of DET-derivatives
of DET-derivatives by Nakagawa-Goto
by Nakagawa-Goto et al. [137].
et al. [137].
Scheme 53. Synthesis of DET-derivatives by Nakagawa-Goto et al. [137].
Amongst synthesized fifty-eight ester analogs of DET (185), an analog with naphtha-
Amongst synthesized fifty-eight ester analogs of DET (185), an analog with naph-
lene acetate,
Amongst synthesized DETD-35
fifty-eight (232),
ester was identified
analogs as the most
of DET (185), potentwith
an analog compound possessing anti-
naphtha-
thalene acetate, DETD-35 (232), wasandidentified as the most potent compound possessing
lene acetate, DETD-35 (232), was identified as the most potent compound possessing anti- 54). More-
TNBC effects in vitro in lung metastasis xenograft mouse model (Scheme
anti-TNBC effects in
TNBC effects in vitroover,
vitro
andDETD-35
and in lung
in lung inhibited
metastasiscell migration, invasion, and motility of MDA-231 cells in a54).
metastasis xenograft mouse model
xenograft mouse model (Scheme 54). More-
(Scheme con-
Moreover, DETD-35 centration-dependent
inhibited manner,
cell migration, suggesting that DETD-35
invasion, (232) might be a potential candi-
over, DETD-35 inhibited cell migration, invasion, and motilityand motility
of MDA-231 of MDA-231
cells in a con- cells in
date as a complementary or sensitizing agent to be used in TNBC chemotherapy [137].
a concentration-dependent manner, suggesting that DETD-35 (232) might be a potential
centration-dependent manner, suggesting that DETD-35 (232) might be a potential candi-
candidate as a complementary
date as a complementary or sensitizing
or sensitizing agent
agent to be usedtoinbe usedchemotherapy
TNBC in TNBC chemotherapy
[137]. [137].
Scheme 54. Synthesis of DETD-35 (232). Reagents and conditions: (a) RCOOH, EDCI, DMAP,
CH2Cl2, rt [137].
2.2.7. Biological Activities of Costunolide (186)

Scheme 54.
Scheme 54.Synthesis of DETD-35
Synthesis (232). Reagents
of DETD-35 and conditions:
(232). Reagents (a) RCOOH, (a)
and conditions: EDCI, DMAP, EDCI, DMAP,
RCOOH,
CH2Cl2, rt [137]. The sesquiterpene lactone, costunolide (186), which belongs to a member of the ger-
CH2Cl2, rt [137]. macranolide subclass, was reported to be first isolated from roots of Saussrea lappa Clarke,
also known as costus [142]. Costunolide (186) can be found in extracts of a number of
2.2.7. Biological
2.2.7. BiologicalActivities
Activitiesof Costunolide (186)(186)
medicinalof Costunolide
plants including Vladimiria souliei Ling, Alucklandia lappa Decne, and Laurus no-
The
Thesesquiterpenebilislactone,
sesquiterpene costunolide
L. lactone,
as well [143]. (186),(186),
Furthermore,
costunolide which belongs
costunolide
which to isa served
(186)
belongs member aofcommon
the ger-
to aasmember ofbiosynthetic
the ger-
macranolide subclass, was reported
precursor to threetomain
be first
typesisolated from roots
of sesquiterpene of Saussrea
lactones lappa
such as Clarke,
germacranolide, eudes-
macranolide subclass, was reported to be first isolated from roots of Saussrea lappa Clarke,
also known as costus [142]. Costunolide
manolide, and guianolide (186) can be found in extracts of a number of
[144,145].
medicinal plants including Costunolide
Vladimiria(186), likeLing,
souliei manyAlucklandia
other naturally occurring
lappa Decne,lactones,
and Laurusexhibits
no- a variety of
biological effects, including anti-cancer, anti-inflammation,
bilis L. as well [143]. Furthermore, costunolide (186) is served as a common biosynthetic anti-oxidant, anti-ulcer, and
so on [146–149]. Anti-cancer effects of costunolide (186) have been extensively explored in
precursor to three main types of sesquiterpene lactones such as germacranolide, eudes-
recent researches [150–152]. Costunolide (186) is reported to modulate cyclin-dependent
manolide, and guianolide [144,145].
kinases (CDKs) and block G2/M phase of the cell cycle to exert anti-proliferative effects
Costunolide (186), like
on various many
tumorother
cellsnaturally
[153,154].occurring lactones, indicate
To date, researches exhibitsthat
a variety of (186) in-
costunolide
Int. J. Mol. Sci. 2021, 22, 1052 34 of 67
also known as costus [142]. Costunolide (186) can be found in extracts of a number of
medicinal plants including Vladimiria souliei Ling, Alucklandia lappa Decne, and Laurus
nobilis L. as well [143]. Furthermore, costunolide (186) is served as a common biosyn-
thetic precursor to three main types of sesquiterpene lactones such as germacranolide,
eudesmanolide, and guianolide [144,145].
Costunolide (186), like many other naturally occurring lactones, exhibits a variety of
biological effects, including anti-cancer, anti-inflammation, anti-oxidant, anti-ulcer, and so
on [146–149]. Anti-cancer effects of costunolide (186) have been extensively explored in
recent researches [150–152]. Costunolide (186) is reported to modulate cyclin-dependent
kinases (CDKs) and block G2/M phase of the cell cycle to exert anti-proliferative effects on
various tumor cells [153,154]. To date, researches indicate that costunolide (186) induces
apoptosis in three different apoptotic pathways, which eventually influences one another:
(a) Mitochondria-mediated (intrinsic) pathway [153–155], (b) Death receptor-mediated
pathway [156], and (c) Endoplasmic reticulum stress pathway [157,158].
According to studies conducted by Jeong et al., costunolide (186) reduced vascular
endothelial growth factor (VEGF)-induced proliferation [159]. VEGF is an angiogenic
molecule involved in formation of new blood vessels, which is particularly important for
survival of cancer cells. Costunolide (186) showed inhibitory effects on VEGF-stimulated
neovascularization in mouse corneal mouse pocket analysis [159]. Moreover, it was re-
ported in another study that costunolide (186) was able to reduce VEGF receptor1 (VEGFR1)
and VEGFR2 expression at both mRNA and protein levels, suggesting the potential anti-
angiogenic activities of costunolide (186) [160].
Migration of cancer cells into surrounding tissues and distant sites in the body to
develop tumors in new locations is called metastasis, which is the leading reason for the
mortality of many patients with cancer [161]. Lymphatic metastasis, of other various forms
of cancer metastasis, is known to be an important determining factor in cancer staging and
therapy. Jeong et al. suggested, in part of their investigation, that costunolide (186) might
provide clinical benefits as an anti-lymphoproliferative agent during tumor metastasis,
based on the observed inhibitory activities of the compound on proliferation and capillary
formation of temperature-sensitive mouse lymphoid endothelial (TL-LE) cells [162].
In an effort to improve cytotoxic effects of costunolide (186) on cancer cells, Srivastava,
et al. synthesized a number of 13-amino costunolide derivatives by means of Michael-type
addition between costunolide (186) and various amines [163]. Among the derivatives,
3-methyl piperidine derivative (264) possessed 2-fold better cytotoxicity (GI50 = 3.3 µM)
than that of costunolide (186) (GI50 = 7.8 µM) on SW-620 colon cancer cells (Figure 13).
Two derivatives of hydroxyl piperidine series (structures not shown) also showed also in-
creased cytotoxicity against MIAPaCa2, K-562, and PA-1 cell lines. Moreover, it is notewor-
thy that the replacement at position-13 with an acyclic N,N-dimethyl group (265) increased
cytotoxicity in all cancer cell lines except for A-549 and SW-620. Authors suggested that
the amino substituents at position-13 of cosutnolide (186) might play an important role in
eliciting cytotoxicity [163].
More recent study on the structure and activity relationship of costunolide (186)
was conducted by Vadaparthi, et al. [164]. The group was able to synthesize a series of
analogs by utilizing Heck reaction conditions with various aryl iodides and cytotoxic
activities of the compounds were examined against a panel of human cancer cell lines,
including cervical cancer (HeLa), breast cancer (MCF-7), lung cancer (A-549), melanoma
(B-16), and prostate cancer (DU-145) cell lines in vitro. Amongst derivatives, compound
266c and 266j displayed potent activity against Hela, DU-145, and MCF-7 cell lines [164].
Further investigation to establish concrete effects brought by incorporating aromatic and
hetero-aromatic rings on costunolide (186) scaffold would be indispensable.
Taken all together, costunolide (186) is a potential anti-cancer agent with cytotoxic,
anti-angiogenic, and anti-lymphoproliferative activities. Therefore, structural modifications
of costunolide (186) might provide more opportunities in developing new natural lactone-
based cancer therapeutics.
13). Two derivatives of hydroxyl piperidine series (structures not shown) also showed
also increased cytotoxicity against MIAPaCa2, K-562, and PA-1 cell lines. Moreover, it is
noteworthy that the replacement at position-13 with an acyclic N,N-dimethyl group (265)
increased cytotoxicity in all cancer cell lines except for A-549 and SW-620. Authors sug-
Int. J. Mol. Sci. 2021, 22, 1052 gested that the amino substituents at position-13 of cosutnolide (186) might play an im-
35 of 67
portant role in eliciting cytotoxicity [163].
Figure 13. Structures of Costunolide Derivatives.

Derivatives.
2.2.8. Chemistry of Costunolide (186)
2.2.8.More recent
Chemistry
The first study
of
total on theofstructure
Costunolide
synthesis (186) and activity
(+)-costunolide (186)relationship
via the Copeofrearrangement
costunolide (186) was
of syn-
conducted
theticThe by Vadaparthi,
first total synthesis
dehydrosaussurea et al. [164]. The group
of (+)-costunolide
lactone was able
(186) viaby
(267) was reported to
theGriecosynthesize a
Cope rearrangement series of analogs
of synthetic
et al. in 1976 (Scheme 55)
by utilizing
dehydrosaussurea
[165]. Heck reaction
lactone conditions
(267) was with various
reported by aryl
Grieco iodides
et al. in and
1976 cytotoxic
(Scheme activities
55) [165]. of
the compounds were examined against a panel of human cancer cell lines, including cer-
vical cancer (HeLa), breast cancer (MCF-7), lung cancer (A-549), melanoma (B-16), and
prostate cancer (DU-145) cell lines in vitro. Amongst derivatives, compound 266c and 266j
displayed potent activity against Hela, DU-145, and MCF-7 cell lines [164]. Further inves-
tigation to establish concrete effects brought by incorporating aromatic and hetero-aro-
matic rings on costunolide (186) scaffold would be indispensable.
Taken all together, costunolide (186) is a potential anti-cancer agent with cytotoxic,
anti-angiogenic, and anti-lymphoproliferative activities. Therefore, structural modifica-
tions of costunolide (186) might provide more opportunities in developing new natural
lactone-based cancer therapeutics.
Scheme 55. Synthesis of costunolide
costunolide (186)
(186) from
from dehydrosaussurea
dehydrosaussurea (267).
(267). Reagents
Reagentsand
andconditions:
conditions:
(a) 210 ◦°C
C [165].
The synthesis
synthesisbegan
beganwithwiththe
theketo-lactone 269,
keto-lactone which
269, waswas
which obtained fromfrom
obtained santonin 268
santonin
in
268two steps
in two (Scheme
steps 56). 56).
(Scheme Keto-lactone waswas
269 269
Keto-lactone treated withwith
treated tosylhydrazine to provide
tosylhydrazine the
to provide
corresponding
the corresponding hydrazone, which
hydrazone, was subsequently
which treated
was subsequently with lithium
treated diisopropylamide
with lithium diisopropyl-
to afford
amide toolefin
afford270. The270.
olefin resulting olefin underwent
The resulting ozonolysis
olefin underwent followed followed
ozonolysis by treatment with
by treat-
sodium borohydride to yield diol 271. Authors expected bis-o-nitrophenyl
ment with sodium borohydride to yield diol 271. Authors expected bis-o-nitrophenyl sele-selenide 272
would be directly obtained from the diol 271, which would, after oxidation, result
nide 272 would be directly obtained from the diol 271, which would, after oxidation, result in the
formation of saussurea lactone 273. However, this reaction with 271 only provided
in the formation of saussurea lactone 273. However, this reaction with 271 only provided a side
product illustrated
a side product in ref. [165].
illustrated in ref. [165].
Gratifyingly, diol 271, upon treatment with o-nitrophenyl selenocyanate, tributylphos-
phine in tetrahydrofuran-pyridine (1:1), provided mono-selenide 274 exclusively (Scheme 57).
However, no bis-selenide could be isolated, in spite of their attempt to convert 274 to
bis-selenide 272 by previously described reaction condition. In two subsequent reactions,
saussurea lactone 275 was afforded from 274. Selenylation of the lactone 275 followed by
treatment with 30% hydrogen peroxide in tetrahydrofuran provided key intermediate de-
hydrosaussurea lactone 277, which, upon thermolysis, provided a 20% yield of costunolide
(186) [165].
The second synthesis of costunolide (186) was reported by Kitagawa et al. [166].
The synthesis also commenced with a readily available terpenoid, E,E-farnesol (278), which
was converted to ω-bromo-farnesal (279) in three steps (Scheme 58). The key reaction step
involved in the synthesis is the intramolecular C-C bond formation of ω-bromo-farnesal
(279) to generate a racemic germacrane-skeletone (280), which was mediated by a low
valent chromium reagent. Dihydrocostunolide (281) obtained in 2 steps from germacrane-
skeletone (280), was then treated with lithium diisopropylamide (LDA), diphenyl selenide,
and hydrogen peroxide to afford costunolide (186) as a racemic mixture.
Scheme 56. Initial synthetic route for (+)-costunolide (186) According to Grieco and Nishizawa. Re-
agents and conditions: a, TsNHNH2, PhH, BF3·Et2O; b, LDA, THF, −78 → 0 °C, 65%; c, O3, CH2Cl2-
MeOH (1:1), −78 °C; d, NaBH3, −78 → 25 °C, 91%; e, NO2C6H4SeCN, PBu3, THF [165].
Gratifyingly, diol 271, upon treatment with o-nitrophenyl selenocyanate, tribu-

the corresponding hydrazone, which was subsequently treated with lithium diisopropyl-
amide to afford olefin 270. The resulting olefin underwent ozonolysis followed by treat-
ment with sodium borohydride to yield diol 271. Authors expected bis-o-nitrophenyl sele-
nide 272 would be directly obtained from the diol 271, which would, after oxidation, result
Int. J. Mol. Sci. 2021, 22, 1052 in the formation of saussurea lactone 273. However, this reaction with 271 only provided
36 of 67
a side product illustrated in ref. [165].
Scheme 56. Initial

