10 3390@molecules24224165 PDF

molecules
Review
Spirocyclic Motifs in Natural Products
Evgeny Chupakhin 1 , Olga Babich 1,2 , Alexander Prosekov 2 , Lyudmila Asyakina 2 and
Mikhail Krasavin 1,3, *
1 Immanuel Kant Baltic Federal University, 236016 Kaliningrad, Alexandra Nevskogo 14, Russia;
chupakhinevgen@gmail.com (E.C.); olich.43@mail.ru (O.B.)
2 Kemerovo State University, 650000 Krasnaya, Kemerovo, Russia; rector@kemsu.ru (A.P.);
alk_kem@mail.ru (L.A.)
3 Saint Petersburg State University, 199034 Saint Petersburg, Russia
* Correspondence: m.krasavin@spbu.ru; Tel.: +7-9313617872
Academic Editor: José Rubén Tormo
Received: 17 October 2019; Accepted: 12 November 2019; Published: 17 November 2019
Abstract: Spirocyclic motifs are emerging privileged structures for drug discovery. They are also
omnipresent in the natural products domain. However, until today, no attempt to analyze the
structural diversity of various spirocyclic motifs occurring in natural products and their relative
populations with unique compounds reported in the literature has been undertaken. This review
aims to fill that void and analyze the diversity of structurally unique natural products containing
spirocyclic moieties of various sizes.
Keywords: natural products; spirocycles; chemical diversity; biological activity; privileged structures
1. Introduction
Natural products play the central role in drug discovery [1] due to their inherent biological activity
and because have a wide span of structural diversity. Spirocyclic compounds have also occupied
a special place in medicinal chemistry [2]. Spirocycles are thought to possess a good balance of
conformational rigidity and flexibility to be, on one hand, free from absorption and permeability
issues characteristic of conformationally more flexible, linear scaffolds. On the other hand, spirocycles
are more conformationally flexible compared to, for example, flat aromatic heterocycles and can
adapt to many proteins as biological targets; thus, increasing the chances of finding bioactive hits [3].
Spirocycles are distinctly three-dimensional and initial hits can be further optimized via manipulation
of the molecular periphery whose three-dimensional positioning is well defined [4]. We thought it
worthwhile to gain insight into the structural diversity of naturally-occurring spirocyclic compounds in
relation to the information of their biological activity which would provide a new angle for designing
novel bioactive, druglike compounds. Modern literature features a limited number of reviews devoted
to total syntheses of spirocyclic natural products [5], including one for spirolactones [6] and one for
spirooxyindoles [7]. Illustrative examples of approved natural-product drugs containing a spirocyclic
motif include antifungal drug griseofulvin (1) and diuretic drug spironolactone (2). Interesting related
compounds that have not achieved clinical approval include isochromanquinone antibiotic griseusin B
(3) [8,9] and spirotriprostatin (4) [10] (Figure 1).
For the purpose of the analysis presented in this review, we considered the chemical diversity of
structurally unique and well characterized (i.e., those whose structures were assigned using modern
analytical techniques) spirocyclic compounds registered in the ChemBL or SciFinder databases, or the
Dictionary of Natural Products (DNP). The occurrence of various ring combinations (A = any atom,
mostly carbon or oxygen) selected for discussion in this review is presented in Table 1.
Molecules 2019, 24, 4165; doi:10.3390/molecules24224165 www.mdpi.com/journal/molecules

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Molecules 2019, 24, 4165 3 of 37
Considering the uneven distribution of the ring combination occurrence statistics (Table 1), the
Considering the uneven distribution of the ring combination occurrence statistics (Table 1),
present review is structured according to the size of the [x.y.0] spirocyclic system. The review aims
the present review is structured according to the size of the [x.y.0] spirocyclic system. The review aims
to cover either rare representatives of the spirocyclic systems that seldom occur in the natural
to cover either rare representatives of the spirocyclic systems that seldom occur in the natural product
product realm or only structurally-unique, representative compounds for those spirocyclic systems
realm or only structurally-unique, representative compounds for those spirocyclic systems that are
that are more widely populated with natural products reported in the literature, with an emphasis
more widely populated with natural products reported in the literature, with an emphasis on their
on their associated biological activities and the solid structure assignment techniques employed
associated biological activities and the solid structure assignment techniques employed (structures
(structures assigned solely based on mass-spectrometric measurements are not taken into account).
assigned solely based on mass-spectrometric measurements are not taken into account).
2. [2.4.0]
2. [2.4.0] Spirocyclic
Spirocyclic System
System
Spirocyclic motifs
Spirocyclic motifscontaining
containinga cyclopropane
a cyclopropane unitunit
werewere found
found in some
in some sesquiterpenes
sesquiterpenes (5–7)
(5–7) which
were isolated from the essential oils of South-American Schinus terebinthifolius fruit [11] (Figure 2).[11]
which were isolated from the essential oils of South-American Schinus terebinthifolius fruit
(Figure 2).
Figure 2. Sesquiterpenes from Schinus terebinthifolius fruit containing a [2.4.0] spirocyclic moiety.
Figure 2. Sesquiterpenes from Schinus terebinthifolius fruit containing a [2.4.0] spirocyclic moiety.
In 2017, a novel condensed [2.4.0] spirocycle (8) was reported [12]. It was isolated and
In 2017, a novel condensed [2.4.0] spirocycle (8) was reported [12]. It was isolated and
characterized among the secondary metabolites of the Helminthosporium velutinum plant and was
characterized among the secondary metabolites of the Helminthosporium velutinum plant and was
named cyclohelminthol X (Figure 3). This compound was shown to inhibit the growth of a human
named cyclohelminthol X (Figure 3). This compound was shown to inhibit the growth of a human
colon adenocarcinoma (COLO201) cell line with moderate potency (IC50 = 16 µM), and, much more
colon adenocarcinoma (COLO201) cell line with moderate potency (IC 50 = 16 μM), and, much more
potently (IC50
Molecules 2018, 23, =
x 0.35 µM)—leukemia HL60 cell line [12]. 4 of 39
potently (IC50 = 0.35 μM)—leukemia HL60 cell line [12].
Figure 3. Cyclohelminthol X (8) from Helminthosporium velutinum plant.

Bioassay-guided separation of Valerianae Radix plant extract led to the isolation and characterization
Bioassay-guided separation of Valerianae Radix plant extract led to the isolation and
of valtrate (9), which inhibited Rev protein mediated transport of HIV-1 from the nucleus to cytoplasm
characterization of valtrate (9), which inhibited Rev protein mediated transport of HIV-1 from the
(Figure 4). This compound also inhibited p-24 production of HIV-1 virus without any notable
nucleus to cytoplasm (Figure 4). This compound also inhibited p-24 production of HIV-1 virus
cytotoxicity displayed against MT-4 cells. The presence of the chemically labile oxirane ring as part of
without any notable cytotoxicity displayed against MT-4 cells. The presence of the chemically labile
the generalized [2.4.0] spirocyclic system is likely critical for the observed inhibition, as 9 was shown
oxirane ring as part of the generalized [2.4.0] spirocyclic system is likely critical for the observed
to covalently interact with cysteine [13].
inhibition, as 9 was shown to covalently interact with cysteine [13].
Additional two compounds (31 and 32) containing this and another ([4.4.0]) spirocyclic system
are discussed in Section 7 of this review.
nucleus to cytoplasm (Figure 4). This compound also inhibited p-24 production of HIV-1 virus
withoutBioassay-guided
any notable cytotoxicity
separationdisplayed against
of Valerianae MT-4plant
Radix cells. extract
The presence
led toofthe
the chemically
isolation andlabile
characterization
oxirane of valtrate
ring as part (9), which inhibited
of the generalized Rev proteinsystem
[2.4.0] spirocyclic mediated transport
is likely of HIV-1
critical from
for the the
observed
nucleus to
inhibition, as cytoplasm
9 was shown (Figure 4). This compound
to covalently also
interact with inhibited
cysteine p-24 production of HIV-1 virus
[13].
without any notable cytotoxicity displayed against MT-4 cells. The presence of the chemically labile
Molecules 2019, 24, 4165 4 of 37
oxirane ring as part of the generalized [2.4.0] spirocyclic system is likely critical for the observed
inhibition, as 9 was shown to covalently interact with cysteine [13].
Figure 4. Valtrate (9) isolated from Valerianae Radix plant extract inhibiting HIV-1 transport.
Additional
Figure Figuretwo
4. Valtratecompounds
(9) isolated
4. Valtrate (31
from
(9) isolated and
from 32) containing
Valerianae
Valerianae Radix thisextract
Radixplant
plant and another
extract ([4.4.0])
inhibiting
inhibiting spirocyclic
HIV-1HIV-1 system
transport.
transport.
Additional System
two compounds (31 and 32) containing this and another ([4.4.0]) spirocyclic system
3. [2.5.0] Spirocyclic System
This group of spirocyclic natural products is represented by sesquiterpenoids illudins M and S
This
(10 and3.11, group of spirocyclic
respectively) natural products is represented by sesquiterpenoids illudins 0 M and S
[2.5.0] Spirocyclicisolated
System from fungi, including the highly poisonous Jack-o -lantern mushroom
(10 and 11, respectively) isolated from fungi, including the highly poisonous
Omphalotus illudens. Compound 11 is currently in Phase II clinical trials against ovarian, prostate, Jack-o′-lantern
This group
mushroom of spirocyclic
Omphalotus natural
illudens. Compoundproducts is currently
11 is represented
in by sesquiterpenoids
Phase illudins
II clinical trials M and
against S
ovarian,
and gastrointestinal cancers (Figure 5).
(10 and 11, respectively) isolated from fungi, including the highly poisonous Jack-o′-lantern
prostate, and gastrointestinal cancers (Figure 5).
mushroom Omphalotus illudens. Compound 11 is currently in Phase II clinical trials against ovarian,
prostate, and gastrointestinal cancers (Figure 5).
Figure 5. Structures of fungi-derived illudins M and S.

Figure 5. Structures of fungi-derived illudins M and S.
Structurally Figure 5. Structures
are ofsesquiterpenes
fungi-derived illudins M andisolated
S. Agrocybe
Molecules 2018, 23,analogous
x to illudins 12–14 from fungus5 of 39
aegerita [14] also containing
Structurally analogousa to
[2.5.0]
illudinsspirocyclic system (Figure
are sesquiterpenes 6). These
12–14 isolated compounds
from displayed
fungus Agrocybe
antifungal Structurally
aegerita [14] also
activity analogous
containing
against to illudins
a [2.5.0]
Candida are
andsesquiterpenes
spirocyclic
albicans system
Candida 12–146).isolated
(Figure
kefyr. from fungusdisplayed
These compounds Agrocybe
aegerita [14]
antifungal also containing
activity a [2.5.0]
against Candida spirocyclic
albicans system
and Candida (Figure 6). These compounds displayed
kefyr.
antifungal activity against Candida albicans and Candida kefyr.
Figure 6. Structures
Figure ofofsesquiterpenes
6. Structures isolatedfrom
12–14isolated
sesquiterpenes 12–14 from fungus
fungus Agrocybe
Agrocybe aegerita.
aegerita.
Figure 6. Structures of sesquiterpenes 12–14 isolated from fungus Agrocybe aegerita.
An oxirane-bearing
An oxirane-bearing sesquiterpene
sesquiterpene(−)-ovalicin (15)also
(−)-ovalicin (15) alsocontaining
containing a [2.5.0]
a [2.5.0] spirocyclic
spirocyclic systemsystem
was isolated from
was isolated fungus
An oxirane-bearing
from Pseudorotium
fungus Pseudorotiumovalis
sesquiterpene ovalis Stolk
(−)-ovalicin [15]. It—and
(15) also
Stolk [15]. the
containing
It—and the structurally similar
a [2.5.0] similar
structurally spirocyclic monoester
system
monoester
fumagillin (16)(16)
was isolated
fumagillin displayed
from potent
fungus
displayed antiparasitic
Pseudorotium
potent activities
ovalis Stolk
antiparasitic andare
[15]. It—and
activities and are
thegenerally
structurally
generally devoid
devoid similar of toxicity
[16] [16]
monoester
of toxicity
fumagillin
(Figure
(Figure 7). For (16)both
7). For
both displayed
compounds potent
compounds antiparasitic
1515and
and16,
16,total activities and
total syntheses
syntheses haveare
havebeengenerally
been reported
reporteddevoid
[17].[17].of toxicity [16]
(Figure 7). For both compounds 15 and 16, total syntheses have been reported [17].
Figure 7. Structures of antiparasitic, fungus-derived (−)-ovalicin (15) and fumagillin (16).