Scheme Initialsynthetic
syntheticroute
routefor
for(+)-costunolide (186)
(+)-costunolide According
(186) to Grieco
According andand
to Grieco Nishizawa. Re-
Nishizawa.
Int. J. Mol. Sci. 2021, 22, x FOR PEER Reagents
REVIEW
agents and conditions: a, TsNHNH 2, PhH, BF3·Et2O; b, LDA, THF, −78 → 0 °C, 65%; 38 2of
◦ c, O3, CH Cl69
2-
and conditions: a, TsNHNH 2 , PhH, BF3 ·Et2 O; b, LDA, THF, −78 → 0 C, 65%; c, O3 ,
MeOH ◦ 3, −78 → 25 °C, 91%; e, ◦NO2C6H4SeCN, PBu3, THF [165].
(1:1), −78 °C; d, NaBH
CH2 Cl2 -MeOH (1:1), −78 C; d, NaBH3 , −78 → 25 C, 91%; e, NO2 C6 H4 SeCN, PBu3 , THF [165].
Gratifyingly, diol 271, upon treatment with o-nitrophenyl selenocyanate, tribu-

tylphosphine in tetrahydrofuran-pyridine (1:1), provided mono-selenide 274 exclusively
(Scheme 57). However, no bis-selenide could be isolated, in spite of their attempt to con-
vert 274 to bis-selenide 272 by previously described reaction condition. In two subsequent
reactions, saussurea lactone 275 was afforded from 274. Selenylation of the lactone 275
followed by treatment with 30% hydrogen peroxide in tetrahydrofuran provided key in-
termediate dehydrosaussurea
Scheme 57. Revised lactone
synthetic route 277, which, upon
for (+)-costunolide thermolysis,
according provided
to Grieco a 20% yield
and Nishizawa. Rea-
of costunolide
gents (186) [165].
and Conditions: a, NO2C6H4SeCN, Bu3P, THF-Py (1:1); b, LDA, (PhSe)2, HMPA, THF, −78 °C
to 20 °C; c, 30% H2O2 in THF; d, 210 °C [165].
The second synthesis of costunolide (186) was reported by Kitagawa et al. [166]. The
synthesis also commenced with a readily available terpenoid, E,E-farnesol (278), which
Scheme
valent 57. Revised
57.
Schemechromium synthetic
Revisedreagent.
synthetic route
routeforfor
(+)-costunolide according
(+)-costunolide
Dihydrocostunolide (281) to Grieco
according
obtained to and and
inGrieco
2 steps Nishizawa. Reagents
Nishizawa.
from Rea-
germacrane-
gents
and and Conditions:
Conditions: a, NO a,CNOH 2C 6H4SeCN,
SeCN, Bu Bu
P, 3P, THF-Py
THF-Py (1:1);
(1:1); b, b,
LDA, LDA, (PhSe)
(PhSe) , 2, HMPA,
HMPA, THF,THF,
− 78 ◦ C to
−78 °C
skeletone (280), was then treated with lithium diisopropylamide (LDA), diphenyl sele-
2 6 4 3 2
to
20 ◦ C;°C;
20 c, c,
30% 30%
H H
O 2O 2 in
in THF;
THF; d, d, ◦ C°C
210
210 [165].
[165].
nide, and hydrogen 2 2 peroxide to afford costunolide (186) as a racemic mixture.
The second synthesis of costunolide (186) was reported by Kitagawa et al. [166]. The
synthesis also commenced with a readily available terpenoid, E,E-farnesol (278), which
valent chromium reagent. Dihydrocostunolide (281) obtained in 2 steps from germacrane-
skeletone (280), was then treated with lithium diisopropylamide (LDA), diphenyl sele-
nide, and hydrogen peroxide to afford costunolide (186) as a racemic mixture.
Scheme 58. Synthesis of costunolide (186) according

Scheme according to Kitagawa
Kitagawa et al. Reagents and conditions: (a).
CrCl33-LiAlH44 (2:1),(2:1),DMF,DMF, 42%;
42%; (b).
(b). (i).
(i).TBDMSCl,
TBDMSCl,(ii).
(ii).9-BBN,
9-BBN,(iii).
(iii).HH2O
2O /− OH,
2/−2OH, 72%;
72%; (b). (b). (i). LDA,
(i). LDA, (ii).
(PhSe)
(ii). 2, (iii).
(PhSe) 2 , H
(iii).
2 OH2 , 49%
O
2 2 , [166].
49% [166].
More recently, the highly stereo-controlled total synthesis of costunolide (186) by uti-
lizing a synthetic germacrane skeletone has been reported [97]. Yang et al., inspired by the
biosynthetic route of sesquiterpene lactones, utilized the 6,7-trans-germacrane ring system
(207) as the key intermediate [167]. An intramolecular α-alkylation was employed as the
Int. J. Mol. Sci. 2021, 22, 1052 37 of 67
More recently, the highly stereo-controlled total synthesis of costunolide (186) by

utilizing a synthetic germacrane skeletone has been reported [97]. Yang et al., inspired
by the biosynthetic route of sesquiterpene lactones, utilized the 6,7-trans-germacrane
ring system (207) as the key intermediate [167]. An intramolecular α-alkylation was
employed as the crucial step involved in the synthesis of 207. The synthesis began with
known compound 282, which underwent a Horner–Wadsworth–Emmons (HWE) reaction
with diethylphophonoacetic acid to generate the sulfonate 283 in 58% yield over 239steps
Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW of 69
(Scheme 59). Subsequently, another fragment, aldehyde 285, was prepared by oxidation of
the alcohol 284 in 88% yield.
Scheme 59.
59. Synthesis of fragments 283
283 and
and 285
285 by
by Yang
Yang et
et al. [97].
[97].
Scheme Synthesis of fragments Yang et al.
al. [97].
Since the aldol

aldol reaction
reaction between
between283
283and
and285
285unfortunately
unfortunatelyresulted
resultedin poor
poorregiose-
Since the aldol reaction between 283 and 285 unfortunately resulted ininpoor regios-
regiose-
lectivity,
electivity,with
withexpected
expected 286a
286a obtained
obtained as
as aa minor product, an alternative approach was was
lectivity, with expected 286a obtained as a minor product, an alternative approach was
necessitated (Scheme 60). The approach selected by the authors
authors presumably
presumably proceeded
proceeded
necessitated (Scheme 60). The approach selected by the authors presumably proceeded
through a chelated transition state to generate 286a
286a as
as the
the major
major product
product over
over 22 steps.
steps.
through a chelated transition state to generate 286a as the major product over 2 steps.

Next, the
Next, the cyclization
cyclizationprecursor
precursor288 wasobtained
288was obtainedoverover 7 steps.
7 steps. In order
In order to achieve
to achieve the
the Next, the cyclization
intramolecular precursor
cyclization of 288
288, was obtained
various bases overexplored:
were 7 steps. InNaHMDS,
order to achieve
LiHMDS,the
intramolecular cyclization of 288, various bases were explored: NaHMDS, LiHMDS, and
intramolecular
and KHMDS, cyclization
among whichof 288, various
4 equivalent bases were
of KHMDS explored:
provided NaHMDS,
the cyclized LiHMDS,
product and
289
KHMDS, among which 4 equivalent of KHMDS provided the cyclized product 289 with
KHMDS,
with the among
best which
yield (84%)4 (Scheme
equivalent 61) of[97].
KHMDS
The provided
sulfone the cyclized
group of 289 product
was removed289 with
with
the best yield (84%) (Scheme 61) [97]. The sulfone group of 289 was removed with treat-
the best yield
treatment (84%) (Scheme
of Mg/MeOH 61) 290
to afford [97].inThe sulfone groupwasof 289 was removed with treat-
ment of Mg/MeOH to afford 290 in 73%73% yield,
yield, whichwhich
was then then treated
treated with
with pyridinium
pyridinium p-
ment of Mg/MeOH
p-toleunesulfonate to afford 290
(PPTS)ininMeOH in 73%
MeOHtotogive yield,
givethe which
thekey was then
keyintermediate treated
intermediate291291in with
in 78% pyridinium
78% yield. p-
yield. Lastly,
Lastly,
toleunesulfonate (PPTS)
toleunesulfonate
oxidation of (PPTS) in MeOH to give the key intermediate 291 in 78% yield. Lastly,
oxidation 291 with
of 291 with MnO in CH
MnO22 in CH22ClCl22produced
produced(+)-costunolide
(+)-costunolide(186)
(186)in in82%
82%yield.
yield.
oxidation of 291etwith
Srivastava MnO2 in CHand
al. synthesized 2Cl2evaluated
produced13-amino
(+)-costunolide (186) derivatives.
costunolide in 82% yield.Simple
Michael-type reaction with secondary amines were used to synthesize the derivatives
(Scheme 62). The stereochemistry at position-11 has been assumed, based on the following
literature finding in the reference [168]. With 264 and 265 as the most potent compounds,
authors indicated that N,N-dimethyl substituation at position-13 of costunolide (186) plays
a significant role in improving the cytotoxicity of the parent compound (186) [163].
intramolecular cyclization of 288, various bases were explored: NaHMDS, LiHMDS, and
KHMDS, among which 4 equivalent of KHMDS provided the cyclized product 289 with
the best yield (84%) (Scheme 61) [97]. The sulfone group of 289 was removed with treat-
ment of Mg/MeOH to afford 290 in 73% yield, which was then treated with pyridinium p-
Int. J. Mol. Sci. 2021, 22, 1052 toleunesulfonate (PPTS) in MeOH to give the key intermediate 291 in 78% yield. Lastly,
38 of 67
oxidation of 291 with MnO2 in CH2Cl2 produced (+)-costunolide (186) in 82% yield.

Srivastava et al. synthesized and evaluated 13-amino costunolide derivatives. Simple

Srivastava et al. synthesized and evaluated 13-amino costunolide derivatives. Simple
literature finding in the reference [168]. With 264 and 265 as the most potent compounds,
Scheme
Scheme 61.
literature Synthesis
61.finding in of
Synthesis the (+)-costunolide
reference [168].
(+)-costunolide (186)
(186) from264
With
from theand
the keyintermediate
key intermediate
265 as the most
291. Reagents
291.Reagents
potent andcondi-
condi-
compounds,
and
authors indicated that ◦N,N-dimethyl substituation at position-13 of costunolide (186)
tions: (a) KHMDS,
tions:
authors indicatedTHF,that0 °C, C, 25 h, 85%;
85%; (b)
N,N-dimethyl Mg,
Mg, MeOH,
MeOH, rt,
(b)substituation 16
16h,
rt,at h,74%;
74%;(c)
(c)PPTS,
position-13 PPTS, MeOH,
MeOH,rt,
rt,20
of costunolide 20min,
min,
(186)
plays
78%; (d)a significant
(d) MnO22,, CH role
CH22Cl in48improving
2,, rt, h, the cytotoxicity of the parent compound (186) [163].
78%;
plays a MnO
significant Cl 2 rt,
role h, 82%
82% [97].
in48improving [97].the cytotoxicity of the parent compound (186) [163].
Scheme 62. Synthesis of 13-amino costunolide derivatives 264 and 265 [163].
Scheme 62.
Synthesis of
of 13-amino
13-amino costunolide
costunolide derivatives
derivatives 264
264 and
and 265
265 [163].
[163].
Another synthesis of costunolide (186) derivatives was reported by Vadaparthi et al.
Another
Anothersynthesis
synthesisofofcostunolide
costunolide (186) derivatives
(186) waswas
derivatives reported by Vadaparthi
reported by Vadaparthiet al. [164].
et al.
[164]. The α-methylene-γ-lactone moiety was arylated by means of the Pd (II)-catalyzed
The α-methylene-γ-lactone
[164]. The α-methylene-γ-lactonemoietymoiety
was arylated by means
was arylated of the of
by means Pdthe
(II)-catalyzed Heck
Pd (II)-catalyzed
Heck coupling reaction. In this study, costunolide (186) was coupled with various aryl
coupling reaction.
Heck coupling In thisIn
reaction. study,
this costunolide (186) was
study, costunolide coupled
(186) with various
was coupled with aryl iodides
various aryl
iodidesstandard
under under standard
Heck Heck reaction
reaction conditioncondition
(Scheme (Scheme
63). 63).reaction
The The reaction seamlessly
seamlessly pro-
provided
iodides under standard Heck reaction condition (Scheme 63). The reaction seamlessly pro-
vided
the the E-olefin
E-olefin productsproducts (266a–266l),
(266a–266l), exclusively.
exclusively. The C11-C13
The C11-C13 olefin olefin was determined
was determined to be
vided the E-olefin products (266a–266l), exclusively. The C11-C13 olefin was determined
to
thebe the E-configuration
E-configuration based
based based
on theonon the observed
observed diagnostic
diagnostic vinyl
vinyl proton proton at C-13,
at C-13,atwith with
rangeaa
to be the E-configuration the observed diagnostic vinyl proton C-13,a with
range
of of 7.57–7.97
7.57–7.97 ppmMoreover,
ppm [164]. [164]. Moreover, no structural
no structural reorganization
reorganization or decomposition
or decomposition occurred
range of 7.57–7.97 ppm [164]. Moreover, no structural reorganization or decomposition
occurred
during during
the the
reaction reaction
process process
[164]. Among[164].
the Among the
derivatives, derivatives,
266c, 266d, 266c,
and 266d,
266j were and 266j
highly
occurred during the reaction process [164]. Among the derivatives, 266c, 266d, and 266j
were
active highly active
against active against
Hela (cervical Hela (cervical cancer), DU-145 (prostate cancer), and MCF-7
were highly against cancer), DU-145 cancer),
Hela (cervical (prostateDU-145
cancer), (prostate
and MCF-7 (breast and
cancer), cancer)
MCF-7cell
(breast cancer) cell lines.
lines.
(breast cancer) cell lines.
Scheme 63. Synthesis of arylated costunolide derivatives (266a–266l) [164].

[164].
Scheme 63. Synthesis of arylated costunolide derivatives (266a–266l) [164].
Overall, those fruitful researches carried out on the chemistry of costunolide (186)
provided new insight with regard to the efficient synthesis and structural modification of
the natural lactone (186).
2.2.9. Biological Activities of Antrocin (187)
Int. J. Mol. Sci. 2021, 22, 1052 39 of 67

Antrocin (187) is a sesquiterpene lactone mainly present in the extracts of Antrodia
camhorata (also known as Antrodia cinnamomea), a medical mushroom widely used as a
dietary supplement for cancer prevention and hepatoprevention in Asia [169]. Antrodia
camhorata has been traditionally used as a remedy for drug intoxication, abdominal pain,
food poisoning, and cancer [170]. Currently, antrocin (187) is identified as the compound
that contributes to the pharmacological efficacy of Antrodia camhorata [169]. Rao et al.
explored antrocin (187) and its biological mode of action [171]. During the evaluation of
antrocin (187) on cell proliferation, antrocin exhibited the most potent inhibitory activity
against breast cancer line MDA-MB-231 cells with a GI50 value of 0.6 µM [171]. Moreover,
authors insisted antropin (187) might be a novel molecule with efficacy as dual Akt/mTOR
inhibitor, based on their observation that the natural lactone inhibits cancer cell prolifer-
ation by promoting apoptosis through down-regulation of AKt/mTOR/GSK-3β/NF-κB
signaling pathways [171].
The group subsequently sought to investigate the capability of antrocin (187) to inacti-
vate other survival signaling pathways [172]. In this study, the effect of antrocin (187) on a
panel of non-small cell lung cancer (NSCLC) cells was examined. H1975 and H441 being
two representative cell lines exhibited high sensitivity to antrocin (187) (36–78% inhibition,
49–85% inhibition, respectively) [172]. Antrocin (187) also inactivated STAT3 and pre-
vented its nuclear localization in H441 cells, indicating its action as a JAK/STAT3 signaling
inhibitor. Furthermore, antrocin (187) suppressed tumorigenesis in lung cancer mouse
xenograft in vivo and enhanced tumor inhibitory response upon combinatorial treatment
of antrocin (187) and JAK2 inhibitor [172].
More recently, Chen et al. reported antrocin (187) as an anti-TNBC agent without
apparent systematic toxicity, based on their preliminary toxicological evaluation performed
with antrocin (187) in a 28-day rat study (at 37.5 mg/kg) [173]. In addition, another study
demonstrated that antrocin (187) effectively enhances sensitization radio-resistant prostate
cancer cells to radiation [174]. Given together, antrocin (187) has the capability to be a
therapeutic and sensitizing agent for various cancers.
2.2.10. Chemistry of Antrocin (187)

A concise and asymmetric synthesis of antrocin (187) has been reported by Li et al. [175].
The synthesis began with the naturally abundant carnosic acid as a chiral pool. After subjec-
tion of carnosic acid (292) to ozonolysis, followed by reduction with NaBH4 , optically pure
lactone 293 was afforded in 58% yield (Scheme 64). Lactone 293 was directly converted to
hydroxyl lactone 295 in two steps, which was subsequently treated with I2 in the presence
of PPh3 and imidazole to produce iodide 296. Lastly, treatment of 296 with DBU afforded
antrocin (187) in 50%. The asymmetric synthesis of antrocin (187) as achieved by the group
with a 16.1% overall yield in five steps [175]
Recently, the total synthesis of natural (−)-antrocin (187) and its enantiomer has been
reported [176]. Despite remarkable antitumor activities, the difficulties to prepare (−)-
antrocin (187) triggered researchers to find a synthetic alternative. Since there was no
available simple and inexpensive synthetic method for (−)-antrocin (187) until recently,
authors focused on developing a synthetic approach using inexpensive, readily available
starting material 6-methoxy-2-tetralone 297 and simple chemical operations.
From commercially available starting material 297, trans-cyano bicyclic ketone (±)-298
was obtained as a major product over 4 steps (Scheme 65). Resolution of the compound
(±)-298 was performed by utilizing (+)-dimethyl tartrate (DMT), which yielded separable
1:1 diasteromic mixture of ketal (−)-299 and (+)-300.
subjection of carnosic acid (292) to ozonolysis, followed by reduction with NaBH4, opti-
cally pure lactone 293 was afforded in 58% yield (Scheme 64). Lactone 293 was directly
converted to hydroxyl lactone 295 in two steps, which was subsequently treated with I2 in
the presence of PPh3 and imidazole to produce iodide 296. Lastly, treatment of 296 with
Int. J. Mol. Sci. 2021, 22, 1052 DBU afforded antrocin (187) in 50%. The asymmetric synthesis of antrocin (187) 40 of as
67
achieved by the group with a 16.1% overall yield in five steps [175]
Recently, the total synthesis of natural (−)-antrocin (187) and its enantiomer has been
reported [176]. Despite remarkable antitumor activities, the difficulties to prepare (−)-an-
trocin (187) triggered researchers to find a synthetic alternative. Since there was no avail-
able simple and inexpensive synthetic method for (−)-antrocin (187) until recently, authors
focused on developing a synthetic approach using inexpensive, readily available starting
material 6-methoxy-2-tetralone 297 and simple chemical operations.
Scheme From Synthesis of antrocin
commercially
64. Synthesis (187) from
available (+)-carnosic
starting
from materialacid
(+)-carnosic 297,
acid (292). Reagents
Reagents and
trans-cyano
(292). conditions:
bicyclic
and ketone
conditions: (a) O3 ,
(a)(±)-
O 3, 2
CH ◦ C, 78 ◦78
CH
298 Cl22Cl
was 2/MeOH
/MeOH
obtained (3/1),
as78a78
(3/1), °C,
1.51.5
major h, then
h,product
then NaBH
NaBH (6.0
4 (6.0
over 44 equiv.),
equiv.),
steps (Scheme °Crt,
C to to 1rt,h Resolution
65). 1(58%);
h (58%); (b)3of
(b) Ph Ph(1.3
P 3P (1.3
the equiv),
com-
equiv), I(±)-298
2 (1.5 equiv), imidazole (1.5 ◦ C to
I2 (1.5 equiv),
pound imidazole
was performed byequiv),
(1.5 equiv), THF, 0THF,
utilizing 0 rt,
°C 1tohrt,
(+)-dimethyl 1 tartrate
h (99%);
(99%); and
and (c) DBU
(DMT), (c) DBU
(10.0
which (10.0
equiv),equiv),
yielded toluene,
sep-
toluene,
80 ◦ C, 80 °C,
overnight overnight
(50%) (50%)
[175]. [175].
arable 1:1 diasteromic mixture of ketal (−)-299 and (+)-300.

of intermediate −)-299 [176].
intermediate ((−)-299 [176].
Ketal (−)-299was
Ketal (−)-299 wasselected
selectedfor
forfurther
further reaction
reaction to
to complete
complete the
the synthesis
synthesis ofof antrocin
antrocin
(187). Keto aldehyde (+)-301 was prepared from ( − )-299 over 3 steps (Scheme
(187). Keto aldehyde (+)-301 was prepared from (−)-299 over 3 steps (Scheme 66). Next, 66). Next,
α-
α-hydroxymethylation of (+)-301 by reacting with lithium enolate with gaseous
hydroxymethylation of (+)-301 by reacting with lithium enolate with gaseous formalde- formalde-
hyde in
hyde in THF
THF yielded
yielded aa single
single lactol
lactol (+)-302. The authors
(+)-302. The authors proposed
proposed that
that this
this reaction
reaction is
is
controlled kinetically [176]. Lactol (302) was then oxidized with silica-supported
controlled kinetically [176]. Lactol (302) was then oxidized with silica-supported pyri- pyri-
dinium chlorochromate (PCC) to give lactone (−)-303. Authors attempted both standard
and modified Wittig olefination (Ph PCH and THF, 0 ◦ C and Ph3 PCH2 , toluene, and
and modified Wittig olefination (Ph33PCH2 2and THF, 0 °C and Ph3PCH 2, toluene, and t-
t-BuOH, rt) [177], which ended up with a poor conversion rate (30–30%). Gratifyingly,
BuOH, rt) [177], which ended up with a poor conversion rate (30–30%). Gratifyingly, an-
another attempt with non-basic Lombardo’s reagent (Zn, TiCl , CH Br ) led to successful
other attempt with non-basic Lombardo’s reagent (Zn, TiCl44, CH22Br22) led to successful
olefination of ketone (−)-303 to antrocin (187) in excellent yield (98%) [178].
2.2.11. Biological Activities of EM23 (188) and Brevilin A (189)
EM23 (188) is a natural sesquiterpene lactone derived from Elephantopus mollis. Shao et al.
investigated anticancer effects of EM23 (188). EM23 (188) exhibited growth inhibitory activity
against various cancer cell lines, including A549 (lung cancer), MCF-7 (breast cancer), TE-1,
EC109, and EC9706 (esophageal cancer), CaSki and SiHa (cervical cancer), and HL-60 and
K562 (leukemia) [179]. EM23 (188) showed the most potent anti-proliferative activity against
CaSki and SiHa with a GI50 value of 5.8 and 6.6 µM, respectively. Furthermore, the authors
proposed the mechanism of EM23-induced apoptosis. Thioredoxin reductase (TrxR) catalyzes
the reduction of thioredoxin (Trx), which participates in various cellular processes [180].
Overexpression of Trx/TrxR is found to be related in the development and progression of
cancer [181,182]. EM23 (188) inhibits the expression levels of TrX/TrxR to facilitate ROS
accumulation, which results in the dissociation of ASK1 from complex with Trx and activation
of downstream JNK signaling pathway [179]. Taken together, EM23 (188) can be potentially
Scheme
applied66.as Complete Synthesis
an anticancer of antrocin
agent for human(187)cervical
[176]. cancer by a structural modification to
achieve further enhancement in potency.
2.2.11. Biological Activities of EM23 (188) and Brevilin A (189)
EM23 (188) is a natural sesquiterpene lactone derived from Elephantopus mollis. Shao
et al. investigated anticancer effects of EM23 (188). EM23 (188) exhibited growth inhibitory
activity against various cancer cell lines, including A549 (lung cancer), MCF-7 (breast can-
cer), TE-1, EC109, and EC9706 (esophageal cancer), CaSki and SiHa (cervical cancer), and
HL-60 and K562 (leukemia) [179]. EM23 (188) showed the most potent anti-proliferative
activity against CaSki and SiHa with a GI50 value of 5.8 and 6.6 μM, respectively. Further-
more, the authors proposed the mechanism of EM23-induced apoptosis. Thioredoxin re-
controlled kinetically [176]. Lactol (302) was then oxidized with silica-supported pyri-
and modified Wittig olefination (Ph3PCH2 and THF, 0 °C and Ph3PCH2, toluene, and t-
BuOH, rt) [177], which ended up with a poor conversion rate (30–30%). Gratifyingly, an-
Int. J. Mol. Sci. 2021, 22, 1052 other attempt with non-basic Lombardo’s reagent (Zn, TiCl4, CH2Br2) led to successful
41 of 67
cellular processes [180]. Overexpression of Trx/TrxR is found to be related in the develop-

ment and progression of cancer [181,182]. EM23 (188) inhibits the expression levels of
TrX/TrxR to facilitate ROS accumulation, which results in the dissociation of ASK1 from
complex with Trx and activation of downstream JNK signaling pathway [179]. Taken to-
gether, EM23 (188) can be potentially applied as an anticancer agent for human cervical
Scheme
cancer by 66.aComplete
structural Synthesis of antrocin
modification (187) [176].
to achieve further enhancement in potency.
Brelivin A (189) is a bioactive component mainly present in Centipeda minima (L.) A
2.2.11.Brelivin A (189) is a bioactive
EM23 component mainlyApresent in Centipeda minima (L.)
[183]. ItBiological
has beenActivities
reported to of display (188) and Brevilin
anticancer (189)
activities. In acute promyelocytic leuke-
A [183]. It has been reported to display anticancer activities. In acute promyelocytic
mia EM23
HL-60(188)cells,isBrevilin
a naturalAsesquiterpene
(189) inducedlactone apoptosis through
derived from aElephantopus
mitochondrial/caspase
mollis. Shao
leukemia HL-60 cells, Brevilin A (189) induced apoptosis through a mitochondrial/caspase
pathway
et al. [184]. Moreover,
investigated anticancer treatment
effects of of Brevilin
EM23 AEM23
(188). (189) (188)
reversed vincristine
exhibited growth resistance
inhibitory in
pathway [184]. Moreover, treatment of Brevilin A (189) reversed vincristine resistance in
multidrug-resistant
activity against variouscolorectal
cancer cancer
cell lines,cellincluding
line HCT-8/VCR
A549 bycancer),
(lung inhibiting the intracellular
MCF-7 (breast can-
multidrug-resistant colorectal cancer cell line HCT-8/VCR by inhibiting the intracellular
accumulation
cer), TE-1, EC109,
accumulation ofofYB-1
YB-1
andand and
EC9706 down-regulating
(esophagealMDR1
down-regulating MDR1
cancer), expression,
CaSki andtwo
expression, SiHa two important
(cervical
important cancer),
factors factors
and
closely
closely
HL-60
relatedand related to multidrug
K562 (leukemia)
to multidrug resistance.
[179].This
resistance. EM23 This suggests
(188) showed
suggests Brevilin
Brevilinthe mostas
A (189) A (189)
potent as a potential
anti-proliferative
a potential anti-
anticancer
cancer
activity drug
againstadjuvant
CaSki to
andreverse
SiHa drug
with a resistance
GI 50 valuein chemotherapy
of
drug adjuvant to reverse drug resistance in chemotherapy [185]. In addition,5.8 and 6.6 μM, [185]. In addition,
respectively. Chen Chen
Further-
et al.
et al.
more, reported
the authorsthat Brevilin
proposed A
the (189) acts
mechanism as a STAT3
of signaling
EM23-induced
reported that Brevilin A (189) acts as a STAT3 signaling inhibitor [186]. Persistent STAT3 inhibitor
apoptosis. [186]. Persistent
Thioredoxin re-
STAT3
ductase activity
(TrxR) is associated
catalyzes the with cancer
reduction of progression,
thioredoxin most
(Trx),
activity is associated with cancer progression, most of which show aberration of JAKs, of
whichwhich show
participates aberration
in various of
JAKs, Src, or other receptor tyrosine kinases. Brevilin A (189)
Src, or other receptor tyrosine kinases. Brevilin A (189) inhibited both constitutivelyinhibited both constitutively
activated-STAT3 driven
activated-STAT3 driven DU145
DU145 (prostate
(prostate cancer)
cancer) and
and MDA-MB-468
MDA-MB-468 (breast (breast cancer)
cancer) cellcell
lines [186].
lines [186]. It is also
It is also noteworthy
noteworthy that that Brevilin
Brevilin A A (189)
(189) specifically
specifically inhibits
inhibits JAKs
JAKs without
without
other signaling proteins such as p65, AKT, GSK-3β, and Src.
other signaling proteins such as p65, AKT, GSK-3β, and Src. A number of Brevilin A A number of Brevilin A (189)
(189)
derivatives were synthesized and their anticancer potential was
derivatives were synthesized and their anticancer potential was evaluated in a structure- evaluated in a structure-
activity relationships
activity relationships study study conducted
conducted by by LeeLee et
et al.
al. [187].
[187]. During
During the the course
course of of the
the study,
study,
it was
it was found
found out out that
that thethe alkene
alkene or or carbonyl
carbonyl of of the
the enone
enone moiety
moiety is is crucial
crucial in in achieving
achieving
cytotoxicity. Most Mostnotably,
notably,introducing
introducingdifferentdifferentsubstituents
substituentstotothe theα-position
α-position of of
thetheγ-
lactone ring
γ-lactone exhibited
ring exhibited a significantly
a significantly increased
increasedcytotoxicity in the
cytotoxicity intested cancer
the tested cell lines.
cancer cell
In the MDA-MB-231
lines. In the MDA-MB-231 and A549 and cell lines,
A549 BA-9
cell (304)
lines, and(304)
BA-9 BA-10 and(305)
BA-10displayed a GI50 value
(305) displayed a
of 4.647 μM and 6.385 μM against MDA-MB-231 and 6.239
GI50 value of 4.647 µM and 6.385 µM against MDA-MB-231 and 6.239 µM and 6.392 µM μM and 6.392 μM against A549,
respectively
against A549,(Figure 14). These
respectively values
(Figure 14).exhibited by the exhibited
These values derivatives byaretheroughly
derivativestwo-fold
are
greater than
roughly that of
two-fold the parent
greater than compound
that of the Brevilin A (189) (GIBrevilin
parent compound 50 in MDA-MB-231
A (189) (GI=507.03 in
μM, A549 = 10.09
MDA-MB-231 = 7.03μM),µM,indicating
A549 = 10.09 potential of BA-9 (304)
µM), indicating and BA-10
potential of BA-9 (305)
(304)as and
promising
BA-10
(305) as promising
candidates for further candidates for further
development development
as cancer therapeuticsas cancer
[187]. therapeutics [187].
Figure 14. Structure of Brevilin A (189) derivatives

derivatives BA-9
BA-9 (304)
(304) and
and BA-10
BA-10 (305).
(305).
2.2.12. Chemistry of EM23 (188) and Brevilin A (189)