Figure 7. Structures
Figure of of
7. Structures antiparasitic,
antiparasitic,fungus-derived (−)-ovalicin
fungus-derived (−)-ovalicin (15)
(15) andand fumagillin
fumagillin (16). (16).
A [2.5.0] spirocyclic system is recognizable in the structure of duocarmycin SA (17) and
A [2.5.0]
duocarmycinspirocyclic
A [2.5.0] Aspirocyclic
(18)—new system
systemisisrecognizable
antitumor recognizable
antibiotics in the
in
isolated the structure
structure
from of of
streptomyces duocarmycin
duocarmycin
sp. (Figure 8)SA SA (17)
(17)
[18]. and and
duocarmycin A (18)—new
duocarmycin A (18)—new antitumor
antitumorantibiotics
antibiotics isolated
isolated from streptomyces
fromstreptomyces sp.sp. (Figure
(Figure 8) [18].
8) [18].
Figure 7. Structures of antiparasitic, fungus-derived (−)-ovalicin (15) and fumagillin (16).
Molecules 2019, 24,Figure
4165 7. Structures of antiparasitic, fungus-derived (−)-ovalicin (15) and fumagillin (16). 5 of 37
A [2.5.0] spirocyclic system is recognizable in the structure of duocarmycin SA (17) and
duocarmycin
A [2.5.0]Aspirocyclic
(18)—new system
antitumor
is antibiotics
recognizableisolated from
in the streptomyces
structure sp. (Figure 8)SA
of duocarmycin [18].
(17) and
duocarmycin A (18)—new antitumor antibiotics isolated from streptomyces sp. (Figure 8) [18].
Figure Structures
8. 8.
Figure Structuresof
ofduocarmycin antitumor
duocarmycin antitumor antibiotics.
antibiotics.
Figure 8. Structures of duocarmycin antitumor antibiotics.
4. [3.4.0] System
Spirocyclic System
4. [3.4.0]
This This Spirocyclic
is anis an System
exceedingly
exceedingly rare typeofofspirocyclic
rare type spirocyclic motif
motif encountered
encountered amongamong natural products.
natural products. The
The only
onlycompound
compound
This reportedininrare
reported
is an exceedingly theliterature
the literature
type to to date
date containing
containing
of spirocyclic motif suchsuch aamong
spirocyclic
a spirocyclic
encountered system system
natural presented
presented
products. as
Thea as
combination
a combination
only compoundof aofβ-lactone
a β-lactone
reported in theaand
and a pyrrolidine
pyrrolidine
literature ring
ringcontaining
to date (19) was(19) was
isolated
such isolated from
systemmarine-derived
from marine-derived
a spirocyclic Streptomyces
presented as a
strainStreptomyces
collected instrain
combination a collected
of southern
the β-lactone inand
area the asouthern
of the Koreanarea
Jejuof
pyrrolidine the(19)
ring
Island Korean
[19]was Jeju Island
isolated
(Figure [19]
from
9). This (Figure 9).intriguing
This
marine-derived
structurally
structurally
Streptomyces intriguing
strain compound
collected
compound displayed antibacterial activity.in displayed
the southern antibacterial
area of theactivity.
Korean Jeju Island [19] (Figure 9). This
structurally intriguing compound displayed antibacterial activity.
Molecules
Molecules2018,
2018,23,
23,xx 66 of
of 39
39
Figure
Figure 9.
Figure 9. The
9. The only
The only known
only known natural
known natural product
natural product containing
product containing aaa [3.4.0]
containing [3.4.0] spirocyclic
[3.4.0] spirocyclic motif.
spirocyclic motif.
5. [3.5.0]
System
Spirocyclic System
The only
The spirocyclic combination of a four and six-membered rings represented in natural products
The only
only spirocyclic
spirocyclic combination
combination of of aa four
four and
and six-membered
six-membered ringsrings represented
represented in in natural
natural
is rather
products simple achiral 1-oxaspiro[3.5]nonan-7-ol substituted cleroindicin A (20) [20]. This compound
products is rather simple achiral 1-oxaspiro[3.5]nonan-7-ol substituted cleroindicin A (20) [20].
is rather simple achiral 1-oxaspiro[3.5]nonan-7-ol substituted cleroindicin A (20) [20]. This
This
was isolatedwas
compound fromisolated Clerodendrum
fungusfrom fungus japonicum (Figure
Clerodendrum 10). (Figure 10).
japonicum
compound was isolated from fungus Clerodendrum japonicum (Figure 10).
10. Cleroindicin A
Figure 10.
Figure A isolated from Clerodendrum japonicum.
from fungus Clerodendrum
Figure 10. Cleroindicin
Cleroindicin A isolated
isolated from fungus
fungus Clerodendrum japonicum.
japonicum.
6.
6. [3.7.0]
[3.7.0] Spirocyclic
Spirocyclic System
System
This intriguing spirocyclic combination of four and eight-membered rings is represented in only
This
This intriguing spirocyclic
spirocyclic combination
intriguingsesquiterpene combination of four and
and eight-membered rings is
is represented in
four closely-related bis-lactones,of21–24
four (Figure
eight-membered rings
11), isolated from represented
poisonous in
plants in
only
only four
four closely-related
closely-related sesquiterpene
sesquiterpene bis-lactones,
bis-lactones, 21–24
21–24 (Figure
(Figure 11),
11), isolated
isolated from
from poisonous
poisonous
the Illicium genus grown in China [21]. These structures could also be viewed as possessing a [3.5.0]
plants
plants inin the
the Illicium
Illicium genus
genus grown
grown inin China
China [21].
[21]. These
These structures
structures could
could also
also be
be viewed
viewed asas possessing
possessing
spirocyclic motif.
aa [3.5.0] spirocyclic motif.
Figure 11. Sesquiterpene bis-lactones isolated from Illicium plants containing a [3.7.0] spirocyclic motif.
Figure
Figure 11.
11. Sesquiterpene
Sesquiterpene bis-lactones
bis-lactones isolated
isolated from
from Illicium
Illicium plants
plants containing
containing aa [3.7.0]
[3.7.0] spirocyclic
spirocyclic
motif.
motif.
7.
7. [4.4.0]
[4.4.0] Spirocyclic
Spirocyclic System
System
Besides
Besides the
the approved
approved diuretic
diuretic spironolactone
spironolactone (2,
(2, vide
vide supra),
supra), heteroatom-containing
heteroatom-containing [4.4.0]
[4.4.0]
Molecules 2019, 24, 4165 6 of 37
Figure 11. Sesquiterpene bis-lactones isolated from Illicium plants containing a [3.7.0] spirocyclic
motif.
Besides the approved diuretic spironolactone (2, vide supra), heteroatom-containing [4.4.0]
spirocyclic Besides the widely
motifs are approvedrepresented
diuretic spironolactone
by various(2, vide supra),
lactones heteroatom-containing
(Figure 12). [4.4.0]
spirocyclic motifs are widely represented by various lactones (Figure 12).
Figure Various
12. 12.
Figure Variousnaturally occurring
naturally occurring [4.4.0]
[4.4.0] spirocyclic
spirocyclic lactones.
lactones.
The most structurally simple, naturally occurring spirocyclic lactone, 1,7-dioxaspiro[4.4.0]nonane

or longianone (25) was isolated from higher fungi Xylaria longiana [22]. The absolute configuration
of longianone was confirmed by stereoselective total synthesis [23]. Hyperolactones A (26) and
C (27) isolated from Hypericum chainens plant [24] displayed antiviral activity [25]. The Nicolaou
group reported a photochemical, [2 + 2]-cycloaddition based synthesis of a library based on natural
product biyouyanagin (28) which allowed revising its originally reported absolute configuration [26].
(+)-Crassalactone D (29) is a styryl-lactone isolated from the leaves of Polyalthia crassa plant which
displayed cytotoxic properties [27]. Pyrenolide D (30) is a highly oxygenated tricyclic spirolactone
isolated from phytopathogenic fungus Pyrenophora teres, also displaying potent cytotoxicity [28].
Sesequiterpene levantenolide (31) also contained a [4.4.0] spirocyclic lactone moiety; it was isolated
from tobacco grown in Turkey [29]. It exerted potent suppression of cytokine cascades and can,
therefore, be considered a lead for anti-inflammatory drug development [30]. Complex polycyclic
alkaloids represented by compound 32 were isolated from Stemona genus shrubs. These compounds
contain a basic cyclopenta[1,2-b]pyrrolo[1,2-a]azepine scaffold and display promising anti-cough
medicinal properties [31] (Figure 12).
A [4.4.0] spirocyclic lactone moiety is found (in combination with a [2.4.0] spirocyclic oxirane)
in limonoids 33–34, which were recently isolated from Trichilia connaroides (Figure 13). For these
compounds, some insights into a possible biosynthetic pathway have been provided. Likewise, these
compounds were screened for various types of bioactivity and have been shown to inhibit NO
production in a cellular model of inflammation (induced in RAW264.7 cell line with LPS) by 25.89%
and 37.13% at 25 and 50 µM, respectively [32].
Studies of secondary metabolite structures in endophyte fungus Penicillium purpurogenum unveiled
a series of unique sesquiterpene lactone compounds (35–37) containing spirocyclic combinations of
three five-membered rings (Figure 14). All three compounds were screened against several cancer cell
lines (melanoma M14, colon cancer HCT-116, glioma U87, ovary cancer A2780, stomach cancer BG-823,
hepatoma Bel-7402, and lung cancer A549) and several pathogenic microorganisms (Mycobacterium
spegmatis (ATCC70084), Staphylococcus aureus (ATCC25923), and Staphylococcus epidermidis (ATC12228));
however, no activity was detected at 50 µM [33].
Rather intriguing are the structures of curcumanolides 38–41, natural [4.4.0] spirocyclic lactones
recently isolated from Curcuma heyneana, a traditional medicinal plant of Indonesia (Figure 15) [34].
A [4.4.0] spirocyclic lactone moiety is found (in combination with a [2.4.0] spirocyclic oxirane)
in limonoids 33–34, which were recently isolated from Trichilia connaroides (Figure 13). For these
compounds, some insights into a possible biosynthetic pathway have been provided. Likewise, these
compounds were screened for various types of bioactivity and have been shown to inhibit NO
Molecules
production 24,a4165
2019,in 7 of 37
cellular model of inflammation (induced in RAW264.7 cell line with LPS) by 25.89%
and 37.13% at 25 and 50 μM, respectively [32].
Figure 13. Limonoids 31–32 containing both a [4.4.0] and a [2.4.0] spirocyclic system.
Studies of secondary metabolite structures in endophyte fungus Penicillium purpurogenum

unveiled a series of unique sesquiterpene lactone compounds (35–37) containing spirocyclic
combinations of three five-membered rings (Figure 14). All three compounds were screened against
several cancer cell lines (melanoma M14, colon cancer HCT-116, glioma U87, ovary cancer A2780,
stomach cancer BG-823, hepatoma Bel-7402, and lung cancer A549) and several pathogenic
microorganisms (Mycobacterium spegmatis (ATCC70084), Staphylococcus aureus (ATCC25923), and
Figure
Staphylococcus 13. Limonoids
epidermidis 31–32 containing
(ATC12228)); however,both
no aactivity
[4.4.0] and
wasa detected
[2.4.0] spirocyclic
at 50 μM system.
[33].
Figure 13. Limonoids 31–32 containing both a [4.4.0] and a [2.4.0] spirocyclic system.
Studies of secondary metabolite structures in endophyte fungus Penicillium purpurogenum

unveiled a series of unique sesquiterpene lactone compounds (35–37) containing spirocyclic
combinations of three five-membered rings (Figure 14). All three compounds were screened against
several cancer cell lines (melanoma M14, colon cancer HCT-116, glioma U87, ovary cancer A2780,
Molecules 2018,
stomach 23, x BG-823, hepatoma Bel-7402, and lung cancer A549) and several pathogenic
cancer 8 of 39
microorganisms (Mycobacterium spegmatis (ATCC70084), Staphylococcus aureus (ATCC25923), and

Figure
Molecules 14.23,Tricyclic
2018, x spirolactones (incorporating two [4.4.0] spirocyclic systems) isolated from
Staphylococcus epidermidis (ATC12228)); however, no activity was detected at 50 μM [33].8 of 39
Penicillium purpurogenum.
Figure 14. Tricyclic spirolactones (incorporating two [4.4.0] spirocyclic systems) isolated from
Figure Tricyclic spirolactones (incorporating two [4.4.0] spirocyclic systems) isolated from
14. purpurogenum.
Rather intriguing
Penicillium are the structures of curcumanolides 38–41, natural [4.4.0] spirocyclic lactones
Penicillium purpurogenum.
Rather intriguing are the structures of curcumanolides 38–41, natural [4.4.0] spirocyclic lactones
Figure 15. New spirocyclic curcumanolides possessing a [4.4.0] spirocyclic system each, isolated from
Figure 15. New spirocyclic curcumanolides possessing a [4.4.0] spirocyclic system each, isolated
Curcuma
Figure heyneana.
15. New spirocyclic curcumanolides possessing a [4.4.0] spirocyclic system each, isolated
from Curcuma heyneana.
from Curcuma heyneana.
In the course of the thorough structural investigation of a series of iridoid glycosides
In the
isolated course
the of the thorough
Morinda structural
citrifolia investigation of a series of iridoid glycosides isolated
In from
the course of the thorough plant,investigation
structural a revised ofstructure
a series of was assigned.
iridoid In particular,
glycosides isolated
from
from thethe Morinda
Morinda citrifolia
dehydromethoxygaertneroside plant,
citrifolia (42),
plant, a a revised
revisedstructure
structure
dehydroepoxymethoxygaertnoside was was assigned.
assigned.
(43), andIn In particular,
particular,
citrifolinoside A (44)
dehydromethoxygaertneroside
dehydromethoxygaertneroside
were shown to be structurally distinct (42), dehydroepoxymethoxygaertnoside
(42), dehydroepoxymethoxygaertnoside
compounds, all of which, however, (43), (43), and citrifolinoside
and citrifolinoside
possessed A A
a [4.4.0] spirocyclic
(44) were
(44) wereshown
shown to be
to be16)structurally
structurally distinct compounds, all of which, however, possessed
distinct compounds, all of which, however, possessed a [4.4.0] a [4.4.0]
lactone moiety (Figure [35].
spirocyclic lactone
spirocyclic lactonemoiety
moiety (Figure
(Figure 16) 16)[35].
[35].
Figure 16. New iridoid glycosides isolated from Morinda citrifolia plant.
Figure 16.
Two diastereomers of New iridoid glycosides
spirophthalides, 45 andisolated frompossess
46, which Morindaa citrifolia
unique plant.
presentation of a
[4.4.0] spirocyclic lactone, were recently isolated from a marine-sponge-derived fungus, Setosphaeria
sp.Two diastereomers
(Figure 17) [36]. of spirophthalides, 45 and 46, which possess a unique presentation of a
sp. (Figure 17) [36].
Molecules 2019, 24, 4165 8 of 37
Two diastereomers of spirophthalides, 45 and 46, which possess a unique presentation of a [4.4.0]
Two diastereomers of spirophthalides, 45 and 46, which possess a unique presentation of a
spirocyclic lactone, were recently isolated from a marine-sponge-derived fungus, Setosphaeria sp.
(Figure 17) [36].
sp. (Figure 17) [36].
Figure 17.
Figure Diastereomeric spirophthalides
17. Diastereomeric spirophthalides recently
recently isolated
isolated from
from marine-sponge-derived
marine-sponge-derived fungus
fungus
Setosphaeria sp.
Setosphaeria sp.
Unique spirocyclic dihydroindole-containing [4.4.0] spirocyclic lactones 47 and 48, also possessing a
Unique
Molecules 2018, 23,spirocyclic
x dihydroindole-containing [4.4.0] spirocyclic lactones 47 and 48,9 ofalso 39
quinazolone substituent, were identified among mycotoxins produced by P. aethiopicum (Figure 18) [37].
possessing a quinazolone substituent, were identified among mycotoxins produced by P. aethiopicum
(Figure 18) [37].
Figure 18. Spirocyclic mycotoxins produced by P. aethiopicum.