2.2.12. Chemistry of EM23 (188) and Brevilin A (189)
To the best of our knowledge, there are no reports elucidating total synthesis of
To the best of our knowledge, there are no reports elucidating total synthesis of EM23
EM23 (188) and Brevilin A (189) up-to-date. Semi-synthetic derivatives of Brevilin A
(188) and Brevilin A (189) up-to-date. Semi-synthetic derivatives of Brevilin A (189) were
(189) were prepared by Lee et al. [187]. Key intermediate BA-8 (306) was obtained via
prepared by Lee et al. [187]. Key intermediate BA-8 (306) was obtained via aldol reaction
between Brevilin A (189) and paraformaldehyde in the presence of sodium carbonate
(Scheme 67). Subsequently, C11-hydroxylmethyl of BA-8 (306) was actylated with p-nitro-
bezoyl chloride and methacrylic anhydride to yield BA-9 (304) and BA-10 (305), respec-
tively.
Int. J. Mol. Sci. 2021, 22, 1052 42 of 67
aldol reaction between Brevilin A (189) and paraformaldehyde in the presence of sodium
carbonate (Scheme 67). Subsequently, C11-hydroxylmethyl of BA-8 (306) was actylated
Int. J. Mol. Sci. 2021, 22, x FOR PEERwith
REVIEW
p-nitrobezoyl chloride and methacrylic anhydride to yield BA-9 (304) and BA-10 44 of 69
(305),
respectively.
Scheme 67.Synthesis
Scheme67. Synthesisof
ofBrevilin
BrevilinAA(11)
(11)derivatives 304and
derivatives304 305[187].
and305 [187].
2.3.Diacylglycerol
2.3. DiacylglycerolLactones
Lactones
Diacylglycerol
Diacylglycerol lactones
lactones (DAGLs)
(DAGLs) are synthetic
are synthetic lactones
lactones derivedderived from syn-1,2-diacyl-
from syn-1,2-diacylglycerol
glycerolwhich
(DAG), (DAG), is awhich
key lipidis asecond
key lipid secondthat
messenger messenger
binds tothat binds
the C1 to the
domain inC1
manydomain
regula-in
many
tory regulatory
proteins [188].proteins [188]. This
This lipophilic lipophilic
second messenger second
playsmessenger
a key roleplays a key
in signal role in sig-
transduction
nal transduction
pathways [14]. DAG pathways
especially [14].
actsDAG
as anespecially
endogenous actsactivator
as an endogenous
by binding activator
to the C1 by bind-
domain
ing
of to thekinase
protein C1 domainC (PKC).of protein kinase Cit(PKC).
Upon binding, Upon binding,
allosterically activates itthe
allosterically
enzyme in the activates
pres-
ence of phospholipid
the enzyme [189]. The
in the presence PKC family can
of phospholipid be classified
[189]. The PKCinto three
family canisoenzyme groups:
be classified into
conventional
three isoenzyme (α, βI, βII, and
groups: γ), novel (δ,(α,ε,βI,
conventional andand
η, βII, θ), and atypical
γ), novel (ζη,and
(δ, ε, andι/λ) [189].
θ), and Only
atypical
conventional and novel
(ζ and ι/λ) [189]. Onlyisoenzymes
conventional contain
and C1 regions.
novel PKC isoforms
isoenzymes contain constitute the most
C1 regions. PKC
prominent family of signaling
isoforms constitute proteins that
the most prominent control
family of cellular
signaling functions
proteinssuchthatas proliferation,
control cellular
survival,
functionsmotility,
such astumorigenesis,
proliferation,and metastasis
survival, [189]. tumorigenesis,
motility, Therefore, their andsignificance in patho-
metastasis [189].
genesis has driven much interest in the C1 domain as a therapeutic target
Therefore, their significance in pathogenesis has driven much interest in the C1 domain [189]. Furthermore,
implication of PKCs
as a therapeutic in a range
target [189]. of cancer in different
Furthermore, organsofincreases
implication PKCs initsapotential
range ofascancer
a thera-
in
peutic target [190–192], which eventually led to a thorough investigation on
different organs increases its potential as a therapeutic target [190–192], which eventually DAG-based small
molecule PKC modulators.
led to a thorough investigation on DAG-based small molecule PKC modulators.
2.3.1.
2.3.1.Biological
BiologicalActivities
Activitiesof
ofDiacylglycerol
DiacylglycerolLactones
Lactones
DAG binds to the C1 domain of PKC isoenzymes containing a cysteine-rich, zinc
DAG binds to the C1 domain of PKC isoenzymes containing a cysteine-rich, zinc fin-
finger-like motif [193]. However, competence between DAG and phorbol esters might
ger-like motif [193]. However, competence between DAG and phorbol esters might occur
occur because they share the same binding site. The binding affinity of phorbol esters
because they share the same binding site. The binding affinity of phorbol esters is higher
is higher than that of DAG by at least 3 orders of magnitude [14]. Upon binding of
than that of DAG by at least 3 orders of magnitude [14]. Upon binding of the phorbol
the phorbol esters, PKC activation bypasses the normal physiological signal-mediated
esters, PKC activation bypasses the normal physiological signal-mediated mechanism, in
mechanism, in which responses irrelevant to DAG could be activated [194]. To overcome
which responses irrelevant to DAG could be activated [194]. To overcome this challenge,
this challenge, the group of Blumberg and Marquez designed a series of structurally simple
the group of Blumberg and Marquez designed a series of structurally simple cyclic DAG-
cyclic DAG-based molecules to surpass the binding affinity of DAG to PKC [14]. They
based molecules to surpass the binding affinity of DAG to PKC [14]. They reasoned that
reasoned that the low binding affinity of DAG is caused by the flexible nature of the glycerol
the low binding affinity of DAG is caused by the flexible nature of the glycerol backbone
backbone and, therefore, giving it an entropy penalty by restricting the conformation would
and, therefore, giving it an entropy penalty by restricting the conformation would increase
increase the binding affinity towards PKC. With this rationale, Kang et al. obtained 4,4-
the binding affinity towards PKC.
disubstituted-γ-butyrolactone as anWith
idealthis rationale,
glycerol Kang[189].
template et al. obtained 4,4-disubsti-
Their extensive SAR
tuted-γ-butyrolactone
studies as an ideal glycerol
based on pharmacophore-guided templateguided
and receptor [189]. approaches
Their extensive SARnotable
provided studies
based ontopharmacophore-guided andfrom
receptor
DAGguided
(307, Kapproaches provided notable find-
findings increase binding affinity i ≈ 1 µM) through cyclization to
ings to increase binding affinity from DAG (307, Ki ≈ 1 μM) through cyclization to the
the structurally constrained 5-tetradecanoyl DAG-lactone (308, Ki ≈ 138 nM), shifting of
structurally constrained 5-tetradecanoyl DAG-lactone (308, Ki ≈ 138 nM), shifting of the
hydrophobic alkyl chain from the 5-acyl to the 3-alkylidene position (309, Ki ≈ 30 nM), and
incorporating highly branched alkyl chain (310, Ki ≈ 2.9 nM) (Figure 15).
Int. J. Mol. Sci. 2021, 22, 1052 43 of 67
Int. J. Mol. Sci. 2021, 22, x FOR PEER the hydrophobic

REVIEW 45 of 69(309, Ki ≈ 30 nM),
alkyl chain from the 5-acyl to the 3-alkylidene position
and incorporating highly branched alkyl chain (310, Ki ≈ 2.9 nM) (Figure 15).
Figure 15.
Figure 15.
Figure 15. DAG-Lactones
DAG-Lactones asligands
as PKCas
DAG-Lactones PKC [189].
PKC ligands [189].
ligands [189].
Moreover, the authors envisioned that an additional conformational restriction of the restriction of the
Moreover, the the authors
authors envisioned
envisioned that
thatanan additional
additional conformational
conformational restriction of
remaining 5-acyl group would achieve further enhancement in binding activity [189]. To
remaining
the remaining 5-acyl group
5-acyl would
group would achieve
achieve further enhancement
further enhancement
this end, macrocyclization strategy to link the two terminal alkyl ends of the 5-acyl
in binding
inand
binding
3-
activity [189].
activity To
[189].
this
To end,
this macrocyclization
end, macrocyclization strategy to
strategy link
to the
link two
the terminal
two alkyl
terminal
alkylidene groups was used. They expected that this strategy would allow the ester to ends
alkyl of the
ends 5-acyl
of the and
5-acyl3-
alkylidene
and groups
adopt3-alkylidene
the preferred wasconfiguration
groups
S-trans used. They
was used. expected
forThey that than
expected
ring sizes greater thisten,
that strategy
this would
asstrategy
well as would
render- allow thethe
allow ester to
ester
ing adopt
to the physicochemical
adopt thethe
preferred
preferredproperties
S-trans of the
S-trans ligand suitable
configuration
configuration asfor
for ringdrug candidates
sizes
ring sizes [189].
greater than
greaterAmong
ten,
than as ten,
wellas as well
render-
as
synthesized macrocyclic DAG-bis-lactones evaluated, compound 311 exhibited in Ki value
ing the physicochemical
rendering the physicochemicalproperties of the ligand
properties of thesuitable as drug as
ligand suitable
of 6.07 nM against PKCα (Figure 16). In addition, the molecular docking study of 311 with
candidates [189]. Among
drug candidates [189].
Among
synthesizedsynthesized
PKCα suggests macrocyclic macrocyclic 311DAG-bis-lactones
DAG-bis-lactones
that the macrolactone exclusivelyevaluated, evaluated,
binds in the compound compound
sn-1 binding to 311 exhibited
311 exhibited
mode in
in Ki value
K
of value
i 6.07
the nMof against
C1b domain 6.07 nMprotein
of the against
PKC PKCα16).
(Figure
α [189]. (Figure 16). In addition,
In addition, the molecular the molecular docking
docking study study
of 311 of
with
PKCwith
311 PKCα that
α suggests suggests that the macrolactone
the macrolactone 311 exclusively
311 exclusively binds
binds in the in binding
sn-1 the sn-1 mode
binding
to
mode
the C1bto domain
the C1b of
domain of the[189].
the protein protein [189].
Figure 16. Structure of macrocyclic DAG-bis-lactones 311 [189].
Kang et al. synthesized and investigated a series of DAG-lactones with polar 3-alkyli-
dene substituents as PKCα and antitumor agents (Figure 17). The structure-activity rela-
tionships revealed that compounds 312, 313, and 314 with an ether side chain have high
binding affinities (Ki = 3–5 nM) and excellent antitumor effects on colon cancer (Colo205,
16.
GI50 = 0.120–0.260
Figure μg/mL)
Structure of
of macrocyclic
and leukemiaDAG-bis-lactones
macrocyclic DAG-bis-lactones 311 [189].
cancer (K562, GI50 = 311
0.140–0.200
[189]. μg/mL) cell lines
[195].
Kang
Kang etetal.
al.synthesized
synthesized and
and investigated
investigated a series
a series of DAG-lactones
of DAG-lactones with 3-alkyli-
with polar polar 3-
alkylidene substituents as PKCα and antitumor agents (Figure 17). The structure-activity
dene substituents as PKCα and antitumor agents (Figure 17). The structure-activity rela-
relationships revealed
tionships revealed thatthat compounds
compounds 312,
312, 313,
313, and314
and withan
314with anether
etherside
side chain
chain have
have high
high
GI50 = 0.120–0.260 µg/mL) and leukemia cancer (K562, GI50 = 0.140–0.200 µg/mL) cell
GI50 = 0.120–0.260 μg/mL) and leukemia cancer (K562, GI50 = 0.140–0.200 μg/mL) cell lines
lines [195].
[195].
Int. J. Mol. Sci. 2021, 22, 1052 44 of 67
Figure 17. Structure of DAG-lactones with polar 3-alkylidene chain (312–314) [195].
Figure 17. Structure of
of DAG-lactones
DAG-lactones with
with polar
polar 3-alkylidene
3-alkylidene chain
chain (312–314)
(312–314) [195].
[195].
Individual PKC isotypes show different patterns of tissue distribution, subcellular
Individual
Individual PKC
PKC isotypes
isotypes show
show different patterns of
of tissue
tissue distribution, subcellular
localization, substrate specificity, anddifferent
biologicalpatterns
functions [196,197].distribution,
Consequently, subcellular
it is an
localization,
localization, substrate
substrate specificity,
specificity,PKCand biological
and isotypes
biological functions [196,197]. Consequently, it is an
important issue to discriminate tofunctions
avoid an[196,197].
undesiredConsequently,
effect. Ann etital.is fo-
an
important
important issue to
issue to discriminate
discriminatePKC PKCisotypes
isotypestotoavoid avoidanan undesired
undesired effect.
effect. Ann Ann
et et fo-
al. al.
cused on protein kinase C epsilon (PKCε), a calcium-independent but phorbol ester/di-
focused
cused on protein
on protein kinase
kinasePKC C epsilon
C epsilon (PKCε), (PKCε), a calcium-independent
a calcium-independent but phorbol
but phorbolexpressed es-
ester/di-
acylglycerol dependent
ter/diacylglycerol dependentisotype [198]. PKCε,
PKC isotype along with
[198]. PKCε, alongother withfrequently
other frequently ex-
acylglycerol
PKCs (PKCα dependent PKC isotype [198]. PKCε, along with other frequently expressed
pressed PKCsand PKCδ),
(PKCα andisPKCδ),
reported to triggerto
is reported mitogenic/tumor
trigger mitogenic/tumorpromotingpromoting
or conversely or
PKCs (PKCα and PKCδ), is reported to trigger mitogenic/tumor promoting or conversely
conversely anti-mitogenic/tumor suppressor responses [14]. They have identified(315)
anti-mitogenic/tumor suppressor responses [14]. They have identified AJH-836 (Fig-
AJH-836
anti-mitogenic/tumor
ure 18), which thesuppressor responses [14]. They
withhave identified AJH-836alkyl (315) (Fig-
(315) (Figure 18),has
which sn-2
has thecarbonyl substituted
sn-2 carbonyl substituted a with
saturated-branched
a saturated-branched chain alkyl
ure 18),
with an which has
E-conformation, the sn-2 carbonyl
as a selective substituted
ligand ligand with
for PKCε a saturated-branched alkyl chain
chain with an E-conformation, as a selective for (K i of PKCα = 46 nM, Ki of PKCε
PKCε (Ki of PKCα = 46 nM, Ki of=
with an E-conformation,
1.43 nM). Moreover, as a selective
it should be noted ligand for PKCε (Ki ofwas PKCα = 46 nM, Ki of PKCε
in the=
PKCε = 1.43 nM). Moreover, it should be that
noted thethat
selectivity
the selectivity further enhanced
was further enhanced
1.43 nM).
nuclear Moreover,
membrane it should
conditions, be noted
indicating that the
strengthenedselectivity was
interactions further enhanced
between the in the
DAG-lac-
in the nuclear membrane conditions, indicating strengthened interactions between the
nuclear membrane
tone side chain conditions, indicating strengthened interactions between the DAG-lac-
DAG-lactone sideand theand
chain protein-membrane
the protein-membrane interface [198]. [198].
interface With With
the help of chemically
the help of chemi-
tone side DAG-lactone,
modified chain and theAJH-836 protein-membrane
(315),(315), interface
additional [198].
efforts were With
madethetohelp of chemically
cally modified DAG-lactone, AJH-836 additional efforts were madehighlight the the
to highlight im-
modified DAG-lactone,
portance of PKCs in the AJH-836 (315),
transcriptional additional
gene efforts
regulation were
in lung made
cancer to highlight
cellscells
[199]. the
Authorsim-
importance of PKCs in the transcriptional gene regulation in lung cancer [199]. Au-
portance
have added of PKCs
that thein the transcriptional
discovery gene
of selective regulation
C1 domain in
ligandslung cancer
may lead cells [199]. Authors
thors have added that the discovery of selective C1 domain ligands may to
leadpromising
to promisingther-
have
apeuticadded
leads
therapeutic that
andthe
leads and discovery
pharmacological of selective
pharmacological tools for
tools C1 domain
identifying
for ligands
identifying may lead to promising
pathophysiological
pathophysiological mechanism
mechanism ther-
of
apeutic
diseases leads
[199].
of diseases [199].and pharmacological tools for identifying pathophysiological mechanism of
diseases [199].
18. Structure of AJH-836