Figure 18. Spirocyclic mycotoxins produced by P. aethiopicum.
During a chemical and Figure 18. Spirocyclic
structural mycotoxins of
investigation produced by P. aethiopicum.
secondary metabolites of Penicillium dangeardii,
During a chemical and structural investigation
a series of related [4.4.0] spirocyclic lactones (penicillactones A-C) of secondary
49–51 wasmetabolites of Penicillium
identified. These possessed
dangeardii,During a chemical
a series offramework and
related [4.4.0] structural investigation of secondary metabolites of Penicillium
a complex molecular richspirocyclic
in carboxylatelactones (penicillactones
functionality and a well A-C) 49–51 wassubstitution
stereodefined identified.
dangeardii, a series of related [4.4.0] spirocyclic lactones (penicillactones A-C) 49–51 was identified.
These
pattern possessedthe a complex molecular framework rich in carboxylate functionality andleads
a well
Thesearound
possessed aspirocyclic core (Figure
complex molecular 19). Compounds
framework 49–51 showed
rich in carboxylate promise
functionality and aaswell for
stereodefined
newstereodefined substitution
antibiotic development. pattern around
Additionally, the spirocyclic
penicillactones B core
and C (Figure
(50 and 19).
52, Compounds
respectively) 49–51
showed
substitution pattern around the spirocyclic core (Figure 19). Compounds 49–51
showed
inhibitionpromise
showedofpromise
as asleads
the release offor
leads
new antibiotic development.
development.
for new antibiotic from
β-glucuronidase Additionally,
polymorphonuclear penicillactones
Additionally, leukocytes with
penicillactones EDB50
B and
and
C values
(50
C (50
of
and 52,
2.58and respectively)
and52,1.57 showed inhibition of the release of β-glucuronidase from
µM [38]. showed inhibition of the release of β-glucuronidase from polymorphonuclear
respectively) polymorphonuclear
leukocytes with
leukocytes EDED
with 50 values
50 valuesofof2.58
2.58and
and 1.57 μM[38].
1.57 μM [38].
Figure 19.Spirocyclic
Figure19. lcatonesisolated
Spirocyclic lcatones isolated from
from Penicillium
Penicillium dangeardii.
dangeardii.
Figure 19. Spirocyclic lcatones isolated from Penicillium dangeardii.
Rather intriguing and unique is the structure of spirocyclic hydantoins possessing a furanose
unit. One of the first representatives of these natural products (hydantocidine 52) was isolated from
Streptomyces hygroscopicus (Figure 20). Hydantocidine displayed herbicidal properties which were
linked to its ability to inhibit adenylate succinate synthase [39].
Molecules 2019, 24, 4165 9 of 37
Figure 19. Spirocyclic lcatones isolated from Penicillium dangeardii.
Figure 20. Structure of herbicidal hydantocidine isolated from Streptomyces hygroscopicus.

Figure 20. Structure of herbicidal hydantocidine isolated from Streptomyces hygroscopicus.
A unique presentation of a [4.4.0] spirocyclic system is featured in spirocyclic benzofuranones
53–55Aisolated
Moleculesunique
2018, presentation
x x ethanolicofextracts
from
23,23, a [4.4.0]ofspirocyclic
Ganodermasystem is featured
Applanatum (Figurein21)
spirocyclic
[40]. benzofuranones
Molecules 2018, 10 10 of 39
of 39
53–55 isolated from ethanolic extracts of Ganoderma Applanatum (Figure 21) [40].
Figure
Figure21.
Figure Spirocyclic
21.Spirocyclic
21. benzofuranones
Spirocyclicbenzofuranones isolated
benzofuranones isolated from
isolatedfrom Ganoderma
fromGanoderma Applanatum.
GanodermaApplanatum.
Applanatum.
Not
Notless interesting
less interestingthan
thanthethespirocyclic
spirocyclic benzofuranones discussedabove
benzofuranones discussed above arenatural
natural products
Not less interesting than the spirocyclic benzofuranones discussed aboveare products
are natural products
possessing
possessing a spirooxyindole
a spirooxyindole motif.
motif. One
One of
of the first representatives
representativesofof[4.4.0]
[4.4.0]spirocyclic
compounds
possessing a spirooxyindole motif. One of the first representatives of [4.4.0] spirocyclic compounds
reported
reportedininthe literature
the literatureisisspirotriprostatine
spirotriprostatine (56),
(56), possessing moderate(IC
possessing moderate (IC50 = =197.5
197.5 µM)
μM) cytotoxic
cytotoxic
reported in the literature is spirotriprostatine (56), possessing moderate (IC5050 = 197.5 μM) cytotoxic
activity
activity [41].Naturally
[41]. Naturallyoccurring
occurring spirooxyindoles
spirooxyindoles were werefirst
firstisolated
isolatedfrom
fromplants
plantsApocynaceae
Apocynaceaeandand
activity [41]. Naturally occurring spirooxyindoles were first isolated from plants Apocynaceae and
Rubiacae,
Rubiacae, andandfromfrom Aspidosperma,
Aspidosperma, Mitragyna,
Mitragyna, Ourouparia,
Ourouparia, Rauwolfia
Rauwolfia and Vinca and Vinca These
genera. genera. These
compounds
Rubiacae, and from Aspidosperma, Mitragyna, Ourouparia, Rauwolfia and Vinca genera. These
cancompounds
be furthercan be further
classified intoclassified into two substructural
two substructural classes: theclasses: the tetracyclic
tetracyclic secoyohimbanesecoyohimbane
type (e.g.,
compounds can be further classified into two substructural classes: the tetracyclic secoyohimbane
type (e.g., rhynchophylline (57)) and the pentacyclic heteroyohimbane type (e.g.,
rhynchophylline (57)) and the pentacyclic heteroyohimbane type (e.g., formosanine (58)) (Figure 22) formosanine (58))
[42].
type (e.g., rhynchophylline
(Figure 22) [42].
(57)) and the pentacyclic heteroyohimbane type (e.g., formosanine (58))
(Figure 22) [42].
Figure 22. Examples of naturally occurring spirooxyindoles.

Figure 22. Examples of naturally occurring spirooxyindoles.
A Avery interestingFigure
class22.
ofExamples
natural of naturallycontaining
products occurring spirooxyindoles.
a [4.4.0] spirocyclic motif includes
very interesting class of natural products containing a [4.4.0] spirocyclic motif includes
spiropseudoindoxyl
spiropseudoindoxyl alkaloids.
alkaloids. Microbial transformation of the alkaloid mitragynine by
thethe fungus
A very interesting class ofMicrobial
natural transformation of the alkaloid
products containing a [4.4.0]mitragynine
spirocyclicbymotif fungus
includes
Helminthosporum
Helminthosporumsp. was
was reported
sp.alkaloids.
reported in
in 1974
1974 to
to yield two major
yield two major metabolites.The Thecompounds
compounds were
spiropseudoindoxyl Microbial transformation of the metabolites.
alkaloid mitragynine by the were
fungus
isolated from the biological milieu and their structures were elucidated as mitragynine
isolated from the biological milieu and their structures were elucidated as mitragynine pseudoindoxyl
Helminthosporum sp. was reported in 1974 to yield two major metabolites. The compounds were
(59) and hydroxy mitragynine
pseudoindoxyl pseudoindoxyl
(59) and hydroxy (60) (Figure
mitragynine 23) [43]. These
pseudoindoxyl (60)compounds
(Figure 23)were laterThese
[43]. shown
to compounds
possess opioid analgesic
were activity
later shown by exerting
to possess opioid mu agonism
analgesic and delta
activity antagonism
by exerting while not
mu agonism andrecruiting
delta
pseudoindoxyl (59) and hydroxy mitragynine pseudoindoxyl (60) (Figure 23) [43]. These
β-arrestin-2
antagonism [44].
while not recruiting β-arrestin-2 [44].
compounds were later shown to possess opioid analgesic activity by exerting mu agonism and delta
antagonism while not recruiting β-arrestin-2 [44].
spiropseudoindoxyl alkaloids. Microbial transformation of the alkaloid mitragynine by the fungus
Helminthosporum sp. was reported in 1974 to yield two major metabolites. The compounds were
pseudoindoxyl (59) and hydroxy mitragynine pseudoindoxyl (60) (Figure 23) [43]. These
Molecules
compounds 2019, 24,
were4165later shown to possess opioid analgesic activity by exerting mu agonism and10delta
of 37
antagonism while not recruiting β-arrestin-2 [44].
Figure 23. Structures of mitragynine pseudoindoxyl (59) and hydroxy mitragynine pseudoindoxyl (60).
Figure 23. Structures of mitragynine pseudoindoxyl (59) and hydroxy mitragynine pseudoindoxyl
(60). [4.4.0] spirocyclic pseudoindoxyl motif represents a rather common feature in indole alkaloids,
The
as can be illustrated by such examples as fluorocurine (61) [45], several diketopiperazines isolated from
The [4.4.0] spirocyclic
holothurianderived pseudoindoxyl
fungus Aspergillus motif
fumigatus represents
(62a–d) a rather common
[46], brevianamide feature
B (63) [47], in indole
and rauniticine
alkaloids, as can(64)
Molecules 2018,
pseudoindoxyl 23, x be [48]
illustrated
(Figureby such examples as fluorocurine (61) [45], several diketopiperazines
24). 11 of 39
isolated from holothurianderived fungus Aspergillus fumigatus (62a–d) [46], brevianamide B (63) [47],
and rauniticine pseudoindoxyl (64) [48] (Figure 24).
Figure 24.
Figure Structures of
24. Structures of [4.4.0]
[4.4.0] spirocyclic
spirocyclic pseudoindoxyl
pseudoindoxyl alkaloids
alkaloids fluorocurine
fluorocurine (61),
(61), fungus-derived
fungus-derived
diketopiperazines (62a–d), brevianamide B (63), and rauniticine pseudoindoxyl
diketopiperazines (62a–d), brevianamide B (63), and rauniticine pseudoindoxyl (64). (64).
A structurally unique [4.4.0] spiroheterocyclic system is represented by a series of highly

oxygenated lactone lactams (65–69) isolated from marine sediment-derived fungus Aspergillus sydowi
oxygenated lactone lactams (65–69) isolated from marine sediment-derived fungus Aspergillus
D2–6 (Figure 25). Compounds 65–69 were shown to inhibit growth of adenocarcinoma cell line A549
sydowi D2–6 (Figure 25). Compounds 65–69 were shown to inhibit growth of adenocarcinoma cell
with an IC50 value of 10 µM [49].
line A549 with an IC50 value of 10 μM [49].
Figure 24. Structures of [4.4.0] spirocyclic pseudoindoxyl alkaloids fluorocurine (61), fungus-derived
diketopiperazines (62a–d), brevianamide B (63), and rauniticine pseudoindoxyl (64).

oxygenated lactone lactams (65–69) isolated from marine sediment-derived fungus Aspergillus
Molecules 2019, 24, 4165 11 of 37
sydowi D2–6 (Figure 25). Compounds 65–69 were shown to inhibit growth of adenocarcinoma cell
line A549 with an IC50 value of 10 μM [49].
Figure
Figure 25. Members of
25. Members of aa family
family of
of spirocyclic
spirocyclic lactone
lactone lactams
lactams isolated
isolated from
from marine
marine sediment-derived
sediment-derived
fungus Aspergillus sydowi D2–6.
fungus Aspergillus sydowi D2–6.
A wide diversity of heterocyclic spirocyclic scaffolds all belonging to the generalized [4.4.0] system
A wide diversity of heterocyclic spirocyclic scaffolds all belonging to the generalized [4.4.0]
(70–73) (Figure 26) have been isolated recently. Two regioisomeric phytoalexins—erucalexin (70) and
system (70–73) (Figure 26) have been isolated recently. Two regioisomeric phytoalexins—erucalexin
its regioisomer (+)-1-methoxyspirobrassinin (71) were isolated from the wild crucifer Erucastrum
(70) and its regioisomer (+)-1-methoxyspirobrassinin (71) were isolated from the wild crucifer
gallicum [50].
Erucastrum gallicum [50].
Figure 26. Natural products illustrating the range of heterospirocyclic [4.4.0]-sized motifs.
Figure 26. Natural products illustrating the range of heterospirocyclic [4.4.0]-sized motifs.
Mycotoxins related to tryptoquialanine A (71) were isolated from Penicillium spp. and Aspergillus
Mycotoxins
clavatus [51]. Forrelated to tryptoquialanine
tryptoquialanines, A (71) pathway
the biosynthetic were isolated from
has been Penicillium
recently spp. [25].
elucidated and
Aspergillus clavatus [51]. For tryptoquialanines, the biosynthetic pathway has
Another spirooxyindole lactone lactam compound 73 isolated from Coix lachryma-jobi L. has been been recently
elucidated
recently [25]. and
reported Another
shown to spirooxyindole
possess activitylactone lactam lung
against human compound 73 isolated
cancer (A549) and colonfrom Coix
carcinoma
lachryma-jobi L. has been recently
(HT-29 and COLO205) cell lines [52]. reported and shown to possess activity against human lung cancer
(A549) and colonmetabolite
Secondary carcinoma (HT-29 and COLO205)
investigation cell lines
of the liquid [52]. of entomogenous fungus Isaria
culture
Secondary led
cateniannulata metabolite
to the investigation
identification ofof the liquidspirocyclic
a new culture of compound
entomogenous fungus Isaria
74 containing a
cateniannulata led to the identification of a new spirocyclic
1,6-dioxaspiro[4.4]nonane moiety (Figure 27). The compound showed weak inhibitorycompound 74 containing a
activity
1,6-dioxaspiro[4.4]nonane moiety
against the HeLa cancer cell line [53]. (Figure 27). The compound showed weak inhibitory activity
against the HeLa[4.4.0]
Spirocyclic cancertetrahydrofurans
cell line [53]. are featured in a series of twelve natural products 75a–l
dubbed bipolaricins (Figure 28). These compounds are ophiobolin-type tetracyclic sesterterpenes
from a phytopathogenic Bipolaris sp. fungus. They were tested for HMGCoA reductase inhibition as
well as anti-inflammatory and cytotoxic activities. The biological activity discovered provided the
basis for considering these compounds as leads for antiinflammation and antihyperglycemic therapy
developments [54].
Figure 27. 1,6-Dioxaspiro[4.4]nonane secondary metabolite isolated from entomogenous fungus
Isaria cateniannulata.
Spirocyclic [4.4.0] tetrahydrofurans are featured in a series of twelve natural products 75a–l
elucidated [25]. Another spirooxyindole lactone lactam compound 73 isolated from Coix
lachryma-jobi L. has been recently reported and shown to possess activity against human lung cancer
(A549) and colon carcinoma (HT-29 and COLO205) cell lines [52].
Secondary metabolite investigation of the liquid culture of entomogenous fungus Isaria
cateniannulata led to the identification of a new spirocyclic compound 74 containing a
Molecules 2019, 24, 4165 12 of 37
1,6-dioxaspiro[4.4]nonane moiety (Figure 27). The compound showed weak inhibitory activity
against the HeLa cancer cell line [53].
Figure 27. 1,6-Dioxaspiro[4.4]nonane secondary metabolite isolated from entomogenous fungus

Figure
Molecules
Molecules 2018,27.
2018, 23, xx1,6-Dioxaspiro[4.4]nonane secondary metabolite isolated from entomogenous fungus
23, 13
13 of
of 39
39
Spirocyclic [4.4.0] tetrahydrofurans are featured in a series of twelve natural products 75a–l
well as anti-inflammatory and cytotoxic activities. The biological activity discovered provided the
basis for considering these compounds as leads for antiinflammation and antihyperglycemic
therapy developments [54].
Figure 28. Bipolaricins from phytopathogenic Bipolaris sp. fungus.

Figure
Figure 28.
28. Bipolaricins
Bipolaricins from
from phytopathogenic
phytopathogenic Bipolaris
Bipolaris sp.
sp. fungus.
fungus.
An interesting type of [4.4.0] spirocyclic motif is present in fredericamycin A (76), an antitumor
An
An interesting
interesting type of
of [4.4.0]
[4.4.0] spirocyclic motif is
is present in fredericamycin A (76), an antitumor
antibiotic produced type
by Streptomycesspirocyclic motif 29)
griseus (Figure present
[55,56].in fredericamycin A (76), an antitumor
antibiotic
antibiotic produced
produced byby Streptomyces
Streptomyces griseus
griseus (Figure
(Figure 29)
29) [55,56].
[55,56].
Structure of fredericamycin
Figure 29. Structure
Figure fredericamycin A possessing
possessing a [4.4.0] spirocyclic
spirocyclic motif.
Figure 29.
29. Structure of
of fredericamycin A
A possessing aa [4.4.0]
motif.
Summing
Summing up,
up, the
the overall
overall scaffold
scaffold distribution
distribution within
within the
the general
general [4.4.0]
[4.4.0] spirocyclic
spirocyclic system
system is
is
shown
shown in
in Figure
Figure 30.
30.
Molecules 2019, 24, 4165 13 of 37

Summing up, the overall scaffold distribution within the general [4.4.0] spirocyclic system is
shown in Figure 30.
Figure 30. Overall diversity of [4.4.0] spirocyclic scaffolds represented in the natural products
Figure 30. Overall diversity of [4.4.0] spirocyclic scaffolds represented in the natural products domain.
Figure 30. Overall diversity of [4.4.0] spirocyclic scaffolds represented in the natural products
domain.
domain.
Spirolactones are the most widely represented motifs in the [4.4.0] spirocyclic systems,
with Spirolactones
over 20 examples are the most widely
discussed above. represented motifs in
Spirocyclic lactams arethe [4.4.0] spirocyclic
exemplified systems,
by 10 natural with
products.
Spirolactones
over 20 examples are the
discussed most widely
above. represented
Spirocyclic motifs in the
lactams are exemplified[4.4.0] spirocyclic
bycommon systems,
10 natural with
products.
However, [4.4.0] spirocyclic lactam lactones and spirooxyindoles are much less in the natural
over 20 examples
However, [4.4.0] discussed lactam
spirocyclic above. lactones
Spirocyclic andlactams are exemplified
spirooxyindoles are muchby 10 natural
less common products.
in the
products and are represented by only a handful of examples. In terms of biological activity, the current
However,
natural [4.4.0] and
products spirocyclic
are lactam lactones
represented by only and
a spirooxyindoles
handful of examples. are
In much
terms less
of commonactivity,
biological in the
data are mostly limited to cytostatic and antibacterial properties. The natural products isolated within
natural
the last products
current andmostly
data are are represented
limited toby only a handful
cytostatic and to of examples.
antibacterial In terms The
properties. of biological activity,
the 1–2 years are poorly investigated with regard their biological properties. natural products
the current
isolated datathe
within arelast
mostly limited
1–2 years areto cytostatic
poorly and antibacterial
investigated with regard properties. The natural
to their biological products
properties.
isolated within the last
8. [4.5.0] Spirocyclic System1–2 years are poorly investigated with regard to their biological properties.
Secondary
8. [4.5.0] Systeminvestigation of Teucrium viscidum led to the identification of a [4.5.0]
metabolite
Spirocyclic
Secondary
spirocyclic metabolite
compound investigation
(77) possessing of Teucrium
a unique viscidum
skeleton [57]. Aled to the of
skeleton identification of a [4.5.0]
similar complexity had
only Secondary
spirocyclic
been featured metabolite
compound once(77) investigation
possessing
in the of
literaturea three Teucrium
unique viscidum
skeleton
decades led
[57].that
before to
A skeleton the identification
of similar
[58] (Figure of
31). complexity a [4.5.0]
had
spirocyclic compound
only been featured once(77) possessing
in the a three
literature unique skeleton
decades [57]. that
before A skeleton of similar
[58] (Figure 31). complexity had
only been featured once in the literature three decades before that [58] (Figure 31).
Figure 31. Spiro pentacyclic secondary metabolite isolated from Teucrium viscidum.
The [4.5.0] spirocyclic motifs are featured in many natural terpenes. Recently, new spirocyclic
The [4.5.0]78–79
triterpenoids spirocyclic
were motifs
isolatedarefrom
featured in many
Leonurus natural
japonicus terpenes.
fruit (FigureRecently, newcompounds
32). These spirocyclic
triterpenoids 78–79 were isolated from Leonurus japonicus fruit (Figure 32). These compounds
Molecules 2019, 24, 4165 14 of 37
The [4.5.0] spirocyclic motifs are featured in many natural terpenes. Recently, new spirocyclic
triterpenoids
Molecules
Molecules 2018, 78–79
2018, 23,
23, xx were isolated from Leonurus japonicus fruit (Figure 32).
These compounds displayed
15
15 of
of 39
39
moderately potent (IC50 < 10 µM) growth inhibition of five human cancer cell lines (stomach cancer
displayed moderately
displayed moderately potent
potent (IC
(IC50 < 1010 μM)
μM) growth
growth inhibition
inhibition of
of five
five human
human cancer
cancer cell
cell lines
lines
displayedand
BGC-823 moderately potent (IC5050 << Huh-7,
KE-97, hepatocarcinoma 10 μM)Jurkat
growth inhibition
T-cell of five
limphoblasts, andhuman
breast cancer cell lines
adenocarcinoma
(stomach cancer
(stomach cancer BGC-823
BGC-823 and KE-97,
KE-97, hepatocarcinoma Huh-7,
Huh-7, Jurkat T-cell
T-cell limphoblasts, and
and breast
cancer BGC-823 and
(stomach[59].
MCF-7) and KE-97, hepatocarcinoma
hepatocarcinoma Huh-7, Jurkat
Jurkat T-cell limphoblasts,
limphoblasts, and breast
breast
adenocarcinoma
adenocarcinoma MCF-7) [59].
adenocarcinoma MCF-7)
MCF-7) [59].
[59].
Figure 32. New spirocyclic triterpenoids isolated from Leonurus japonicas.

Figure
Figure 32.
32. New
New spirocyclic
spirocyclic triterpenoids
triterpenoids isolated
isolated from
from Leonurus
Leonurus japonicas.
japonicas.
Another example of an all-carbon [4.5.0] spirocyclic system is provided by spirocarolitone (80),
Another example
Another example of
of an
an all-carbon [4.5.0]
[4.5.0] spirocyclic
spirocyclic system
system is
is provided
provided by spirocarolitone
spirocarolitone (80),
Another
recently example
isolated of an all-carbon
all-carbon
from Ruptiliocarpon [4.5.0] [60]
caracolito spirocyclic
(Figuresystem
33). is provided by
by spirocarolitone (80),
(80),
recently
recently isolated
isolated from
from Ruptiliocarpon
Ruptiliocarpon caracolito
caracolito [60]
[60] (Figure
(Figure 33).
33).
recently isolated from Ruptiliocarpon caracolito [60] (Figure 33).
Figure 33.
Figure 33. Spirocarolitone isolated
isolated from Ruptiliocarpon
Ruptiliocarpon caracolito.
Figure 33. Spirocarolitone
Spirocarolitone isolated from
from Ruptiliocarpon caracolito.
caracolito.
novel
novel tricyclic-iridal
Structurally novel
Structurally triterpenoids
triterpenoids belamcandanes
tricyclic-iridal triterpenoids belamcandanesA A and
and BB (81
(81 and
and 82)
82) (Figure 34)
(Figure 34)
34)
Structurally novel tricyclic-iridal
tricyclic-iridal triterpenoids belamcandanes
belamcandanes A A and
and BB (81
(81 and
and 82)
82) (Figure
(Figure 34)
were
were recently isolated from Belamcanda
Belamcanda chinensis and shown to possess
possess moderate
moderate hepatoprotective
hepatoprotective
were recently
recently isolated
isolated from
from Belamcanda
Belamcanda chinensis
chinensis and
and shown
shown to
to possess
possess moderate
moderate hepatoprotective
hepatoprotective
properties.
properties. A possible biosynthetic pathway has been proposed [61].
properties. A
A possible
possible biosynthetic
biosynthetic pathway
pathway has
has been
been proposed
proposed [61].
[61].
Figure 34. Structurally novel triterpenoids isolated from Belamcanda chinensis.

34. Structurally
Figure
Figure 34. Structurally
Structurally novel
novel triterpenoids
triterpenoids isolated
isolated from
from Belamcanda
Belamcanda chinensis.
chinensis.
New biologically active sesquiterpenoids 83–85 possessing an all-carbon [4.5.0] spirocyclic
New biologically
New biologically active
active sesquiterpenoids
sesquiterpenoids 83–85
83–85 possessing
possessing an an all-carbon
all-carbon [4.5.0]
[4.5.0] spirocyclic
spirocyclic
New
system werebiologically active
isolated from sesquiterpenoids
rhizomes 83–85 possessing
of Acorus calamus (Figure 35).anCompound
all-carbon 83
[4.5.0] spirocyclic
exhibited weak
system were
system were isolated
isolated from
from rhizomes
rhizomes of
of Acorus
Acorus calamus
calamus (Figure
(Figure 35).
35). Compound
Compound 83 83 exhibited
exhibited weak
weak
system were isolated from rhizomes of Acorus calamus (Figure 35).
hepatoprotective activities against APAP-induced HepG2 cell damage [62]. Compound 83 exhibited weak
hepatoprotective
hepatoprotective activities
activities against
against APAP-induced
APAP-induced HepG2
HepG2 cell
cell damage
damage [62].
[62].
hepatoprotective activities against APAP-induced HepG2 cell damage [62].
The ethyl acetate soluble fraction of a MeOH extract of the dried stems and roots of Capsicum
annum gave several new sesquiterpenoids, among which two [4.5.0] spirocyclic compounds termed
canusesnols (86–87, Figure 36) were identified and evaluated for their cytotoxic activities [63].
Figure 34. Structurally novel triterpenoids isolated from Belamcanda chinensis.
New biologically active sesquiterpenoids 83–85 possessing an all-carbon [4.5.0] spirocyclic

Molecules were24,isolated
system 2019, 4165
from rhizomes of Acorus calamus (Figure 35). Compound 83 exhibited 15weak
of 37
hepatoprotective activities against APAP-induced HepG2 cell damage [62].