Figure 18. AJH-836 (315).
(315).
Figure 18. Structure of AJH-836 (315).
2.3.2.
2.3.2. Chemistry
Chemistry ofof Diacylglycerol
Diacylglycerol Lactones
Lactones
2.3.2.Synthesis
ChemistryofofDAG-bis-macrolactone
Diacylglycerol Lactones commenced with condensation reaction of γ-
Synthesis of DAG-bis-macrolactone commenced with condensation reaction of γ-lac-
lactone with aldehydes 317–320 to affordcommenced which werereaction
converted into
tone Synthesis of DAG-bis-macrolactone with condensation ofinto
γ-lac-
β-hydroxylactones,
with aldehydes 317–320 to afford β-hydroxylactones, which were converted 3-
3-alkylidene
tone with γ-lactone
aldehydes (321–327)
317–320 to as mixtures
afford of E/Z isomers
β-hydroxylactones, (Scheme
which were 68). With the
converted key
into 3-
alkylidene γ-lactone (321–327) as mixtures of E/Z isomers (Scheme 68). With the key in-
intermediate 328–334
alkylidene γ-lactone obtained over
(321–327)over 3 steps,
as mixtures macrolactonization was
of E/Z isomers (Scheme utilized according
68). Withaccording to
the key in-
termediate 328–334 obtained 3 steps, macrolactonization was utilized to
Keck and Boden’s
termediate 328–334 method to yield
obtained over 13,
3 17, 21,
steps, and 25-memberedwas
macrolactonization macrolactones
utilized (335–341),
according to
Keck and Boden’s method to yield 13, 17, 21, and 25-membered macrolactones (335–341),
respectively
Keck and [200]. Lastly,
Boden’s method benzyl
to group
yield 13, was
17, removed
21, and to provide macrolactones
25-membered the target macrolactones
(335–341),
respectively [200]. Lastly, benzyl group was removed to provide the target macrolactones
(311, [189].Lastly, benzyl group was removed to provide the target macrolactones
342–347)[200].
respectively
(311, 342–347) [189].
Due to high
(311, 342–347) [189]. lipophilicity of synthesized DAGLs, it was attempted to reduce the
lipophilicity by incorporating more polar side substituents in the 3-alkylidene chain. DAG-
lactones with polar 3-alkylidene chains were synthesized by alkylation of the protected
5,5-disubstituted γ-lactone with various polar side chains (Scheme 69) [195].
Int. J. Mol. Sci. 2021, 22, 1052 45 of 67
Scheme 68. Synthesis of DAG-bis-macrolactones [189]. Reagents and conditions: (a) (i) LiHMDS,
THF, −78 °C; (ii) RCHO (13–16); (b) (i) MsCl, NEt3, CH2Cl2; (ii) DBU, 45–52% in 2 steps; (c) DMAP,
DMAP/HCl, DCC, CH2Cl2, 60–70%; (d) BCl3, CH2Cl2, 80–92%.
Due to high lipophilicity of synthesized DAGLs, it was attempted to reduce the lip-
Scheme 68.by
ophilicity Synthesis
Synthesis of DAG-bis-macrolactones
of
incorporatingDAG-bis-macrolactones [189].Reagents
[189].
more polar side substituents Reagents andconditions:
inand
the conditions:
(a)(a)
3-alkylidene (i)(i) LiHMDS,
LiHMDS,
chain. DAG-
THF,
THF, −
−78
78 ◦ C;(ii)
°C; (ii) RCHO
RCHO (13–16);
(13–16); (b)
(b) (i)
(i) MsCl,
MsCl, NEt
NEt , ,CH
CH 2ClCl; (ii)
; DBU,
(ii) DBU,45–52%
45–52%in 2
in steps;
2 steps;(c) DMAP,
(c) DMAP,
lactones with polar 3-alkylidene chains were synthesized 33 2
2 2 by alkylation of the protected
DMAP/HCl, DCC,
DMAP/HCl, DCC, CH
5,5-disubstituted CH22ClCl2,2 ,60–70%;
γ-lactone 60–70%; (d)
(d)BCl
with variousBCl3,3polar
CH 2ClCl
, CH 2, 80–92%.
2 side2 , 80–92%.
chains (Scheme 69) [195].
Due to high lipophilicity of synthesized DAGLs, it was attempted to reduce the lip-
ophilicity by incorporating more polar side substituents in the 3-alkylidene chain. DAG-
lactones with polar 3-alkylidene chains were synthesized by alkylation of the protected
5,5-disubstituted γ-lactone with various polar side chains (Scheme 69) [195].
Scheme 69. 69. Synthesis

Synthesisof of
hydroxyl
hydroxyl andand ether DAG-lactone
ether analogs
DAG-lactone [195].[195].
analogs Reagents and conditions:
Reagents and con-
(a) CAN, (a)
ditions: CHCAN,
3CN–HCH2O, 0 °C;
CN–H (b) (CH
O, 0 3◦
) CCOCl,
3C; (b) Et
(CH 3N,
) DMAP,
CCOCl, CH
Et 2Cl2DMAP,
N, ; (c) LiHMDS,
CH CH
Cl ; 3(CH
(c) 2)12CHO
LiHMDS,
3 2 3 3 3 2 2
for
CH3350–351, RO(CH
(CH2 )12 CHO for2)nCHO
350–351,for 352–362,
RO(CH TrO(CH
)nCHO for 2)nCHO for 363–366, THF, −78 °C; (d) (i) MsCl,
352–362, TrO(CH )nCHO for 363–366, THF, −78
2 2
NEt 3, CH2Cl2, (ii) DBU; (e) BCl3, CH2Cl2, −78 °C; (f) CF3CO2H, CH
◦ C; (d) ◦ 2Cl2, 0 °C.
(i) MsCl, NEt , CH Cl , (ii) DBU; (e) BCl , CH Cl , −78 C; (f) CF CO H, CH Cl , 0 C. ◦
3 2 2 3 2 2 3 2 2 2
Scheme AJH-836
AJH-836 (315),
69. Synthesis aa PKCε
(315), of hydroxyl
PKCε selective DAG-lactone,
and ether
selective DAG-lactonewas
DAG-lactone, synthesized
analogs
was by
by Ann
[195]. Reagents
synthesized andet
Ann al.
al. [198].
etconditions:
[198].
(a) CAN,
The
The CH3CN–H
synthesis
synthesis 2O, 0with
started
started °C; (b)
with (CH3)3CCOCl, Et3N,(PMP)
p-methoxyphenyl
p-methoxyphenyl DMAP,and
(PMP) CHbenzyl
and Cl2; (c) LiHMDS,
2benzyl CH3(CHracemic
(Bn) protected
(Bn) protected 2)12CHO
racemic
for 350–351,
lactone RO(CH
(Scheme 2)nCHO for 352–362, TrO(CH2)nCHO for 363–366, THF, −78 °C; (d) (i) MsCl,
70). Aldehyde
lactone (Scheme 70). Aldehyde 368 368 was
was reacted
reacted with
with the
the 367 to form
367 to form olefin
olefin 369
369 via
via aldol
aldol
NEt 3, CH2Cl2, (ii) DBU; (e) BCl3, CH2Cl2, −78 °C; (f) CF3CO2H, CH2Cl2, 0 °C.
condensation. After removal of PMP protection, the intermediate 370 was reacted with
condensation. After removal of PMP protection, with
acyl chloride 371, followed by benzyl deprotection to afford afford the
the target
target molecule
molecule 315.
315.
AJH-836 (315), a PKCε selective DAG-lactone, was synthesized by Ann et al. [198].
The Diterpene
2.4. synthesisLactones
started with p-methoxyphenyl (PMP) and benzyl (Bn) protected racemic
lactone (Scheme 70). Aldehyde 368 was reacted with the 367 to form olefin 369 via aldol
Diterpenes are classes of natural products mostly originated from microbes or sec-
condensation. After removal of PMP protection, the intermediate 370 was reacted with
ondary metabolites of fungal sources. Diterpenes can be further classified into subdivisions
acyl chloride 371, followed by benzyl deprotection to afford the target molecule 315.
according to its structural feature (bicyclic, tricyclic, and tetracyclic diterpenes). This class
of compounds attracted researchers due to their potential biological activities including
anti-cancer, anti-oxidant, and anti-inflammatory effects [201,202].
Int. J. Mol. Sci. 2021, 22, 1052 46 of 67
Synthesisof
Scheme 70. Synthesis ofAJH-836
AJH-836(315).
(315).Reagents
Reagents and
and conditions:
conditions: (a).(a). (i) LiHMDS,
(i) LiHMDS, THF,THF, R2 CHO,
R2CHO, −78
− ◦ ◦
78(ii)C.MsCl,
°C. (ii) MsCl,CH2ClCH 2 Cl2 , DBU;
2, DBU; (b)
(b) BCl 3, BCl , CH
CH23Cl 2, −78 2, −
2 Cl°C or78CAN,
C orCH
CAN,
3CN/HCH23O;CN/H 2 O; (c)
(c) EDC, EDC, CH
DMAP, DMAP,
2Cl2,
r.t.;2(d)
CH Cl2BCl
, r.t.;3, (d)
CHBCl
2Cl2,,−78
3 CH°C 2 Clor 78 ◦ CCH
CAN,
2, − CN/H2CH
or 3CAN, O [198].
3 CN/H2 O [198].
2.4.1. Biological
2.4. Diterpene Activities of Andrographolide (373)
Lactones
Andrographolide
Diterpenes are classes (373)ofis natural
a simple bicyclic mostly
products labdaneoriginated
diterpenefromlactone belonging
microbes to
or sec-
the isoprenoid family of natural products and is a well-known
ondary metabolites of fungal sources. Diterpenes can be further classified into subdivi- medicinal plant, which has
been
sionswidely
according used toin
itsAsia [203]. feature
structural The lactone is isolated
(bicyclic, tricyclic,fromandthe leaves of Andro-
stem andditerpenes).
tetracyclic This
graphis paniculata (Burm.f.) Nees, also known as King of Bitters.
class of compounds attracted researchers due to their potential biological activities [204]. The characteristic
includ-
structural features
ing anti-cancer, of andrographolide
anti-oxidant, (373) include: α,β-unsaturated
and anti-inflammatory effects [201,202].γ-butyrolactone ring,
three hydroxy groups (at C-3, C-14, and C-19), and two olefin bonds (∆8(17) and ∆12(13) ).
Biological responses
2.4.1. Biological elicited
Activities of by andrographolide
Andrographolide (373) is mainly due to its ability to form
(373)
H-bonds with biological substrates by utilizing the hydroxyl group [205]. Andrographolide
Andrographolide (373) is a simple bicyclic labdane diterpene lactone belonging to
(373) having potent cytotoxic effects against various cancer cells, it has been reported that
the isoprenoid
andrographolide family
(373)ofexerts
naturaltheproducts
anti-cancerandeffects
is a well-known
by modulating medicinal
several plant, which has
cancer-related
pathways and proteins including JNK-signaling pathway, NF-κB and PI3K signalingofpath-
been widely used in Asia [203]. The lactone is isolated from the stem and leaves An-
drographis paniculata (Burm.f.) Nees, also known as King of Bitters.
way, cyclins and cyclin-dependent kinases (CDKs), metalloproteinases (MMPs) and tumor [204]. The characteristic
structural features
suppressor proteins of (p53andrographolide
and p21) [206]. (373) include: α,β-unsaturated γ-butyrolactone
ring,Dai
threeethydroxy groups (atthat
al. demonstrated C-3,andrographolide
C-14, and C-19), (373) and two olefin proliferation
prevents bonds (Δ8(17) and Δ12(13)).
of human
Biological
gastric responses
cancer cell line elicited
SGC-7901by andrographolide
by blocking cell(373) cycleisprogression,
mainly due promoting
to its abilityintrinsic
to form
H-bonds with biological substrates by utilizing the hydroxyl
apoptosis, and/or repressing invasive activity [207]. Upon increasing concentrations group [205]. Andro- of
grapholide (373) having potent cytotoxic effects against various
andrographolide (373) (10, 20, and 40 µg/mL), cell-cycle inhibitory proteins (cyclin cancer cells, it has been
B1
reported
and CDC2) thatandandrographolide
proapoptotic protein (373) exerts
(Bax) the
were anti-cancer
upregulated effects
andby modulating protein
antiapoptotic several
cancer-related
(Bcl-2) pathways and[207].
was downregulated proteins including JNK-signaling
19-triisopropyl andrographanolidepathway, NF-κB
(374), and PI3K
an analogue
signaling
of pathway, cyclins
androgrphanolide and cyclin-dependent
(373), showed potent cytotoxickinases activity(CDKs),
against metalloproteinases
gastric cancer cell
(MMPs)
lines withanda GI tumor
50 valuesuppressor
of 6.3 µMproteins
and 1.6 (p53
µM forandMKN-45
p21) [206].and AGS cell lines, respectively
Dai et al. demonstrated that andrographolide
(Figure 19). On the other hand, the parent andrographanolide (373) prevents proliferation
(373) is shown of to human
be less
gastric cancer cell line SGC-7901 by blocking cell cycle
potent than the analog (374) with the GI50 values of >50 µM in MKN-45 and 11.3 progression, promoting intrinsic
µM in
apoptosis,
AGS and/or
cell lines [208].repressing invasive activity [207]. Upon increasing concentrations of
andrographolide
Andrographanolide (373) (10,(373)
20, and 40 μg/mL),
is also found tocell-cycle
suppressinhibitory proteins (cyclin
tumor proliferation B1 and
in prostate
CDC2)cells
cancer and by proapoptotic
modulatingprotein (Bax) werecytokines
proimflammatory upregulated and antiapoptotic
(interleukin (IL)-6) andprotein (Bcl-
chemokines
2) was downregulated
(CXCl11, CXCR3, and CXCR7) [207]. 19-triisopropyl
[209]. Moreover, andrographanolide
administration of (374), an analogue of
andrographanolide an-
(373)
drogrphanolide
to DU145 (prostate (373),
cancershowed potent cytotoxic
cell)-xenografted mice activity
delayed against gastric without
tumor growth cancer cell lines
obvious
with a GI
toxicity 50 value
[210]. SRJ23of 6.3 μManother
(375), and 1.6 μM for MKN-45 and(373)
andrographanolide AGSanalog,
cell lines,
was respectively
synthesized (Fig-
to
improve
ure 19). On thetheantitumor
other hand, activity of the parent
the parent compound (373)
andrographanolide against
(373) is shown prostate
to be cancer cell
less potent
lines (Figure
than the analog 19).(374)
SRJ23 with(375)
theselectively
GI50 valuesinhibited
of >50 μM a prostate
in MKN-45 cancer
and cell
11.3(PCa)
μM inwith
AGSa cell
50-
fold
linesimproved
[208]. GI50 (0.4 µM) than that of the parent compound andrographanolide (373)
(GI50 = 19.95 µM) [211].
able to suppress cancer cell proliferation by downregulating the levels of NF-κB protein
and inhibiting p65 DNA binding activity at a concentration of 5 μM [217].
Despite various antitumor activities of andrographanolide (373), poor solubility and
relatively low potency still remained to be the main hurdles for further advancement into
Int. J. Mol. Sci. 2021, 22, 1052 clinical development. To overcome this challenge, more efforts in modification and47opti-
of 67
mization of the chemical structures would be needed.
Figure 19. Structure of andrographolide analogs.
2.4.2.Colorectal
Chemistrycancer is a frequently (373)
of Andrographolide diagnosed solid tumor. The main issue in this can-
cer is the high recurrence rate caused by acquired resistance to chemotherapies such as
Gao et al. reported the first total synthesis of (−)-andrographolide (373) via biomi-
5-fluorouracil (5-FU) and cisplatin [212,213]. In a study conducted by Wang et al. [212], an-
metic cyclization approach, in which an epoxy homoiodo allylsilane precursor (381) was
drographanolide (373), when treated to 5-FU-resistant colorectal cancer cell line (HCT116/5-
utilized [218]. The synthesis commenced with geraniol 377, which was readily converted
FUR), synergistically enhanced 5-FU-induced apoptosis. This suggests that andrographano-
to epoxide 378 in 79% yield over 5 steps (Scheme 71). For the efficient preparation of the
lide (373) could reverse chemotherapy resistance and act as a sensitizing agent in colorectal
key precursor 381, authors optimized the protocol based on their previous protocol, which
cancer Moreover, the clinical relevance of andrographanolide (373) in combination with
includes 3 reaction steps [219]. Cyclopropyl ketone (378) underwent chemoselective 1,2-
capecitabine is being investigated, which initiated a clinical trial in 2014 [214].
addition with (phenyldimethylsilyl)methylcerium chloride to afford cyclopropyl carbinol
Another type of cancer highly related to poor prognosis and high recurrence rate is
(379), which, upon exposed to MgI2, provided intermediate 380 as a crude mixture. Next,
non-small-cell lung cancer (NSCLC). Andrographanolide (373) showed synergistic antitu-
the resulting crude intermediate 380 was briefly treated with K2CO3 in methanol to give
mor activity with chemotherapeutic agents cisplatin and paclitaxel, although the molecular
mechanism behind this synergism is still unclear [215,216]. Lim et al. reported an an-
drographanolide (373) analog, 3,14,19-tripropionylandrographolide (SRS06, 376), which
shows a distinct inhibitory activity against A549 NSCLC cell line. SRS06 (376) was able
to suppress cancer cell proliferation by downregulating the levels of NF-κB protein and
inhibiting p65 DNA binding activity at a concentration of 5 µM [217].
Despite various antitumor activities of andrographanolide (373), poor solubility and
relatively low potency still remained to be the main hurdles for further advancement
into clinical development. To overcome this challenge, more efforts in modification and
optimization of the chemical structures would be needed.
2.4.2. Chemistry of Andrographolide (373)