Figure 35. The [4.5.0] spirocyclic sesquiterpenoids from rhizomes of Acorus calamus.
Figure 35.
Figure 35. The
The [4.5.0]
[4.5.0] spirocyclic
spirocyclic sesquiterpenoids
sesquiterpenoids from
from rhizomes
rhizomes of
of Acorus
Acorus calamus.
calamus.
The ethyl acetate soluble fraction of a MeOH extract of the dried stems and roots of Capsicum
The ethyl
The ethyl acetate
acetate soluble
soluble fraction
fraction of
of aa MeOH
MeOH extract
extract of
of the dried
dried stems
stems and
and roots
roots of
of Capsicum
Capsicum
annum gave several new sesquiterpenoids, among which twothe
[4.5.0] spirocyclic compounds termed
annum
annum gave
gave several
several new
new sesquiterpenoids,
sesquiterpenoids, among
among which
which two
two [4.5.0]
[4.5.0] spirocyclic
compounds termed
termed
canusesnols (86–87, Figure
Figure 35. 36) were
The [4.5.0] identified
spirocyclic and evaluated
sesquiterpenoids fromfor their cytotoxic
rhizomes of Acorusactivities
calamus. [63].
canusesnols (86–87, Figure 36) were identified and evaluated for their cytotoxic activities
canusesnols (86–87, Figure 36) were identified and evaluated for their cytotoxic activities [63]. [63].
Figure
Figure 36.
36. Canusesnols
Canusesnols from
from Capsicum
Capsicum annum.
annum.
Figure 36.
Figure 36. Canusesnols
Canusesnols from
from Capsicum
Capsicum annum.
annum.
Perhaps the most clinically advanced natural natural spirocyclic

spirocyclic compound—spirocyclic
compound—spirocyclic benzofuran
Perhaps the
Perhaps the most
most clinically
clinically advanced
advanced natural
natural spirocyclic
spirocyclic compound—spirocyclic
compound—spirocyclic benzofuran
benzofuran
griseofulvin (88)
(88)isolated
isolatedfrom
from Penicillium
Penicillium griseofulvum
griseofulvum has been
has been employed
employed in clinical
in clinical practicepractice for
for therapy
griseofulvin
griseofulvin (88) isolated
(88) ring
isolated from
from Penicillium
Penicillium griseofulvum
griseofulvum has
has been
been employed
employed in clinical
inname
clinical practice
practice
TM for
for
therapy against
against ring worms worms
[64] and [64]
was and was
marketed by marketed by GlaxoSmithKline
GlaxoSmithKline under the tradeunder the trade
Grisovin name
[65]
therapy TM
therapy against ring
against ring worms [64][64] and
and was
was marketed
marketed by by GlaxoSmithKline
GlaxoSmithKline under
under the
the trade
trade name
name
Grisovin37).
(Figure [65] (Figureworms
37).
Grisovin TM [65] (Figure 37).
GrisovinTM [65] (Figure 37).
Figure 37. Anti-ring worm drug griseofulvin (GrisovinTM

TM).
Figure
Figure 37.
37. Anti-ring worm
worm drug
drug griseofulvin
griseofulvin (Grisovin
(Grisovin ).
TM).
Figure 37. Anti-ring worm drug griseofulvin (Grisovin ).
TM
Natural
Natural [4.5.0]spirocyclic
spirocyclic lactones are characterized by structural
a wide structural diversity and
Natural [4.5.0]
Natural [4.5.0] spirocyclic
[4.5.0]
lactones
spirocyclic are characterized
lactones
lactones are
by a wide
are characterized
characterized by aa wide
by
diversity and
wide structural
structural abundance
diversity
diversity and
and
abundance
of of biological
biologicalofactivities activities
reported reported
for them. Thesefor them.
are These
exemplified are exemplified
byexemplified
the mediatorby by the
of the mediator
mycoparasitism of
abundance
abundance of biological
biological activities
activities reported
reported for
for them.
them. These
These are
are exemplified by the mediator
mediator of
of
mycoparasitism
lambertollol lambertollol
C (89) C (89) chloride
[66], glycine-gated [66], glycine-gated chloride
channel receptor channel(−)-ircinianin
modulator receptor modulator
(90) [67],
mycoparasitism
mycoparasitism lambertollol
lambertollol C (89) [66], glycine-gated
C (89) andirolactone
[66], glycine-gated chloride
chloride channel
channel receptor modulator
receptor [68]
modulator
(−)-ircinianin
and terpenoid(90) [67], and terpenoid
andirolactone (91) isolated from Cedrus(91) isolated
libanotica from
[68] Cedrus
(Figure 38).libanotica (Figure
(−)-ircinianin
(−)-ircinianin (90)
(90) [67], and
[67], and terpenoid
terpenoid andirolactone
andirolactone (91)
(91) isolated
isolated from
from Cedrus
Cedrus libanotica [68]
libanotica [68] (Figure
(Figure
38).
38).
38).
Figure 38. Examples of natural [4.5.0] spirocyclic lactones.

Figure 38. Examples of natural [4.5.0] spirocyclic lactones.
Figure 38. Examples
Figure 38. Examples of
of natural
natural [4.5.0]
[4.5.0] spirocyclic
spirocyclic lactones.
lactones.
More examples of bioactive [4.5.0] spirocyclic lactones are provided by abyssomicins (92a–c,
More
Figure 39),examples of bioactive
which were isolated[4.5.0]
from spirocyclic lactones
Actinobacteria andare provided
shown by abyssomicins
to inhibit (92a–c,
p-aminobenzoate
More
More examples
examples of bioactive
of bioactive [4.5.0]
[4.5.0] spirocyclic
spirocyclic lactones
lactones are
are provided
provided by abyssomicins
by abyssomicins (92a–c,
(92a–c,
Figure 39),
biosynthesis which were isolated from Actinobacteria and shown to inhibit p-aminobenzoate
[69]. were isolated from Actinobacteria and shown to inhibit p-aminobenzoate
Figure
Figure 39), which
39), which were isolated from Actinobacteria and shown to inhibit p-aminobenzoate
biosynthesis [69]. and
Antibacterial antitumor compound lactonamycin Z (93) was isolated from Streptomyces
biosynthesis [69].
biosynthesis [69].
sanglieri [70] and is an example of a [4.5.0] spirocyclic lactone embedded in a complex polycyclic system
(Figure 40).
Molecules 2019, 24, 4165 16 of 37
In 2015, Cech and co-workers reported new antibiotic spirocyclic lactone chaetocuprum (94) [71].
This compound was isolated from an endophyte fungus growing on the roots of wild Anemopsis
californica
Moleculesplant which
2018, 23, x was traditionally used by North American tribes to treat infections
17 of 39 and
inflammation. Similarly, growing endophyte fungal parasites on the roots of Chaetomium indicum
allowed Asai and Oshima [72] to isolate both epimers of spiroindicumide A and B (95 and 96,
respectively) which
Molecules 2018, 23, x feature an unprecedented spirocyclic lactone scaffold (Figure 41). 17 of 39
Figure 39. Abyssomycins from Actinobacteria.
Antibacterial and antitumor compound lactonamycin Z (93) was isolated from Streptomyces
sanglieri [70] and is an example of a [4.5.0] spirocyclic lactone embedded in a complex polycyclic
system (Figure 40).
Figure 39. Abyssomycins from Actinobacteria.
Figure 39.Abyssomycins
39.
Figure fromActinobacteria.
Abyssomycins from Actinobacteria.
system (Figure 40).
system (Figure 40).
Figure 40. Antibacterial and antitumor compound lactonamycin Z isolated from Streptomyces
sanglieri.
In 2015, Cech and co-workers reported new antibiotic spirocyclic lactone chaetocuprum (94)
[71]. This compound was isolated from an endophyte fungus growing on the roots of wild Anemopsis
californica plant which was traditionally used by North American tribes to treat infections and
Figure 40. Antibacterial
Figure and antitumor
40. Antibacterial compound
and antitumor lactonamycin
compound Z isolated
lactonamycin Z isolated Streptomyces
fromfrom sanglieri.
Streptomyces
respectively) which feature an unprecedented spirocyclic lactone scaffold (Figure 41).
sanglieri.
In 2015, Cech and co-workers reported new antibiotic spirocyclic lactone chaetocuprum (94)
Figure 40. Antibacterial and antitumor compound lactonamycin Z isolated from Streptomyces
[71]. This compound was isolated from an endophyte fungus growing on the roots of wild Anemopsis
sanglieri.
inflammation. Similarly,
In 2015, Cech growing endophyte
and co-workers fungal
reported new parasites
antibiotic on the roots
spirocyclic of Chaetomium
lactone chaetocuprumindicum
(94)
allowed Asai and Oshima [72] to isolate both epimers of spiroindicumide A and B
[71]. This compound was isolated from an endophyte fungus growing on the roots of wild Anemopsis(95 and 96,
respectively) which feature an unprecedented spirocyclic lactone scaffold (Figure 41).
respectively) which
Figurefeature an unprecedented
41. Spirocyclic spirocyclic
lactones isolated fromlactone scaffold
endophyte (Figure
fungal 41).
parasites.
Figure 41. Spirocyclic lactones isolated from endophyte fungal parasites.
In addition
In additionto to
lambertollol
lambertollolCC discussed above,two
discussed above, two related
related epimeric
epimeric compounds
compounds labertollol
labertollol A
A (97)
(97)and
and BB(98),
(98),
alsoalso bearing
bearing a 4,8-dihydroxy-2,3,4-trihydronaphthalen-1-one
a 4,8-dihydroxy-2,3,4-trihydronaphthalen-1-one scaffolda and
scaffold and featuring
featuring a spirobutenolide
spirobutenolide moiety
moiety (Figure 42)(Figure 42) were
were reported to reported to possess
possess high antifungalhigh antifungal
activity activity
(IC50 = 0.5
(IC50 = 0.5 µg/mL) [73].
μg/mL) [73].
Traditional Chinese medicinal plant Rehmannia glutinosa turned out to be a rich source of [4.5.0]
spirocyclic lactones: Figure
massarigenin D (99),
41. Spirocyclic spiromassaritone
lactones (100), and
isolated from endophyte paecilospirone
fungal parasites. (101) (Figure 43)
which displayed potent (IC50 from 0.25 to 32 µg/mL) antifungal activity [74].
In addition A
Perenniporide to (102)
lambertollol
was the C only
discussed above, two
spirocyclic related
lactone epimeric of
derivative compounds labertollol A
the naphthalenone family
(97) and B (98), also
of natural products Figure bearing a
perenniporides4,8-dihydroxy-2,3,4-trihydronaphthalen-1-one
A–D isolated scaffold and featuring
of a fungus Perenniporia a sp.
41. Spirocyclic lactones isolatedfrom solid cultures
from endophyte fungal parasites.
spirobutenolide moiety (Figure 42) were reported to possess high antifungal activity (IC50 = 0.5
inhabiting the larva of Euops chinesis, a phytophagous weevil with high host specificity to the medicinal
μg/mL) [73].
In addition
plant Fallopia japonicato(Figure
lambertollol C discussed above, two related epimeric compounds labertollol A
44) [75].
(97) and B (98), also bearing a 4,8-dihydroxy-2,3,4-trihydronaphthalen-1-one scaffold and featuring a
spirobutenolide moiety (Figure 42) were reported to possess high antifungal activity (IC50 = 0.5
μg/mL) [73].
Figure 42. Lambertollols A and B.