Gao et al. reported the first total synthesis of (−)-andrographolide (373) via biomimetic
cyclization approach, in which an epoxy homoiodo allylsilane precursor (381) was uti-
lized [218]. The synthesis commenced with geraniol 377, which was readily converted
to epoxide 378 in 79% yield over 5 steps (Scheme 71). For the efficient preparation of the
key precursor 381, authors optimized the protocol based on their previous protocol, which
includes 3 reaction steps [219]. Cyclopropyl ketone (378) underwent chemoselective 1,2-
addition with (phenyldimethylsilyl)methylcerium chloride to afford cyclopropyl carbinol
(379), which, upon exposed to MgI2 , provided intermediate 380 as a crude mixture. Next,
the resulting crude intermediate 380 was briefly treated with K2 CO3 in methanol to give
the key intermediate 381. Moreover, the authors found out that reaction temperature is
critical for Julia-type cyclopropane ring-opening of 379 [218].
The key reaction step utilized in this study is the biomimetic cation-olefin annula-
tion of epoxy homoiodo allylsilane precursor 381 to form bicyclic iodide 382 (Scheme 72).
By using the optimized cyclization condition (SnCl4 in CH2 Cl2 at −40 ◦ C), bicyclic iodide
382 was furnished as a mixture of C9 epimers (α/β 0.7:1). Subsequently, bicyclic iodide
382 was converted to bicyclic aldehyde 383 over 4 steps, which underwent aldol conden-
sation with the corresponding lithium enolate of (S)-(−)-β-hydroxy butyrolactone (384)
to give dihydroxy lactone 385 as a mixture of C-12 epimers. Compound 385 was then
selectively O-silyated via the mesylate intermediate to provide E-configurated lactone 386
Int. J. Mol. Sci. 2021, 22, 1052 48 of 67
in a regio- and stereoselective manner [218]. Lastly, desilylation and acetonide cleavage
of
the386 provided
key (−)-andrographolide
intermediate (373),
381. Moreover, the whichfound
authors was spectroscopically
out that reactionidentical to the
temperature is
natural andrographolide
critical for [220].
Julia-type cyclopropane ring-opening of 379 [218].
Scheme 71. Synthesis of key intermediate 381 [218]. Reagents and conditions: (a). (i)
PhMe2SiCH2MgCl, CeCl3, THF, 0 °C–23 °C; (ii) 2.5 equiv MgI2·(OEt2)n (0.25 M in Et2O/PhH (1:1)),
PhH, 50 °C, 15 min; (iii) K2CO3, MeOH, 23 °C, 65%.
The key reaction step utilized in this study is the biomimetic cation-olefin annulation
of epoxy homoiodo allylsilane precursor 381 to form bicyclic iodide 382 (Scheme 72). By
using the optimized cyclization condition (SnCl4 in CH2Cl2 at −40 °C), bicyclic iodide 382
was furnished as a mixture of C9 epimers (α/β 0.7:1). Subsequently, bicyclic iodide 382 was
converted to bicyclic aldehyde 383 over 4 steps, which underwent aldol condensation with
the corresponding lithium enolate of (S)-(−)-β-hydroxy butyrolactone (384) to give dihy-
droxy lactone 385 as a mixture of C-12 epimers. Compound 385 was then selectively O-
silyated via the mesylate intermediate to provide E-configurated lactone 386 in a regio-
Scheme
Scheme
and 71.Synthesis
71.
stereoselective of
Synthesis keyofintermediate
manner key 381 [218].
intermediate
[218]. Lastly, Reagents
381 [218].
desilylation and conditions:
Reagents
and acetonide (a).cleavage
and (i)conditions:
PhMe2of SiCH 2 MgCl,
(a).
386 (i)
pro-
PhMe
CeCl ,2 SiCH
THF, 0
2 ◦ C–23CeCl
MgCl, ◦ C; (ii)
3 , THF,
2.5 0 °C–23
equiv MgI °C;
· (ii)
(OEt 2.5
)n equiv
(0.25 MMgI
in Et
2 ·
(OEt
O/PhH
2 )n (0.25
(1:1)),M in
PhH,Et50
2 ◦ C, 15(1:1)),
O/PhH min;
vided 3 (−)-andrographolide (373), which 2 was 2 spectroscopically2 identical to the natural an-
PhH,
(iii) K250
CO°C, 15 min;23 ◦ K2CO3, MeOH, 23 °C, 65%.
(iii)
drographolide 3 , MeOH, [220]. C, 65%.
The key reaction step utilized in this study is the biomimetic cation-olefin annulation
of epoxy homoiodo allylsilane precursor 381 to form bicyclic iodide 382 (Scheme 72). By
using the optimized cyclization condition (SnCl4 in CH2Cl2 at −40 °C), bicyclic iodide 382
was furnished as a mixture of C9 epimers (α/β 0.7:1). Subsequently, bicyclic iodide 382 was
converted to bicyclic aldehyde 383 over 4 steps, which underwent aldol condensation with
the corresponding lithium enolate of (S)-(−)-β-hydroxy butyrolactone (384) to give dihy-
droxy lactone 385 as a mixture of C-12 epimers. Compound 385 was then selectively O-
silyated via the mesylate intermediate to provide E-configurated lactone 386 in a regio-
and stereoselective manner [218]. Lastly, desilylation and acetonide cleavage of 386 pro-
vided (−)-andrographolide (373), which was spectroscopically identical to the natural an-
drographolide [220].
Scheme 72. 72.Synthesis

Synthesisof ofandrographolide
andrographolide (373). Reagents
(373). and conditions:
Reagents (a) 2.0 equiv
and conditions: (a) 2.0SnCl 4 , CH
equiv 2 Cl24,
SnCl
CH
− 402Cl◦ C,
2, ca.
−401 °C,
min.;ca.(b)11.6
min.;
equiv(b)(S)-(
1.6−)-β-hydroxy-γ-butyrolactone,
equiv (S)-(−)-β-hydroxy-γ-butyrolactone,
3.2 equiv LDA, 3.2 THF/HMPA
equiv LDA,
THF/HMPA
(4:1), −78 ◦ C–30(4:1), −78
◦ C, 64%°C–30
(80%°C, 64%(c)
brsm); (80% brsm);
TBSCl, (c) TBSCl,
imidazole, imidazole,
DMF, DMF,
23 ◦ C, 76%; (d)23 °C, 76%;
MsCl, Et3 N,(d)
CHMsCl,
2 Cl2 ,
Et 3N,◦ CH 2◦Cl2, −78 °C–0 °C, 1 h; then iPr2NEt, ◦ CH 2Cl2, 23 °C, 55%; (e) ◦ TBAF, THF,
−78 C–0 C, 1 h; then iPr2 NEt, CH2 Cl2 , 23 C, 55%; (e) TBAF, THF, 23 C, 57%; (f) HOAc/H2 O (7:3), 23 °C, 57%; (f)
HOAc/H
◦ 2O (7:3), 23 °C, 89% [218].
23 C, 89% [218].
A more concise and convergent enantioselective total synthesis of andrographolide

was recently reported by Yang et al. [221]. Key transformations utilized in the synthesis
include: (1) formation of quaternary C4 stereocenter via iridium-catalyzed carbonyl re-
ductive coupling, (2) establishment of the trans-decaline skeleton via diastereoselective
alkene reduction, and (3) installation of the α-alkylidene-β-hydroxy-γ-butyrolactone via
carbonylative lactonizaition. The synthesis began with preparation of acetonide 389, which
Scheme
was 72. Synthesis
achieved of andrographolide
via a 6-step (373).73).
reaction (Scheme Reagents and conditions:
The authors predicted (a)that
2.0 equiv SnCl4,
389 would
CH Cl , −40 °C, ca. 1 min.; (b) 1.6 equiv (S)-(−)-β-hydroxy-γ-butyrolactone, 3.2
undergo cycloaddition diastereoselectively from the convex face of the bicycle. As expected,
2 2 equiv LDA,
THF/HMPA (4:1), −78 °C–30 °C, 64% (80% brsm); (c) TBSCl, imidazole, DMF,
cycloadduct 390 was obtained as a single stereoisomer from Diels–Alder cycloaddition23 °C, 76%; (d) MsCl,
Et3389
of N, CH 2Cl2, −78 °C–0 °C, 1 h; then iPr2NEt, CH2Cl2, 23 °C, 55%; (e) TBAF, THF, 23 °C, 57%; (f)
with dimethylacetylene dicarboxylate (DMAD) [221]. For the construction of the
HOAc/H2O (7:3), 23 °C, 89% [218].
alkene reduction, and (3) installation of the α-alkylidene-β-hydroxy-γ-butyrolactone via
carbonylative lactonizaition. The synthesis began with preparation of acetonide 389,
which was achieved via a 6-step reaction (Scheme 73). The authors predicted that 389
would undergo cycloaddition diastereoselectively from the convex face of the bicycle. As
Int. J. Mol. Sci. 2021, 22, 1052 expected, cycloadduct 390 was obtained as a single stereoisomer from Diels–Alder 49 ofcy-
67
cloaddition of 389 with dimethylacetylene dicarboxylate (DMAD) [221]. For the construc-
tion of the trans-decalin ring, manganese-catalyzed hydrogen atom transfer (HAT) was
chosen because
trans-decalin it enables
ring, diastereselective
manganese-catalyzed hydrogenation
hydrogen of the (HAT)
atom transfer targeted alkene
was [222].
chosen be-
However, HAT reduction
cause it enables of cycloadduct
diastereselective 390 exclusively
hydrogenation provided
of the targeted the cis-decalin
alkene 391 in-
[222]. However,
HAT reduction of cycloadduct 390 exclusively provided the cis-decalin 391 instead.
stead.
Scheme 73. Synthesis of cis-Decalin 391 [221].
This result
This result is
is presumably
presumably duedue toto conformational
conformational constraint
constraint caused
caused by
by the
the acetonide
acetonide
moiety, as diol 392 smoothly underwent HAT reduction to afford trans-decalin
moiety, as diol 392 smoothly underwent HAT reduction to afford trans-decalin (393) (393)asasa
single diastereomer [221], which subsequently converted to iodide 394 over 44 steps
a single diastereomer [221], which subsequently converted to iodide 394 over steps
(Scheme
(Scheme 74).74). The
Theauthors
authorsfound
foundinstallation of of
installation thethe
α-alkylidene-β-hydroxy-γ-butyrolactone
α-alkylidene-β-hydroxy-γ-butyrolac-
especially
tone challenging
especially because
challenging of competing
because elimination
of competing to form
elimination diene
to form by-products
diene by-products or
halide reduction. Pleasingly, diol 395 was obtained in 54% yield via chemoselective
or halide reduction. Pleasingly, diol 395 was obtained in 54% yield via chemoselective cross-
coupling at the terminal
cross-coupling vinyl bromide
at the terminal upon treatment
vinyl bromide with 2-thienyl(cyano)copper
upon treatment lithium
with 2-thienyl(cyano)copper
followedfollowed
lithium by exposure to vinyltobromide
by exposure 396. Lastly,
vinyl bromide bromoalcohol
396. Lastly, bromoalcohol395 underwent
395 underwent car-
bonylative lactonization to furnish α-methylene-β-hydroxy-γ-butyrolactone, which upon
carbonylative lactonization to furnish α-methylene-β-hydroxy-γ-butyrolactone, which
removal of the triisopropylsilyl ethers provided the target compound andrographolide
upon removal of the triisopropylsilyl ethers provided the target compound andro-
Int. J. Mol. Sci. 2021, 22, x FOR
(373). PEER REVIEW
Moreover, it is noteworthy that the described route accomplished the synthesis of an- 52 of
grapholide (373). Moreover, it is noteworthy that the described route accomplished the
drographolide (373) in 14 steps, which is 10 steps lesser than the previous report [218,221].
synthesis of andrographolide (373) in 14 steps, which is 10 steps lesser than the previous
report [218,221].
Scheme 74. Synthesis of andrographolide

Scheme 74. Synthesis(373) [221].
of andrographolide (373) [221].
2.4.3. Anti-Cancer
2.4.3.Activities of Nagilactones
Anti-Cancer Activities of Nagilactones
Nagilactones belong to the group to
Nagilactones belong of the
bioactive
group terpenoids, which was which
of bioactive terpenoids, first isolated
was first isolate
from the evergreen Podocarpus nagi
from the evergreen tree, Podocarpus nagi (Tunb.) Zoll. et Moritz in 1960s
tree, (Tunb.) Zoll. et Moritz in the late the late[223].
1960s [223]. T
To date, a number
date,ofanagilactones, assigned from
number of nagilactones, A to L,
assigned have
from A been
to L, isolated
have been from various
isolated from variou
Podocarpus species [16]. Among
Podocarpus speciesthose, only nagilactone
[16]. Among those, onlyCnagilactone
(397), E (398), F (399),
C (397), andFG(399),
E (398), (400)and G (40
are known to exhibit anticancer
are known activities
to exhibit (Figure
anticancer 20). (Figure 20).
activities
2.4.3. Anti-Cancer Activities of Nagilactones
Nagilactones belong to the group of bioactive terpenoids, which was first isolated
from the evergreen tree, Podocarpus nagi (Tunb.) Zoll. et Moritz in the late 1960s [223]. To
date, a number of nagilactones, assigned from A to L, have been isolated from various
Int. J. Mol. Sci. 2021, 22, 1052 Podocarpus species [16]. Among those, only nagilactone C (397), E (398), F (399), and G
50(400)
of 67
are known to exhibit anticancer activities (Figure 20).
Figure 20.
Figure 20. Structures
Structures of
of Nagilactone
Nagilactone C,
C, E-G
E-G(397–400).
(397–400).
In
Inthethestudy
studyconducted
conductedby byQiQietet
al.,al.,
nagilactone
nagilactoneC (397)
C (397)showed
showed potent antiproliferative
potent antiprolifera-
activity against cancer cell lines such as MDA-MB-231, AGS (gastric
tive activity against cancer cell lines such as MDA-MB-231, AGS (gastric cancer), cancer), and Hela cell
and Hela
lines, with a GI value of 2–5 mM, whereas nagilactone F (399) and
cell lines, with a50GI50 value of 2–5 mM, whereas nagilactone F (399) and G (400) displayed G (400) displayed
even more potent
even more potent activity
activitythan
thannagilactone
nagilactoneC C (397)
(397) against
against thethe
samesame cancer
cancer cell lines
cell lines (IC50
(IC ≈ 1 mM)
≈ 150mM) [224].[224]. In another
In another study,study, nagilactones
nagilactones were reported
were reported to possess
to possess cytotoxiccytotoxic
effects
effects
againstagainst P-388 leukemia
P-388 leukemia cells (GI
cells in vitro in vitro (GI50 of nagilactone
50 of nagilactone G (400) ≈ 0.25 mM≈
G (400) 0.25
and mM and
nagilactone
nagilactone E (398) = 0.25 mg/mL) [225]. Moreover, in a recent study,
E (398) = 0.25 mg/mL) [225]. Moreover, in a recent study, nagilactone E (398) was found to nagilactone E
(398) was found to dose-dependently reduce the growth of
dose-dependently reduce the growth of human NSCLC cells A549 and NIC-H1975, with human NSCLC cells A549
and NIC-H1975,
a GI50 value of 5.2with a GIμM,
and 3.6 50 value of 5.2 and
respectively 3.6Although
[226]. µM, respectively [226].
there is still Although
scarce there
information
is still scarce information regarding efficacy of nagilactones in vivo,
regarding efficacy of nagilactones in vivo, Guo et al. lately demonstrated in vivo efficacy Guo et al. lately
demonstrated
of nagilactonein vivo efficacy
E (398) in an A549of nagilactone
cell lung cancer E (398) in an A549
xenograft mousecellmodel
lung cancer
[227]. xenograft
The intra-
mouse
peritoneal model [227].ofThe
injection intraperitoneal
10 mg/kg/d nagilactone injection of suppressed
E (398) 10 mg/kg/d nagilactone
tumor growth E by(398)
62%
suppressed tumor growth by 62% and inhibited tumor metastasis, without obvious toxicity.
and inhibited tumor metastasis, without obvious toxicity. Furthermore, the authors have
Furthermore, the authors have suggested RIOK2 as a potential target of nagilactone E
suggested RIOK2 as a potential target of nagilactone E (398) after carefully reviewing their
(398) after carefully reviewing their Kaplan–Meier analysis and molecular docking study
Kaplan–Meier analysis and molecular docking study results [227]. RIOK2 is an atypical
results [227]. RIOK2 is an atypical serine/threonine protein kinase related to the biogenesis
serine/threonine protein kinase related to the biogenesis of ribosome. Moreover, the ex-
of ribosome. Moreover, the expression level of RIOK2 is reported to be correlated with
pression level of RIOK2 is reported to be correlated with clinical outcome in NSCLC, in-
clinical outcome in NSCLC, indicating its clinical significance [228]. However, low solubility
dicating its clinical significance [228]. However, low solubility of nagilactone E (398) might
of nagilactone E (398) might prevent it from further development despite the potent
prevent it from further development despite the potent anticancer effects. Therefore, fu-
anticancer effects. Therefore, future works should focus on structural modification to
ture works should focus on structural modification to increase drug-like properties of
increase drug-like properties of nagilactones and, more importantly, further validation of
possible protein targets of nagilactones.
2.4.4. Chemistry of Nagilactones