Molecules 2019, 24, 4165 17 of 37
spirocyclic lactones:
Traditional massarigenin
Chinese medicinalDplant
(99), Rehmannia
spiromassaritone
glutinosa(100),
turnedand
out paecilospirone (101)
to be a rich source (Figure
of [4.5.0]
43)spirocyclic
which displayed potent
lactones: (IC50 from
massarigenin D 0.25
(99), to 32 μg/mL) antifungal
spiromassaritone activity
(100), and [74].
paecilospirone (101) (Figure
43) which displayed potent (IC50 from 0.25 to 32 μg/mL) antifungal activity [74].
spirocyclic lactones: massarigenin D (99), spiromassaritone (100), and paecilospirone (101) (Figure
Figure
Figure
43) which displayed potent (IC50 from 42.toLambertollols
0.25 Lambertollols AAand
andB.B. activity [74].
32 μg/mL) antifungal
spirocyclic lactones: massarigenin D (99), spiromassaritone (100), and paecilospirone (101) (Figure
Figure 43. Spirocyclic lactones from traditional Chinese medicinal plant Rehmannia glutinosa.
43) whichFigure
displayed potent (IC
43. Spirocyclic 50 from
lactones 0.25traditional
from to 32 μg/mL) antifungal
Chinese medicinalactivity [74].
plant Rehmannia glutinosa.
Perenniporide A (102) was the only spirocyclic lactone derivative of the naphthalenone family
of of
natural products perenniporides A–D isolated from solid cultures of a fungus Perenniporia sp.
natural products perenniporides A–D isolated from solid cultures of a fungus Perenniporia sp.
inhabiting
inhabitingthethelarva
larvaofofEuops
Euopschinesis,
chinesis, aa phytophagous weevil with
phytophagous weevil with high
highhost
hostspecificity
specificitytotothethe
medicinal plant
Figure Fallopia
43. japonica
Spirocyclic (Figure
lactones from 44) [75].
traditional
medicinal plant Fallopia japonica (Figure 44) [75]. Chinese medicinal plant Rehmannia glutinosa.
Figure 43. Spirocyclic lactones from traditional Chinese medicinal plant Rehmannia glutinosa.
of natural products perenniporides A–D isolated from solid cultures of a fungus Perenniporia sp.
Figure
inhabiting the 43. Spirocyclic
larva of Euopslactones from atraditional
chinesis, Chinese weevil
phytophagous medicinal planthigh
with Rehmannia glutinosa. to the
host specificity
medicinal plant Fallopia japonica (Figure 44) [75].
of natural products perenniporides A–D isolated from solid cultures of a fungus Perenniporia sp.
inhabiting the larva of Euops chinesis, a phytophagous weevil with high host specificity to the
medicinal plant Fallopia japonica (Figure 44) [75].
Figure 44. Perenniporide
Figure
A, the only spirocycliclactone
lactoneofofthe
the perenniporide family.
Figure 44.44. PerenniporideA,
Perenniporide A,the
theonly
onlyspirocyclic
spirocyclic lactone of theperenniporide
perenniporidefamily.
family.
AA [4.5.0] spirocyclic
[4.5.0]
lactone
spirocycliclactone
moiety
lactonemoiety
is featured
moietyisisfeatured
in secochiliolide
featured in
secochiliolideacid
in secochiliolide
acid103 (Figure
103(Figure 45),
45),
for
forfor
which
which
A [4.5.0]
antiparasite spirocyclic
activity acid 103 (Figure 45), which
antiparasite activitywas
wasreported
reported[76,77].
[76,77].
antiparasite activity was reported [76,77].
Figure 44. Perenniporide A, the only spirocyclic lactone of the perenniporide family.
A [4.5.0] spirocyclic lactone moiety is featured in secochiliolide acid 103 (Figure 45), for which
antiparasite activity was reported [76,77].
Figure 44. Perenniporide A, the only spirocyclic lactone of the perenniporide family.
A [4.5.0] spirocyclic lactone moiety is featured in secochiliolide acid 103 (Figure 45), for which
antiparasite activity was reported [76,77].Figure 45. Secochiliolide acid.
Figure 45. Secochiliolide acid.
Figure 45. Secochiliolide acid.
AA rather unique [4.5.0] spirocyclic lactone moiety was identified in sesquiterpene abiespiroside
rather unique [4.5.0] spirocyclic lactone moiety was identified in sesquiterpene abiespiroside
A A(104),
rather unique
which was[4.5.0] spirocyclic
isolated lactone tree
from Chinese moiety
Abieswas identified
dalavayi in sesquiterpene
(Figure 46). For this abiespiroside
compound,
A (104), which was isolated from Chinese tree Abies dalavayi (Figure 46). For this compound,
A (104), which
anti-inflammatory
Molecules 2018, 23, x was isolated
activity wasfrom Chinese
discovered tree
[78]. Abies dalavayi (Figure 46). For this compound,
19 of 39
anti-inflammatory activity was discovered [78].
anti-inflammatory activity was discovered
Figure[78].
45. Secochiliolide acid.
A rather unique [4.5.0] spirocyclic lactone moiety was identified in sesquiterpene abiespiroside
Figure 45.
anti-inflammatory activity was discovered Secochiliolide acid.
[78].
A rather unique [4.5.0] spirocyclic lactone moiety was identified in sesquiterpene abiespiroside
anti-inflammatory activity was discovered [78].
Figure 46. Abiespiroside A isolated from Chinese tree Abies dalavayi.

A [4.5.0] spirocyclic lactone motif is featured in pathylactone A (105) isolated from marine
sources, which demonstrated Ca2+ channel antagonistic activity (Figure 47) [79].
Molecules 2019, 24, 4165 18 of 37

A [4.5.0] spirocyclicFigure
lactone motif is featured
46. Abiespiroside in pathylactone
A isolated A (105)
from Chinese tree isolated from marine sources,
Abies dalavayi.
A [4.5.0] spirocyclic lactone motif is featured in pathylactone A (105) isolated from marine
which demonstrated Ca2+ channel
A [4.5.0] spirocyclic lactone antagonistic
motif is activity
featured in (Figure 47)
pathylactone [79].
A (105) isolated from marine
sources,Awhich
[4.5.0]demonstrated Ca 2+channel
2+
spirocyclic lactone motif isantagonistic
featured in activity (Figure
pathylactone A 47) [79].
(105) isolated from marine
sources, which demonstrated Ca channel antagonistic activity (Figure 47) [79].
sources, which demonstrated Ca2+ channel antagonistic activity (Figure 47) [79].
Figure 47. Pathylactone

Figure47. Pathylactone AAisolated
isolatedfrom
frommarine
marinesources.
sources.
Figure
Figure47.
47.Pathylactone
Pathylactone A
A isolated frommarine
isolated from marinesources.
sources.
A whole series of spirolactones containing a terpenoid carane system (106–110) was reported as
A whole series of spirolactones containing a terpenoid carane system (106–110) was reported as
A whole
synthesizedA wholeseries ofofspirolactones
in enantioselective
series containing
fashion
spirolactones (Figure aa48).
containing terpenoid carane
For these
terpenoid system(106–110)
compounds,
carane system (106–110) was reported
insect-feeding
was as as
deterrent
reported
synthesized in enantioselective fashion (Figure 48). For these compounds, insect-feeding deterrent
synthesized
synthesized
activity was in in
enantioselective
enantioselectivefashion
fashion (Figure
(Figure 48). For these
these compounds,
compounds,insect-feeding
insect-feeding deterrent
deterrent
activity wasreported
reported[80].
[80].
activity was
activity reported
was reported[80].
[80].
Figure
Figure48.
Figure Spirocyclic
48.48. carane
Spirocyclic
Spirocyclic lactones
caranelactones with
lactoneswith insect-feeding
withinsect-feeding
insect-feeding deterrent
deterrent
deterrent activity.
activity.
activity.
Figure 48. Spirocyclic carane lactones with insect-feeding deterrent activity.
InIn
addition
additionto the
In addition to toabundance
thethe
abundance of [4.5.0]
abundance spirocyclic
ofof[4.5.0]
[4.5.0] lactones
spirocyclic
spirocyclic reported
lactones
lactones in thein
reported
reported literature,
in the somesome
theliterature,
literature, instances
some
In
of instances addition
spirocyclic to the abundance of [4.5.0] spirocyclic lactones reported in the literature, some
of tetrahydrofurans
instances of spirocyclic
spirocyclic can be encountered.
tetrahydrofurans
tetrahydrofurans canbe
can For example,
beencountered.
encountered. For 15-methoxycyclocalopin
For example,
example,15-methoxycyclocalopin A (111)
15-methoxycyclocalopin and
instances
A (111) of spirocyclic tetrahydrofurans can be encountered. For example, 15-methoxycyclocalopin
andand
isocyclocalopin
A (111) Aisocyclocalopin A A(112)
(112) were reported
isocyclocalopin (112)were
were
to reportedto
bereported
isolated to be
be isolated
from isolated calopus
Boletus from
from Boletus
[81]. calopus
Boletus calopus[81].
Notably, Notably,
compound
[81]. Notably,112
A (111) and isocyclocalopin A (112) were reported to be isolated from Boletus calopus [81]. Notably,
can becompound 112112
cancan
also considered
compound bebe also
aalso
[5.5.0]considered a a[5.5.0]
spirocyclic
considered [5.5.0] spirocyclic
hexahydropyran
spirocyclic hexahydropyran
(Figure 49). (Figure
hexahydropyran (Figure49).
49).
compound 112 can be also considered a [5.5.0] spirocyclic hexahydropyran (Figure 49).
Figure 49. Natural spirocyclic tetrahydrofurans.

Figure 49.
49. Natural spirocyclic tetrahydrofurans.
Figure 49.Natural
Figure Natural spirocyclic tetrahydrofurans.
spirocyclic tetrahydrofurans.
The structures of these compounds are reminiscent of spirocyclic dihydrofuran
The structures
The structures ofof these
8,9-dehydrotheaspirone, these compoundsof are
both enantiomers
compounds whichreminiscent
are ofofbeen
(113a–b) have
reminiscent spirocyclic
reporteddihydrofuran
spirocyclic as volatile
dihydrofuran
MoleculesThe structures
2018, 23, x of these compounds are reminiscent of spirocyclic dihydrofuran 20 of 39
8,9-dehydrotheaspirone,
8,9-dehydrotheaspirone, both
both enantiomers
enantiomers of which
of which (113a–b)
(113a–b) havereported
have been been reported
as volatileasconstituents
volatile
8,9-dehydrotheaspirone, both enantiomers of which (113a–b) have been reported as volatile
of nectarines [82]. Their presence in the fruit was connected to some specific organoleptic properties of
constituents of nectarines [82]. Their presence in the fruit was connected to some specific
some kinds of nectarines (Figure 50)
organoleptic properties of some kinds of nectarines (Figure 50)
Figure 50. Enantiomers of [4.5.0] spirocyclic dihydrofuran 8,9-dehydrotheaspirone reported in

Figure 50. Enantiomers of [4.5.0] spirocyclic dihydrofuran 8,9-dehydrotheaspirone reported in the
the literature.
literature.
Rather intriguing labdane-type diterpenoids (114a–b), epimeric to each other, isolated from the
fruit of Vitex agnus-castus plant feature a unique skeleton consisting of both a [4.4.0] and a [4.5.0]
spirocyclic tetrahydrofuran system (Figure 51) [83].
Molecules 2019, 24, 4165 19 of 37
Figure 50.
Figure 50. Enantiomers
Enantiomers of
of [4.5.0]
[4.5.0] spirocyclic
spirocyclicdihydrofuran
dihydrofuran8,9-dehydrotheaspirone
8,9-dehydrotheaspirone reported
reported in
in the
the
literature.
literature.
Rather intriguing labdane-type diterpenoids (114a–b), epimeric to each other, isolated from the
Rather
fruit Rather
of intriguing
Vitexintriguing labdane-type
labdane-type
agnus-castus diterpenoids
diterpenoids
plant feature (114a–b),
a unique(114a–b), epimericto
skeleton epimeric
consisting toofeach
each other,
other,
both isolated
isolated
a [4.4.0] from
andfrom the
the
a [4.5.0]
fruit
fruit of
of Vitex
Vitex agnus-castus
agnus-castus plant
plant feature
feature aa unique
unique
spirocyclic tetrahydrofuran system (Figure 51) [83]. skeleton
skeleton consisting
consisting of
of both
both aa [4.4.0]
[4.4.0] and
and aa [4.5.0]
[4.5.0]
spirocyclictetrahydrofuran
spirocyclic tetrahydrofuransystem
system(Figure
(Figure51)
51)[83].
[83].
Figure 51. Spirocyclic labdane–type diterpenoids isolated from the fruit of Vitex agnus-castus.
Figure51.
Spirocycliclabdane–type
labdane–typediterpenoids
diterpenoidsisolated
isolatedfrom
fromthe
thefruit
fruitof
ofVitex
Vitexagnus-castus.
agnus-castus.
Rather unique is the structure of heliespirone 115 isolated from highly polar fractions of Helianthus
Rather
Rather
annuus unique
unique
L. extract isis the
[84]. the structure
structure
In this natural ofproduct,
of heliespirone
heliespirone 115 isolated
115 isolatedforms
tetrahydrofuran fromahighly
from highly polarmotif
polar
spirocyclic fractions
fractions of
withofa
Helianthus
Helianthus annuus
annuus L.
L. extract
extract
quinone-like moiety (Figure 52). [84].
[84]. In
In this
this natural
natural product,
product, tetrahydrofuran
tetrahydrofuran forms
forms aa spirocyclic
spirocyclic motif
motif
withaaquinone-like
with quinone-likemoiety
moiety(Figure
(Figure52).52).
Figure
Figure Spirocyclic
52.Spirocyclic
Figure52.
52. Spirocyclic natural
natural
natural product
product
product heliespirone
heliespirone
heliespirone featuringfeaturing
featuring a tetrahydrofurane
aatetrahydrofurane
tetrahydrofurane and a
andaaquinone-like
and quinone-like
quinone-like
moiety.
moiety. moiety.
An
Anoxygenated
oxygenated[4.5.0] spirocyclic
[4.5.0] framework
spirocyclic is featured
framework in several toxins,
severalexemplified by arthropod
An oxygenated [4.5.0] spirocyclic framework isis featured
featured in several
in toxins, exemplified
toxins, exemplified by
by
Molecules
toxin 116 2018, 23, x 53) isolated from Dinophysis acuta and shown to potentiate erectile function [85].
(Figure 21 of 39
arthropod toxin
arthropod toxin 116
116 (Figure
(Figure 53)
53) isolated
isolated from
from Dinophysis
Dinophysis acutaacuta and
and shown
shown to to potentiate
potentiate erectile
erectile
function[85].
function [85].
Figure 53. Erectile function-potentiating toxin featuring a [4.5.0] spirocyclic motif.

Another example of similarly polyoxygenated [4.5.0] spirocyclic tetrahydrofuran is provided
Another example of similarly polyoxygenated [4.5.0] spirocyclic tetrahydrofuran is provided by
by quinochalcone 117, named saffloquinoside A, isolated from Carthamus tinctorius (Figure 54) [86].
quinochalcone 117, named saffloquinoside A, isolated from Carthamus tinctorius (Figure 54) [86].
Compound 117 was evaluated in vitro for the inhibitory effect on the release of β-glucuronidase from
Compound 117 was evaluated in vitro for the inhibitory effect on the release of β-glucuronidase
rat polymorphonuclear neutrophils (PMNs) induced by the platelet-activating factor (PAF). It exhibited
from rat polymorphonuclear neutrophils (PMNs) induced by the platelet-activating factor (PAF). It
anti-inflammatory activity and the inhibitory rate was 54.3% (at 10−5 mol/L concentration).
exhibited anti-inflammatory activity and the inhibitory rate was 54.3% (at 10 ⁻5 mol/L concentration).
Another example of similarly polyoxygenated [4.5.0] spirocyclic tetrahydrofuran is provided by
Another117,
quinochalcone example
namedof similarly polyoxygenated
saffloquinoside [4.5.0] spirocyclic
A, isolated tetrahydrofuran
from Carthamus tinctoriusis (Figure
provided54)
by [86].
quinochalcone 117, named saffloquinoside A, isolated from Carthamus tinctorius (Figure 54) [86].
Molecules
from rat2019, 24, 4165
polymorphonuclear neutrophils (PMNs) induced by the platelet-activating factor (PAF). 20 of 37
It
from rat polymorphonuclear neutrophils (PMNs) induced by the platelet-activating factor (PAF). It
FigureFigure 54. [4.5.0]

54. [4.5.0] spirocyclic
spirocyclic quinochalcone saffloquinoside
quinochalcone saffloquinoside AAisolated from
isolated Carthamus
from tinctorius.
Carthamus tinctorius.
Figure 54. [4.5.0] spirocyclic quinochalcone saffloquinoside A isolated from Carthamus tinctorius.
Nitrogen-containing[4.5.0]
Nitrogen-containing [4.5.0] spirocyclic
spirocyclic systems
systems are area alotlotmore
more scarce compared
scarce compared to their
to their
oxygen-containing
Nitrogen-containing
oxygen-containing counterparts
[4.5.0]and
counterparts and canbe
beexemplified
spirocyclic
can exemplified
systems by byonly
are two
a lot
only examples
more
two discussed
scarce
examples below.
compared
discussed to their
below.
Alkaloid (±)-pandamarine
oxygen-containing counterparts (118)
and isolated
can be as a majorby
exemplified component
only two from Pandanus
examples amaryllifbelow.
discussed olius
Alkaloid (±)-pandamarine (118) isolated as a major component from Pandanus amaryllif olius
contains
Alkaloid a (±)-pandamarine
[4.5.0] spirocyclic scaffold
(118) composed
isolated ofa amajor
piperidine and a pyrollen-2-one ringsamaryllif
(Figure olius
contains a [4.5.0] spirocyclic scaffold composed ofasa piperidine component from Pandanus
and a pyrollen-2-one rings (Figure 55) [87].
55) [87].
contains a [4.5.0] spirocyclic scaffold composed of a piperidine and a pyrollen-2-one rings (Figure
55) [87].
Figure 55. Alkaloid (±)-pandamarine isolated from Pandanus amaryllif olius.

Figure 55. Alkaloid (±)-pandamarine isolated from Pandanus amaryllif olius.
Another example of nitrogen-containing [4.5.0] spirocyclic system is provided by surugatoxin

(119)(119)
isolated from from
isolated the toxic Japanese
theAlkaloid ivory shell
toxic Japanese ivory (Babylonica
shell japonica)
(Babylonica (Figure(Figure
japonica) 56). This
56).toxin
This suppresses
toxin
Figure 55. (±)-pandamarine isolated from Pandanus amaryllif olius.
the presynaptic
suppresses the nervous systemnervous
presynaptic [88]. Itssystem
total synthesis, in thesynthesis,
[88]. Its total racemic form,
in thewas achieved
racemic form,inwas
1994 by
Molecules
the Inoue 2018,
group
achieved in 23, x by the Inoue group [89].
[89].
1994 22 of 39
(119) isolated from the toxic Japanese ivory shell (Babylonica japonica) (Figure 56). This toxin
suppresses the presynaptic nervous system [88]. Its total synthesis, in the racemic form, was
achieved in 1994 by the Inoue group [89].
Figure Surugatoxin
56. 56.
Figure isolated
Surugatoxin isolatedfrom
fromthe
the toxic Japaneseivory
toxic Japanese ivory shell
shell (Babylonica
(Babylonica japonica).
japonica).
A [4.5.0] spirocyclic system is recognizable in spirostaphylotrichins which are spirocyclic γ-lactams

A [4.5.0] spirocyclic system is recognizable in spirostaphylotrichins which are spirocyclic
mainly produced
γ-lactams by several
mainly producedendophytic
by severalfungal of Curvularia,
strainsfungal
endophytic strains ofPyrenophora, and Staphylotrichum.
Curvularia, Pyrenophora, and
TheseStaphylotrichum.
are exemplifiedThese
by spirostaphylotrichin X (120), characterized as an antiinfluenza
are exemplified by spirostaphylotrichin X (120), characterized agent
astargeting
an
RNAantiinfluenza
polymerase PB2 [90],
agent and spirostaphylotrichin
targeting RNA polymerase W (121),
PB2 investigated
[90], as a potential mycoherbicide
and spirostaphylotrichin W (121),
investigated
for cheatgrass as a potential
(Bromus tectorum)mycoherbicide for (Figure
biocontrol [91] cheatgrass
57).(Bromus tectorum) biocontrol [91] (Figure
57).
A [4.5.0] spirocyclic system is recognizable in spirostaphylotrichins which are spirocyclic
γ-lactams mainly produced by several endophytic fungal strains of Curvularia, Pyrenophora, and
Staphylotrichum. These are exemplified by spirostaphylotrichin X (120), characterized as an
antiinfluenza agent targeting RNA polymerase PB2 [90], and spirostaphylotrichin W 21
Molecules 2019, 24, 4165
(121),
of 37
investigated as a potential mycoherbicide for cheatgrass (Bromus tectorum) biocontrol [91] (Figure
57).
Figure
Molecules Structures of
57.xStructures
2018, 23,
Figure 57. of representative
representative spirostaphylotrichins
spirostaphylotrichins possessing a [4.5.0] spirocyclic motif.23 of 39
Summarizing this
Summarizing this Section,
Section, the
the scaffold
scaffold diversity
diversity stemming
stemming from
from the
the general
general [4.5.0]
[4.5.0] spirocyclic
spirocyclic
framework is comparable to that of the [4.4.0] spirocyclic system discussed earlier (Figure
framework is comparable to that of the [4.4.0] spirocyclic system discussed earlier (Figure 30)30) and
and is
is
shown in Figure 58.
shown in Figure 58.
Figure 58.58.
Figure Current
Currentdiversity of[4.5.0]
diversity of [4.5.0] spirocyclic
spirocyclic scaffolds.
scaffolds.
Figure 58. Current diversity of [4.5.0] spirocyclic scaffolds.
9.
9. [4.6.0]
9. Spirocyclic
[4.6.0] [4.6.0] System
Spirocyclic
Spirocyclic System
System
As As to the spirocyclic systems combining five and
andseven-memebred ringsrings
(the [4.6.0] [4.6.0]
spirocyclic
As to
to the spirocyclic
the spirocyclic systems
systems combining
combining five
five and seven-memebred
seven-memebred rings (the spirocyclic
(the [4.6.0] spirocyclic
system), spiro meroterpenoids spiroapplanatumines (122–124) isolated from the fruiting bodies of
system), spiro meroterpenoids
system),thespiro meroterpenoidsspiroapplanatumines
spiroapplanatumines(122–124)
(122–124) isolated
isolated fromfromthethe fruiting
fruiting bodies of
bodies
fungus Ganoderma applanatum provide an eloquent example (Figure 59). Biological evaluation of of the
the fungus
fungusthe Ganoderma
Ganoderma
compounds
applanatum
applanatum provide
provide
disclosed that
an eloquent
an eloquent
compound
example
example
124 inhibited
(Figure
JAK3 (Figure
59). Biological
59).anBiological
kinase with IC50 value of
evaluation
evaluation
7.0 ± 3.2 of the
of
the compounds
compounds
μM [92]. disclosed that compound 124 inhibited JAK3 kinase with an IC value
disclosed that compound 124 inhibited JAK3 kinase with an IC50 value of 7.0 ± 3.2 µM [92].
50 of 7.0 ± 3.2
μM [92].
Figure 59. Spiro meroterpenoids spiroapplanatumines (122–124) isolated from fungus Ganoderma
applanatum.
59.SpiroSpiro
Figure 59.
Figure meroterpenoids
meroterpenoids spiroapplanatumines (122–124) isolated from fungus
In 2003, investigation of thespiroapplanatumines
neutral ether extracts (122–124) isolated
of the fungus from
Fomes fungus
cajanderi ledGanoderma
to the
Ganoderma
applanatum. applanatum.
isolation of three novel ketal lactones named fomlactones A (125), B (126), and C (127) (Figure 60).
The compounds clearly possess a [4.6.0] spirocyclic lactone moiety. However, their biological
In potential
2003, investigation of the neutral
remains to be investigated [93]. ether extracts of the fungus Fomes cajanderi led to the
isolation of three novel ketal lactones named fomlactones A (125), B (126), and C (127) (Figure 60).
The compounds clearly possess a [4.6.0] spirocyclic lactone moiety. However, their biological
potential remains to be investigated [93].
Molecules 2019, 24, 4165 22 of 37
In 2003, investigation of the neutral ether extracts of the fungus Fomes cajanderi led to the isolation of
three novel ketal lactones named fomlactones A (125), B (126), and C (127) (Figure 60). The compounds
clearly possess a [4.6.0] spirocyclic lactone moiety. However, their biological potential remains to be
Molecules 2018, 23, x
investigated [93]. 24 of 39
Figure 60. Fomlactones A–C possessing a [4.6.0] spirocyclic moiety.

A very unique spirocyclic [4.6.0] framework formed by a spiro[benzofuranonebenzazepine]
A very unique
skeletonA is
very spirocyclic
featured
unique in [4.6.0]
natural
spirocyclic [4.6.0]framework
products formed
(±)-juglanaloid
framework formed by a spiro[benzofuranonebenzazepine]
A (128a–b)
by and (±)-juglanaloid B (129a–b).
a spiro[benzofuranonebenzazepine]
These benzazepine alkaloids were isolated from the bark of Juglans
skeleton is featured in natural products (±)-juglanaloid A (128a–b) and (±)-juglanaloid
skeleton is featured in natural products (±)-juglanaloid A (128a–b) and mandshurica.
(±)-juglanaloid Remarkably,
B (129a–b). bothB (129a–b).
racemic
These natural products
benzazepine werewere
alkaloids successfully resolved
isolated from by of
the bark chiral separation
Juglans and Remarkably,
mandshurica. absolute configurations
both
These benzazepine alkaloids were isolated from the bark of Juglans mandshurica. Remarkably, both
were unambiguously
racemic assignedwere
natural products (Figure 61). These resolved
successfully enantiopureby versions were screened
chiral separation and for their in vitro
absolute
racemic inhibitory
natural products
configurations were
activities were
unambiguously
against successfully
self-induced assigned resolved
(Figure
Aβ1-42 aggregation61). usingbythe
These chiral
enantiopure
Thioflavin separation
versions
T (Th-T)were
assayand
usingabsolute
configurations
screened
curcumin were
as unambiguously
fora reference
their in vitro assigned
inhibitory The
compound. activities (Figure
against
compounds 61). Aβ
self-induced
demonstrated These enantiopure
1-42 aggregation
promise actingusing theversions
as inhibitors of were
Thioflavin T (Th-T) assay using curcumin as a reference compound. The compounds demonstrated
screenedamyloid
for their in vitro [94].
β aggregation inhibitory activities against self-induced Aβ1-42 aggregation using the
promise acting as inhibitors of amyloid β aggregation [94].
Thioflavin T (Th-T) assay using curcumin as a reference compound. The compounds demonstrated
promise acting as inhibitors of amyloid β aggregation [94].
Figure 61. Enantiopure

Figure61. juglanaloid
Enantiopure juglanaloid AA (128a–b)
(128a–b) andand juglanaloid
juglanaloid B (129a–b)
B (129a–b) isolated
isolated from Juglans
from Juglans
mandshurica
mandshuricaand
andfurther obtainedby
further obtained bychiral
chiral separation.
separation.
Furthermore,
Furthermore,ininthe thelast 1–21–2
last years
yearsthere hashas
there been an avalanche
been an avalancheof new
of new[4.6.0] spirocyclic
[4.6.0] structures
spirocyclic
reported in reported
structures the literature. For examples,
in the literature. lanostane-type
For examples, spirolactone
lanostane-type triterpenoids
spirolactone triterpenoids 130a–cisolated
130a–c
isolated
from from Ganoderma
Ganoderma applanatum applanatum
(Figure 62)(Figure
were 62) were reported
reported to possessto anti-hepatic
possess anti-hepatic
fibrosisfibrosis
activities [95].
Figure 61. Enantiopure
activities
Interestingly, [95]. juglanaloid
Interestingly,
an additional A[2.5.0]
(128a–b)
an additional
[4.5.0] and [4.5.0] and[2.5.0]
and
spirocyclic juglanaloid B motif
motifspirocyclic (129a–b)
is recognizable is isolated from
in recognizable
compounds in Juglans
130b and
compounds
mandshurica 130b and 130c, respectively.
and further obtained by chiral separation.
130c, respectively.
Another recent example (reported in 2019) of a [4.6.0] spirocyclic system is provided by
grayanane diterpenoid
Furthermore, in the lastauriculatol
1–2 years A there
(131) isolated
has been fromanleaves of Rhododendron
avalanche auriculatum
of new [4.6.0] spirocyclic
(Figure 63). This compound is the first example of a 5,20-epoxygrayanane diterpenoid bearing
structures reported in the literature. For examples, lanostane-type spirolactone triterpenoids 130a–c
isolated from Ganoderma applanatum (Figure 62) were reported to possess anti-hepatic fibrosis
activities [95]. Interestingly, an additional [4.5.0] and [2.5.0] spirocyclic motif is recognizable in
compounds 130b and 130c, respectively.
Molecules 2019, 24, 4165 23 of 37
a 7-oxabicyclo[4.2.1]nonane motif and a trans/cis/cis/cis-fused 5/5/7/6/5 pentacyclic ring system.