Synthesis of nagilactone F (399) has been extensively studied in comparison to other
nagilactones, being only one among nagilatone series with an available recent report.
The first total synthesis of Nagilactone F (399) was reported by Hayashi et al. [229]. The syn-
thetic approach by the group started with (+)-podocarpic acid, stereochemistry of which
was already established, and structure of all intermediates formed during the course of
reaction was fully characterized by the authors (Scheme 75). (+)-podocarpic acid methyl
ether (401) was converted to the enolide (402) over 9 steps, which was treated with potas-
sium t-butoxide in DMSO to give a diene-carboxylic acid (403). The authors presumed
the configuration of the 8:14-double bond in 403 to be in more thermodynamically stable
“E” form because 403 was produced under an equilibrium condition [229]. The diene-
carboxylic acid (403) was irradiated with medium pressure mercury lamp in 95% ethanol
to afford 8:9-enolide (404) as a single product. The enolide (404) underwent bromination
with NBS and subsequent debromination with Zn in DMF to afford dienolide ester 405,
which was then hydrolyzed with conc. H2 SO4 to furnish a dienolide acid 406. The diene
acid 406 was treated with excess Pb(OAc)4 in benzene to produce a γ-lactone in 50% yield,
which was found out to be completely identical with natural nagilactone F (399) in IR and
1 H-nmr comparisons [229].
ford 8:9-enolide (404) as a single product. The enolide (404) underwent bromination with
NBS and subsequent debromination with Zn in DMF to afford dienolide ester 405, which
was then hydrolyzed with conc. H2SO4 to furnish a dienolide acid 406. The diene acid 406
was treated with excess Pb(OAc)4 in benzene to produce a γ-lactone in 50% yield, which
Int. J. Mol. Sci. 2021, 22, 1052 was found out to be completely identical with natural nagilactone F (399) in IR and
51 ofH-
1
67
nmr comparisons [229].
Scheme
Scheme 75. Totalsynthesis
75. Total synthesisofofnagilactone
nagilactoneF by F by Hayashi
Hayashi et al.
et al. [229].
[229]. Reagents
Reagents and and conditions:
conditions: (i) t-
(i) t-BuOK,
BuOK, DMSO; (j) hν; (k) NBS, CHCl3; (l) Zn, DMF; (m) H2SO4; (n) H2O; (O) Pb(OAc)4, hν.4 , hν.
DMSO; (j) hν; (k) NBS, CHCl 3 ; (l) Zn, DMF; (m) H 2 SO 4 ; (n) H2 O; (O) Pb(OAc)
Fascinatingly,
Fascinatingly,Hanessian
Hanessianetetal.
al.reported
reportedthe
theasymmetric
asymmetrictotal
totalsynthesis
synthesisofof
nagilactone
nagilactone F
from
F froma common
a commonprecursor, which
precursor, also provided
which accessaccess
also provided to CJ-14,445, LL-Z1271γ,
to CJ-14,445, and oidilo-
LL-Z1271γ, and
lactones A, B, C, and D (structures not shown) [230]. In this review, we will focus on the
oidilolactones A, B, C, and D (structures not shown) [230]. In this review, we will focus on
synthesis of nagilactone F from the intermediate 19. The important synthetic strategies
the synthesis of nagilactone F from the intermediate 19. The important synthetic strategies
employed by the authors to obtain a tricyclic lactone key intermediate 19 include: (1) a
employed by the authors to obtain a tricyclic lactone key intermediate 19 include: (1) a
Morita–Baylis–Hillman reaction, (2) a stereocontrolled bromolactonization reaction, and (3)
Morita–Baylis–Hillman reaction, (2) a stereocontrolled bromolactonization reaction, and
a catalytic Reformatsky-type reaction. According to the retrosynthetic analysis provided
(3) a catalytic Reformatsky-type reaction. According to the retrosynthetic analysis
Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 54 pro-
of 69
by the group, the tricyclic lactone skeleton was sequentially prepared via construction of
vided by the group, the tricyclic lactone skeleton was sequentially prepared via construc-
the AB podolactone ring, followed by the formation of D and C lactone ring (Figure 21).
tion of the AB podolactone ring, followed by the formation of D and C lactone ring (Figure
21).
Figure 21. Retrosynthetic analysis of
of nagilactone
nagilactone FF (399),
(399), CJ-14,445,
CJ-14,445, LL-Z1271γ,
LL-Z1271γ,Oidiolactones
OidiolactonesA-D
A-D
according to Hanessian et al. [230].
The AB
The AB ring
ring system
system was
was accomplished
accomplished as as aa single
single enantiomer
enantiomer from
from the
the readily
readily avail-
avail-
able Wieland-Miescher ketone (407) following the methods reported by Theodorakis and
Danishefsky groups
Danishefsky groups[231,232],
[231,232],which
whichledledtotothe fully
the functionalized
fully ABAB
functionalized ring of podolactone
ring of podolac-
(408)(408)
tone over over
9 steps (Scheme
9 steps 76). Next,
(Scheme with the
76). Next, withintermediate (408) in
the intermediate hand,
(408) construction
in hand, of
construc-
the D lactone ring across C-4 and C-6 was attempted. To achieve this, 408
tion of the D lactone ring across C-4 and C-6 was attempted. To achieve this, 408 under-underwent a
Morita–Baylis–Hillman reaction, utilizing formaldehyde and
went a Morita–Baylis–Hillman reaction, utilizing formaldehyde and dime-dimethylphenylphosphine,
to give 410 in excellenttoyield.
thylphenylphosphine, Based
give 410 on the reaction
in excellent sequence
yield. Based developed
on the reactionby Welch and
sequence de-
co-workers [233], obtained 410 was then subjected to bromolactonization,
veloped by Welch and co-workers [233], obtained 410 was then subjected to bromolac- followed by
tonization, followed by elimination to give the corresponding tricyclic γ-lactone core 411,
which was isolated as the TES ether 412. During the introduction of the δ-lactone moiety,
γ-lactone ring opening, elimination, and poor yield occurred as major problems. This chal-
lenge was overcome by the use of intramolecular Reformatsky reaction, which had seldom
been utilized in natural product synthesis [230]. The Reformatsky-type reaction between
Danishefsky groups [231,232], which led to the fully functionalized AB ring of podolac-
tone (408) over 9 steps (Scheme 76). Next, with the intermediate (408) in hand, construc-
tion of the D lactone ring across C-4 and C-6 was attempted. To achieve this, 408 under-
Int. J. Mol. Sci. 2021, 22, 1052 went a Morita–Baylis–Hillman reaction, utilizing formaldehyde and 52 dime-
of 67
thylphenylphosphine, to give 410 in excellent yield. Based on the reaction sequence de-
veloped by Welch and co-workers [233], obtained 410 was then subjected to bromolac-
tonization,
eliminationfollowed by corresponding
to give the elimination to give the corresponding
tricyclic γ-lactone core tricyclic
411, whichγ-lactone core 411,
was isolated as
which
the TESwas isolated
ether as the the
412. During TESintroduction
ether 412. During
of the the introduction
δ-lactone moiety, of the δ-lactone
γ-lactone moiety,
ring opening,
γ-lactone ringand
elimination, opening, elimination,
poor yield occurred and
aspoor
majoryield occurredThis
problems. as major problems.
challenge This chal-
was overcome
by thewas
lenge useovercome
of intramolecular
by the useReformatsky reaction,
of intramolecular which had
Reformatsky seldom
reaction, beenhad
which utilized
seldomin
natural
been product
utilized synthesis
in natural [230]. synthesis
product The Reformatsky-type reaction between
[230]. The Reformatsky-type enone between
reaction 412 and
ethyliodoacetate
enone in the presence of
412 and ethyliodoacetate in NiCl 2 (PPh3 )2 of
the presence and Et32Zn
NiCl furnished
(PPh 3)2 and Etthe
3Zndesired tertiary
furnished the
alcohol 409 as a single isomer.
desired tertiary alcohol 409 as a single isomer.
76. Synthesis of the common tricyclic precursor 409

Scheme 76.
Scheme 409 [230].
Toward the
Toward thesynthesis
synthesisofofnagilactone
nagilactoneF, the common
F, the common intermediate (409)(409)
intermediate was was
hydrolyzed
hydro-
under acidic conditions and subsequently oxidized with DMP to provide
lyzed under acidic conditions and subsequently oxidized with DMP to provide aldehyde aldehyde 413,
which was further treated with the Burgess reagent followed by HCl in THF
413, which was further treated with the Burgess reagent followed by HCl in THF to give to give lactol
414 (Scheme
lactol 77). Thus,
414 (Scheme the obtained
77). Thus, lactollactol
the obtained 414 was
414 treated with with
was treated isopropylmagnesium
isopropylmagne-
bromide following the protocol reported by Barrero and co-workers [234], which, as op-
sium bromide following the protocol reported by Barrero and co-workers [234], which, as
opposed
posed to expectations,
to expectations, ledlow
led to to yield
low yield and moderate
and moderate selectivity.
selectivity. Hence,Hence, the authors
the authors sought
sought
to to circumvent
circumvent this problem.
this problem. Gratifyingly,
Gratifyingly, treatment treatment
of 414 withofisopropenylmagnesium
414 with isopropenyl-
magnesium
bromide bromide
afforded afforded
dilactone 415dilactone 415 in
in good yield andgood
highyield and high diasteroselectivity,
diasteroselectivity, which in turn
underwent
which in turnhomogeneous
underwenthydrogenation
homogeneousinhydrogenation
the presence ofinWilkinsons’s
the presence catalyst to furnish
of Wilkinsons’s
nagilactone F (399).nagilactone F (399).
catalyst to furnish
intermediate 409
Scheme 77. Synthesis of nagilactone F (399) from the intermediate 409 [230].
[230].
Significance
Significance of
of this
this work
work isis that
that it
it provided
provided access
access to
to seven
seven related
related norditerpenoid
norditerpenoid
dilactones,
dilactones, including nagilactone F (399), from one common precursor. We envision
including nagilactone F (399), from one common precursor. We envision that
that
additional development of such convergent and divergent synthetic approaches
additional development of such convergent and divergent synthetic approaches would be
would
necessary for the synthesis and derivatization of bioactive natural products.
be necessary for the synthesis and derivatization of bioactive natural products.
3. Summary
The biological activities of RALs, SLs, DAGLs, and DLs, including available patent
information, are summarized in Table 1. Based on the research described above, the lac-
tones covered in this review have proved to be valuable compounds with promising bio-
activities. For instance, L-783277 (4) exhibits a highly potent inhibitory activity against
MEK (IC50 = 4 nM), however, it displayed low kinome-wide selectivity. This selectivity
issue was overcome by rationally designed derivatives 99 and 100. 99 is a selective ALK1
Int. J. Mol. Sci. 2021, 22, 1052 53 of 67
3. Summary
The biological activities of RALs, SLs, DAGLs, and DLs, including available patent in-
formation, are summarized in Table 1. Based on the research described above, the lactones
covered in this review have proved to be valuable compounds with promising bioactiv-
ities. For instance, L-783277 (4) exhibits a highly potent inhibitory activity against MEK
(IC50 = 4 nM), however, it displayed low kinome-wide selectivity. This selectivity issue was
overcome by rationally designed derivatives 99 and 100. 99 is a selective ALK1 inhibitor
(IC50 = 62 nM) and it is shown to effectively block BMP-9 induced ALK1 signaling in C2C12
cells. 100 is a dual VEGFR3 and VEGFR2 inhibitor (VEGFR3 IC50 = 1.15 nM, VEGFR2
IC50 = 3.56 nM) and its anti-lymphangiogenic and anti-angiogenic ability was demon-
strated both in 3D microfluidic tumor lymphangiogenesis assay and in vivo corneal assay.
Table 1. Biological activities of resorcylic acid lactones (RALs), sesquiterpene lactones (SLs), diacylglycerol lactones (DAGLs),
and diterpene lactones (DLs).
Class Compound Summary of Biological Activities Patents References

It selectively inhibits HSP90 function (IC50 = 20–23 nM).
Poor in vivo activity, probably due to chemical
RALs Radicicol (1) [235–238] [24]
instability in serum and its rapid conversion into
inactive metabolites.
RALs 32 It selectively inhibits HSP90 function (IC50 = 160 nM). [239] [29]
Significant growth-inhibitory activity against human
breast carcinoma MX-1 cells transplanted into nude
RALs KF25706 (39) [240] [31]
mice at a dose of 100 mg/kg twice daily for five
consecutive iv injections.
RAS-signaling pathway inhibitor.
It also inhibits the production of several cytokines such
as IL2, IL6, IFNγ, and TNFα.
RALs Hypothemycin (2) [241–243] [35]
It inhibited the growth of HT29 and HCT116 cells
in serum-free defined medium, IC50 = 0.078 mM
and 0.90 mM, respectively.
It selectively inhibits (TGF)-β-activated kinase 1
(TAK1) with high potency TAK1, (IC50 = 8.1 nM).
Strongly inhibition JNK/p38 pathway.
It also inhibits MEK1 (IC50 = 411 nM) and
RALs LL-Z1640-2 (3) [244–246] [38]
three other MAPKKKs (IC50 ≥ 268 nM against MEKK1,
ASK1, and MEKK4).
It can be applied clinically to CNS autoimmune
disorders.
Its activity is comparable to 3, but with improved
RALs 74a-d [46]
solubility and pharmacokinetic properties.
Increased metabolic stability and reduced potency than
3, active in vivo,
RALs ER803064 (79) [246,247] [48]
but the ED50 value (13.2 mg/kg, iv) was fairly high in
regard to TNF-α suppression
A MEK1 and MEKK1 inhibitor.
Similar in vitro potency to natural product 3 and
RALs 83 and 84 improved in vivo potency by iv administration. [247,248] [49]
TNFα-PLAP IC50 s: 32 nM for 83, 15 nM for 84.
ED50 : 6.5 mg/kg for 84.
RALs 90 Active against MNK2 kinase (IC50 = 7.2 µM). [50]
Int. J. Mol. Sci. 2021, 22, 1052 54 of 67
Table 1. Cont.

Highly potent inhibitory activity against MEK
(IC50 of 4 nM).
RALs L-783277 (4) Potent inhibitory activities against several kinases [241,243,249,250] [47,52]
including VEGFR2/3, FLT1/3/4, MEK1/2, KDR, and
PDGFRα but with low kinome selectivity.
A selective and potent ALK1 inhibitor
It inhibits ALK1 with an IC50 value of 62 nM and
RALs 99 activates Smad4 by phosphorylating Smad1/5. [56–58]
It acts by selectively blocking BMP9-induced ALK1
signaling in C2C12 cells.
Potent dual VEGFR3 and VEGFR2 inhibitor
(VEGFR3 IC50 = 1.15 nM, VEGFR2 IC50 = 3.56 nM).
RALs 100 It effectively suppresses both lymphangiogenesis and [251] [54]
angiogenesis in a 3D-microfluidic tumor
lymphangiogenesis assay and in vivo corneal assay.
IC50 values against SiHa and MCF-7 cells (8.42 and 9.54
µM, respectively). It prevents resistance of
MDA-MB-231 to doxorubicin and mitoxantrone.
SLs Parthenolide (183) Cytotoxicity in a wide variety of human cancers, [252] [80–83,253]
targeting IKK-β, and FAK 1 inhibition
In a mouse xenograft model, it decreased tumor size in
combination with docetaxel.
It selectively eliminates AML stem cells.
DMAPT (190) significantly suppressed PC-3 tumor
growth until day 95 compared with control (P = 0.0007)
and resulted in greater tumor control than that
observed with docetaxel (P = 0.007).
SLs DMAPT (190) In A549 subcutaneous xenograft, it reduced tumor [252,254] [89,255,256]
growth by 54% (100 mg/kg/day, po).
In UMUC-3 (transitional carcinoma) xenograft, it
suppressed tumor growth by 63%
(100 mg/kg oral twice/day).
It has an increased PK profile compared to 183
IC50 values against MDA-MB 231 and HUVEC cells (40
SLs Alantolactone (184) [257] [104]
µM and 14.2 µM, respectively).
IC50 values against HCT116 (colorectal), K562 (CML),
KB (oral), and T47D (breast) cancer cell lines are 7.46,
Deoxyelephantopin 4.02, 3.35, 1.86 µg/mL, respectively.
SLs [258,259] [130,131,260,261]
(185) IC50 values against PC-3, CNE, and HL-60 cells are 4.6,
2.6, and 0.9 µM, respectively.
It is an inhibitor of NF-κB and targets PPAR-γ.
IC50 value against MDA-MB-231 is 3.5 µM.
In combination with paclitaxel,
it shows synergistic effects on MDA-MB 231 cells.
SLs DETD-35 (232) [262] [127,137]
It also synergistic effects with vemurafenib to
overcome BRAFV600E mutant melanoma in a mouse
model
It shows inhibitory activities on TR-LE cells.
IC50 value against SW-620 cells is 7.8 µM.
SLs Costunolide (186) [263] [162,163,264]
IC50 value against BGC-823 cells at 24 and 48 h is 32.80
and 23.12 µM, respectively.
SLs 264 IC50 value against SW-620 cells is 3.3 µM. [163]
Int. J. Mol. Sci. 2021, 22, 1052 55 of 67
Table 1. Cont.

IC50 value against MDA-MB-231 cells is 0.6 µM.
IC50 values against H441 (wt-EGFR) and H1975
(EGFRT790M ) are 0.75 µM and 0.83 µM, respectively.
It suppressed tumorigenesis in lung cancer mouse
SLs Antrocin (187) [246,265–267] [171–173]
xenograft in vivo and enhanced tumor inhibitory
response in treatment with JAK2 inhibitor.
It showed no apparent systematic toxicity in a 28-day
rat study (at 37.5 mg/kg).
IC50 values against Caski and SiHa cell lines are 5.8
SLs EM23 (188) [179]
and 6.6 µM, respectively.
It selectively inhibits growth of DU145
and MDA-MB-468.
SLs Brevilin A (189) It inhibits JAK-STAT signaling pathway by attenuating [268] [186]
JAKs activity and blocking STAT3 signaling
(IC50 = 10.6 µM) in cancer cells.
It is a selective ligand for PKCε.
DAGLs AJH-836 (315) [14,199]
(Ki of PKCα = 46 nM, Ki of PKCε = 1.43 nM)
IC50 value against PCa cells is 19.95 µM.
Andrographolide
DLs IC50 value against A549 cells of PTX + 30 µM 373 is [205,269] [207,211,212,216]
(373)
0.5 nM, showing significant synergy.
19-triisopropyl
IC50 = 6.3 µM and 1.6 µM for MKN-45 and AGS cell
DLs andrographolide [208]
lines, respectively.
(343)
SRJ23
DLs 50-fold improved IC50 for PCa cells (0.4 µM) than 373. [211]
(375)
IC50 = 2–5 mM against MDA-MB-231, AGS, and Hela
DLs Nagilactone C (397) [224]
cell lines.
IC50 = 5.2 and 3.6 µM against A549 and NIC-H1975,
respectively.
In an A549 xenograft mouse model
DLs Nagilactone E (398) [226,227]
(10 mg/kg/d, ip), it suppressed tumor growth by 62%
and inhibited tumor metastasis without apparent
toxicity
Among sesquiterpene lactones reviewed in this work, parthenolide (183) inhibited

growth of SiHa and MCF-7 cells with an IC50 value of 8.42 and 9.54 µM, respectively.
Furthermore, parthenolide (183), in combination with docetaxel, enhanced survival, and
reduced metastases in a mouse xenograft model of breast cancer without any observed
apparent toxicity [80]. In addition, Parthenolide (183), as a main component of feverfew,
underwent a phase 1 clinical trial to assess its pharmacokinetics and toxicity [81,270]. Pre-
existing poor solubility and bioavailability issues of parthenolide (183) led to development
of DMAPT (190). Methods for preparation of parthenolide (183) derivatives are patented
by Fusan R., et al. and Crooks, P., et al. [252,253]. DMAPT (190) has an increased PK profile
compared to parthenolide (183) and significantly suppressed tumor growth in subcuta-
neous xenografts of A549 and UMUC-3 (transitional carcinoma cells) in athymic nude mice
by 54% (100 mg/kg/day, oral) and 63% (100 mg/kg twice/day, oral), respectively. DMAPT
(190) is reported to be in a phase 1 clinical trial in hematological malignancies in the United
Kingdom [89,271,272]. DETD-35 (232), a derivative of deoxyelephantopin (185), inhibits
growth of MDA-MB-231 cells with an IC50 value of 3.5 µM. Notably, it shows synergistic
effects with vemurafenib to overcome BRAFV600E mutant melanoma in a mouse xenograft
model. Antrocin (187) inhibits growth of EGFR-harboring cell lines H441 (wt-EGFR) and
H1975 (EGFRT790M ) with an IC50 value of 0.75 and 0.83 µM, respectively. It suppressed
Int. J. Mol. Sci. 2021, 22, 1052 56 of 67
tumorigenesis in lung cancer mouse xenograft in vivo. Moreover, it showed no apparent

systematic in a 28-day rat study (at 37.5 mg/kg).
Among diterpene lactones, andrographolide (373) inhibited growth of PCa cells with
an IC50 value of 19.95 µM and enhanced 5-FU induced apoptosis in 5-FU resistant cancer
cells (HCT116/5-FUR). Use of andrographolide (373) derivatives in the manufacture of
medicaments and structural modification of the natural product to increase biological
activities are patented [205,269]. Andrographolide (373) is reported to be in a phase 2
clinical trial as treatment in colorectal neoplasms [273]. Nagilactone E (398) suppressed
tumor growth by 62% in an A549 xenograft mouse model (10 mg/kg/day) and inhibited
tumor metastasis without apparent toxicity.
Overall, it may be said that these natural and synthetic lactones of various classes,
given the activities described in this review, possess suitable properties to initiate further
preclinical and clinical studies leading to advancement into new drugs.
4. Conclusions and Future Prospects

The pharmacologically significant natural products have been providing inspiration
and guidance to make a paradigm shift for innovative drug development strategies, which
serve as a great starting point for initiation of drug discovery programs. Taking into account
the researches elucidated above, the natural and synthetic lactones addressed in this review
strongly suggest that they are promising therapeutic leads for oncology drug discovery
program. Moreover, the synthetic studies of above-mentioned natural products and their
useful analogs will open up a whole new research field, contributing to the foundation of
intriguing new realm in the design and synthesis of natural products and their analogs as
well.
In this review, we mainly focused on recognized natural and synthetic analogs of lac-
tones in each classification (RALs, SLs, DAGLs, and DLs) with notable antitumor activities
and we described their recent advancements made in the field of drug discovery. However,
to reach a clinically viable drug from a potent natural product/-derived compound, there
are still several remaining challenges to be overcome: (a) difficulties in sophisticated syn-
thetic modification due to structural complexity, (b) relatively poor drug-like properties and
target specificity, and (c) elusive exact biological targets and mechanism of action. In this
light, our extensive study on structural modification of L-783277 (4) demonstrated that sim-
ple changes in chemical structure such as saturation or rigidification bring about significant
improvements in terms of potency, target-selectivity, and pharmacokinetic property. In ad-
dition, the research mentioned above exemplified identification of possible cellular targets
of DET (185) by using synthetic DET-related probes. We believe that ongoing studies on the
synthesis and biological evaluation of such compounds result in the establishment of novel
methods for innovative drug design strategies and target identification. Furthermore, we
anticipate that these findings would provide biologists as well as chemists with valuable
insights and resources to achieve the ultimate goal towards cancer drug discovery program.
5. Materials and Methods

A comprehensive search was accomplished by using the following databases to obtain
the recent and relevant references in regards to natural and synthetic lactones: PubMed,
Science-Direct, Springer, ACS, NIH, Google Scholar, MEDLINE, EBSCO, Web of Science,
ClinicalTrials.gov, and Sci-Finder from 1946 to 2020. The keywords used include ‘natural lac-
tones’, ‘synthetic lactones’, ‘macrocyclic lactones’, ‘resorcylic acid lactones’, ‘sesquiterpene
lactones’, ‘diacylglycerol lactones’, and ‘diterpene lactones’ alone or combined with the
keywords ‘derivatives’, ‘anticancer’, ‘signaling pathway’, ‘apoptosis’, ‘cell cycle’, ‘necrosis’,
‘mutation’, ‘angiogenesis’, ‘metastasis’, ‘kinase inhibition’, ‘PI3K’, ‘MAPK’, ‘ROS’, ‘target
identification’, and ‘drug discovery’.
Exclusively, references in English were included in this review due to language barrier.
Compound entries and references were selected according to the following criteria: avail-
ability of researches focused on (a) anticancer activities, (b) total synthesis, (c) synthetic
Int. J. Mol. Sci. 2021, 22, 1052 57 of 67
derivatives, (d) in-vitro and in-vivo studies, and (e) clinical studies. On the other side,
compound entries and references were ruled out according to the following criteria: (a)
researches, which are not focused on anticancer activity, (b) researches without sufficient
information on synthesis, and (c) researches without sufficient information on biological
evaluation. In addition, only 4 resorcylic acid lactones have been selected as representative
because biology and chemistry of resorcylic acid lactones are generally well summarized
in previous reviews [12,21].
Author Contributions: Y.K. drafted the work and revised it. S.S. discussed the chemistry part of
RALs. S.S. and T.S. edited the manuscript. T.S. conceived and supervised the manuscript. All authors
have read and agreed to the published version of the manuscript.
Funding: This research was supported by the Candidate Development Program (NRF2016M3A9B5940991)
from the National Research Foundation in Korea.
Acknowledgments: This work was supported by the KU-KIST Graduate School of Converging
Science and Technology Program.
Conflicts of Interest: The authors declare no conflict of interest.
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Natural and Synthetic Lactones Possessing Antitumor Activities

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Citation: Kim, Y.; Sengupta, S.; Sim,

Int. J. Mol. Sci. 2021, 22, 1052. https://doi.org/10.3390/ijms22031052 https://www.mdpi.com/journal/ijms

Figure 1. Structures of representative resorcylic acid lactones.

2.1.2. Chemistry of Radicicol (1)

Scheme 2. Synthesis of intermediate 11 [26].

Scheme 3. Synthesis of intermediate 12 [26] .

Scheme 6. Synthesis of radicicol (1) according to Winssinger et al. [28].

Scheme 7. Synthesis Scheme 7. Synthesis of (32)

A series of halohydrin andand oxime

Scheme 8. Synthesis of triazole derivative (35) of radicicol (1) [32].

A synthesis of resorcylic acid macrolactam analogs of the natural product radicicol

inhibitor by facilitating ubiquitinating process of cyclin D1 in DT cells. Another study

2.1.4. Chemistry of Hypothemycin (2) and LL-Z1640-2 (3)

10. Synthesis of LL-Z1640-2

Scheme 12. Total

Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 12 of 69

[51]. Reagents and conditions: (a). (i). TBSCl, imidazole,

2.1.5. Biological Activities of L-783277 (4)

upregulates transcription of various target genes involved in angiogenesis [56,57]. Due to

2.1.6. Chemistry of L-783277 (4)

Scheme 22. Synthesis of L783277 (4) by Winssinger et al. [47].

Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 18 of 69

Scheme 26. Synthesis

Scheme 30. Synthesis of intermediate

Scheme 32. Synthesis of fragment 149 by Banwell et al. [65].

50 -Deoxy analog (158) of L-783277 (4) was synthesized stereoselectively in 2011 by

Scheme 36. Synthesis of key intermediate 166

Scheme 38. Synthesis of analogs (99, 172–173) from

Subsequently, 180 underwent saponification followed by cyclization under

Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 25 of 69

2.2. Sesquiterpene Lactones

2.2.2. Chemistry of Parthenolide (183)

The primary attempt of the group to synthesize parthenolide (183) is summarized in

The primary attempt of the group to synthesize parthenolide (183) is summarized in

Scheme 44. Synthesis parthenolide (183) and its its analog

2.2.3. Biological Activities of Alantolactone (184)

2.2.4. Chemistry of Alantolactone (184)

Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 31 of 69

Kaur and co-workers have recently reported a number of semi-synthetic derivatives

50% aq. KOH,

2.2.5. Biological Activities of Deoxyelephantopin (185)

2.2.6. Chemistry of Deoxyelephantopin (185)

Figure 12. Retrosynthetic analysis of Deoxyelephantopin (185)

Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 34 of 69

2.2.7. Biological Activities of Costunolide (186)

Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 37 of 69

Figure 13. Structures of Costunolide Derivatives.

Gratifyingly, diol 271, upon treatment with o-nitrophenyl selenocyanate, tribu-

Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 38 of 69

Scheme 56. Initial

Gratifyingly, diol 271, upon treatment with o-nitrophenyl selenocyanate, tribu-

Scheme 58. Synthesis of costunolide (186) according

More recently, the highly stereo-controlled total synthesis of costunolide (186) by

Since the aldol

Scheme 60. Synthesis of intermediate 286 [97].

Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 40 of 69

Srivastava et al. synthesized and evaluated 13-amino costunolide derivatives. Simple

Scheme 63. Synthesis of arylated costunolide derivatives (266a–266l) [164].

2.2.9. Biological Activities of Antrocin (187)

2.2.10. Chemistry of Antrocin (187)

Int. J. Mol. Sci. 2021, 22, x FOR PEER REVIEW 42 of 69

Scheme 65. Synthesis