Auriculatol A showed analgesic activity in the acetic acid-induced writhing test [96].
Finally another [4.6.0] spirocyclic lactone, seconoriridone A (isolated as a 7:1 epimeric mixture of
(132a) and (132b)) was isolated in 2019 from Belamcanda chinensis (Figure 64). Although no biological
activity was reported for this intriguing molecular structure, a plausible biosynthetic pathway was
proposed [97].23, x
Molecules 2018, 25 of 39
Figure 62. Lanostane-type triterpenoid spirolactones from Ganoderma applanatum.

grayanane diterpenoid
Figure auriculatol A
62. Lanostane-type (131) isolated
triterpenoid from leavesfrom
spirolactones of Rhododendron auriculatum (Figure
Ganoderma applanatum.
63). This compound is the first example of a 5,20-epoxygrayanane diterpenoid bearing a
7-oxabicyclo[4.2.1]nonane motif and a trans/cis/cis/cis-fused 5/5/7/6/5 pentacyclic ring system.
Another recent example (reported in 2019) of a [4.6.0] spirocyclic system is provided
anane diterpenoid auriculatol A (131) isolated from leaves of Rhododendron auriculatum (Fi
This compound is the first example of a 5,20-epoxygrayanane diterpenoid bearin
abicyclo[4.2.1]nonane motif and a trans/cis/cis/cis-fused 5/5/7/6/5 pentacyclic ring sys
Figure 62. Lanostane-type triterpenoid spirolactones from Ganoderma applanatum.
culatol A showed analgesic
Figure 62.activity intriterpenoid
Lanostane-type the acetic acid-induced
spirolactones from Ganoderma writhing
applanatum. test [96].
grayanane diterpenoid auriculatol A (131) isolated from leaves of Rhododendron auriculatum (Figure
63). This compound is the first example of a 5,20-epoxygrayanane diterpenoid bearing a
7-oxabicyclo[4.2.1]nonane motif and a trans/cis/cis/cis-fused 5/5/7/6/5 pentacyclic ring system.
Figure 63. Structure of auriculatol A possessing a [4.6.0] spirocyclic motif.
Finally another [4.6.0] spirocyclic lactone, seconoriridone A (isolated as a 7:1 epimeric mixture
of (132a) and (132b)) was isolated in 2019 from Belamcanda chinensis (Figure 64). Although no
biological activity was reported for this intriguing molecular structure, a plausible biosynthetic
pathway was proposed [97].
Finally another [4.6.0] spirocyclic

Finally another lactone,
[4.6.0] spirocyclic seconoriridone
lactone, A (isolated
seconoriridone A (isolated as mixture
as a 7:1 epimeric a 7:1 epimeric mix
of (132a) and (132b)) was isolated in 2019 from Belamcanda chinensis (Figure 64). Although no
32a) and (132b)) was
biological isolated
activity in for
was reported 2019 from Belamcanda
this intriguing chinensis
molecular structure, a plausible (Figure
biosynthetic 64). Although
gical activity pathway was proposed [97].
was reported for this intriguing molecular structure, a plausible biosynt
way was proposed [97].
Figure 64. Structure of [4.6.0] spirocyclic seconoriridone A.

The [4.6.0] spirocyclic system is amply exemplified in the natural products domain by the gelsenium
The [4.6.0] spirocyclic system
alkaloids—gelsebanine is amply exemplified
(133), 14α-hydroxyelegansamine (134),in14α-hydroxygelsamydine
the natural products (135)domain
[98], by the
Figure
14-acetoxygelsenicine (136), 64. Structure of [4.6.0] spirocyclic seconoriridone
14-acetoxy-15-hydroxygelsenicine A.
(137), 14-hydroxy-19-oxogelsenicine
gelsenium alkaloids—gelsebanine (133), 14α-hydroxyelegansamine (134), 14α-hydroxygelsamydine
(138), and 14-acetoxygelseligine (139) [99] (Figure 65).
(135) [98], The14-acetoxygelsenicine
[4.6.0] spirocyclic system is amply exemplified14-acetoxy-15-hydroxygelsenicine
(136), in the natural products domain by the (137),
gelsenium alkaloids—gelsebanine (133), 14α-hydroxyelegansamine (134), 14α-hydroxygelsamydine
14-hydroxy-19-oxogelsenicine
(135) [98], (138), and 14-acetoxygelseligine
14-acetoxygelsenicine (136), (139) [99] (Figure 65).
14-acetoxy-15-hydroxygelsenicine (137),
14-hydroxy-19-oxogelsenicine (138), and 14-acetoxygelseligine (139) [99] (Figure 65).
The [4.6.0] spirocyclic system is amply exemplified in the natural products domain by
Molecules 2019, 24, 4165 24 of 37

Figure
Figure 65.
Figure65. Structures
65. Structures ofgelsenium
Structures ofof gelsenium
gelsenium alkaloids
alkaloids possessing
possessing
alkaloids aa [4.6.0]
[4.6.0]
a [4.6.0]
possessing spirocyclic
spirocyclic system.system.
spirocyclic system.
10.10.
[4.7.0] Spirocyclic
[4.7.0]Spirocyclic System
Spirocyclic System
System
10. [4.7.0]
Spirocyclic
Spirocyclicnatural
naturalproducts
products whose
whose scaffolds
scaffolds contain
contain rings
rings larger
larger than
than six-membered, e.g., [4.7.0]
six-membered, e.g.,
Spirocyclic natural products whose scaffolds contain rings larger than six-membered, e.g.,
[4.7.0] spirocyclic
spirocyclic systems, systems, are exceedingly
are exceedingly rare. An example
rare. An eloquent eloquent is
example
providedis by
provided
naturalby natural
sugar-containing
[4.7.0] spirocyclic compounds
sugar-containing systems, are exceedingly
phyllanthunin rare.
(140) An eloquent
recently isolated example
from is providedof by
an ethanol the natural
compounds phyllanthunin (140) recently isolated from an ethanol extract of theextract
fruit of Phyllanthus
sugar-containing
fruit of compounds
Phyllanthus phyllanthunin
emblica (Figure 66) [100]. (140) recently isolated from an ethanol extract of the
emblica (Figure 66) [100].
fruit of Phyllanthus emblica (Figure 66) [100].
Figure 66. Natural product phyllanthunin possessing a [4.7.0] spirocyclic moiety isolated from
Phyllanthus emblica.
Figure 66. Natural product phyllanthunin possessing a [4.7.0] spirocyclic moiety isolated from
Figure 66. Natural
Additionally, product illustrative
remarkably phyllanthunin possessing
of the presence aof[4.7.0]
[4.7.0]spirocyclic
spirocyclicmoiety
motifs isolated from
in natural
Phyllanthus emblica.
Phyllanthus
products, are emblica.
portimines A (141) and B (142) isolated from the marine benthic dinoflagellate
Additionally, remarkably illustrative of the presence of [4.7.0] spirocyclic motifs in natural products,
Additionally,
are portimines remarkably
A (141) illustrative
and B (142) isolatedoffrom
the the
presence
marine of benthic
[4.7.0] spirocyclic
dinoflagellatemotifs in natural
Vulcanodinium
products,collected
rugosum are portimines A (141)New
from Northland, and Zealand
B (142) [101,102].
isolated from the marine
In addition benthic
to a [4.7.0] dinoflagellate
spirocyclic system,
Molecules
Molecules2018,
Molecules 2018,23,
2018, 23,xxx
23, 27
27 of
27 of 39
of 39
39
Molecules 2019, 24, 4165 25 of 37
Vulcanodinium
Vulcanodinium rugosum
Vulcanodinium rugosum collected
rugosum collected from
collected from Northland,
from Northland, New
Northland, New Zealand
New Zealand [101,102].
Zealand [101,102]. In
[101,102]. In addition
In addition to
addition to aaa [4.7.0]
to [4.7.0]
[4.7.0]
spirocyclic
spirocyclic
spirocyclic system,
system,
system, these
these
these compounds
compounds
compounds also
also
also contain
contain
contain a
aa [4.5.0]
[4.5.0]
[4.5.0] spirocycle
spirocycle
spirocycle (Figure
(Figure
(Figure 67).
67).
67). Portimine
Portimine
Portimine
these compounds also contain a [4.5.0] spirocycle (Figure 67). Portimine has also been shown to induce has
has
has also
also
also
been
been shown
been shown
shown
apoptosis to
andtoto induce
induce
induce
reduce apoptosis
theapoptosis
apoptosis and
growth ofand
and reduce
reduce
reduce
a variety the
of the
the growth
growth
cancergrowth of
of a variety
of aaatvariety
cell lines variety of
of cancer
of cancer cell
cell lines
cell lines
lines at
cancerconcentrations.
low nanomolar at low
at low
low
nanomolar
nanomolarconcentrations.
nanomolar concentrations.
concentrations.
Figure
Figure
Figure67.
Figure 67. Portimines
67.Portimines
PortiminesA
Portimines A
A and
Aand
andBBBisolated
and isolated fromVulcanodinium
isolatedfrom
from Vulcanodinium rugosum
Vulcanodiniumrugosum containing
rugosumcontaining
rugosum both
containingboth
containing one
bothone
both [4.7.0]
one[4.7.0]
one and
[4.7.0]and
[4.7.0] and
and
one
one
one [4.5.0]
[4.5.0]
one [4.5.0] spirocyclic
spirocyclic
spirocyclic motif.
motif.
11.
11.[5.5.0]
11. [5.5.0]Spirocyclic
[5.5.0] SpirocyclicSystem
Spirocyclic System
System
Among natural products containing a [5.5.0] spirocyclic motif, new spirocyclic chamigrane
Among
Among natural
Among natural products
natural products containing
products containing aaa [5.5.0]
containing [5.5.0] spirocyclic
[5.5.0] spirocyclic motif,
spirocyclic motif, new
motif, new spirocyclic
new spirocyclic chamigrane
spirocyclic chamigrane
chamigrane
sesquiterpenes, merulinols B (143), C (144), E (145), and F (146) are notable examples (Figure 68).
sesquiterpenes,
sesquiterpenes, merulinols
sesquiterpenes, merulinols BBB (143),
merulinols (143), C
(143), C (144),
C (144), EEE (145),
(144), (145), and
(145), and FFF (146)
and (146) are
(146) are notable
are notable examples
notable examples (Figure
examples (Figure 68).
(Figure 68).
68).
These compounds were isolated from basidiomycetous endophytic fungus XG8D associated with the
These
These compounds
These compounds
compounds werewere isolated
were isolated from
isolated from basidiomycetous
from basidiomycetous endophytic
basidiomycetous endophytic fungus
endophytic fungus XG8D
fungus XG8D associated
XG8D associated with
associated with
with
mangrove Xylocarpus granatum [103]. The in vitro cytotoxicity of all compounds was evaluated against
the
the mangrove
the mangrove Xylocarpus
mangrove Xylocarpusgranatum
Xylocarpus granatum [103].
granatum [103]. The
[103]. The in
The in vitro
in vitro cytotoxicity
vitro cytotoxicity of
cytotoxicity of all
of all compounds
all compounds was
compounds was evaluated
was evaluated
evaluated
three human cancer cell lines, MCF-7, Hep-G2, and KATO-3. Compound 144 selectively displayed
against
against three
against three human
three human cancer
human cancer cell
cancer cell lines,
cell lines, MCF-7,
lines, MCF-7, Hep-G2,
MCF-7, Hep-G2, and
Hep-G2, and KATO-3.
and KATO-3. Compound
KATO-3. Compound 144
Compound 144 selectively
144 selectively
selectively
cytotoxicity against KATO-3 cells with an IC50 value of 35.0 µM.
displayed
displayed cytotoxicity
displayed cytotoxicity against
cytotoxicity against KATO-3
against KATO-3 cells
KATO-3 cells with
cells with
with anan IC
an IC value
IC5050 value
50 of
value of 35.0
of 35.0 μM.
35.0 μM.
μM.
Figure 68. Spirocyclic chamigrane sesquiterpenes, merulinols B (143), C (144), E (145), and F (146).
Figure
Figure68.
68. Spirocyclicchamigrane
Spirocyclic chamigranesesquiterpenes,
chamigrane sesquiterpenes,merulinols
sesquiterpenes, merulinolsBBB(143),
merulinols (143),C
(143), C(144),
C (144),EEE(145),
(144), (145),and
(145), andFFF(146).
and (146).
(146).
Highly oxygenated acylphloroglucinol, hyperbeanol C (147), was isolated from the methanol
Highly
Highly
Highly oxygenated
oxygenated
oxygenated acylphloroglucinol,
acylphloroglucinol,
acylphloroglucinol, hyperbeanol
hyperbeanol
hyperbeanol C
C (147),
(147), was
was isolated
was isolated from
from the
from the methanol
the methanol
extract of Hypericum beanie [104]. This compound containsCan (147),
all-carbon isolated
[5.5.0] spirocyclic methanol
system,
extract
extract of
of Hypericum
Hypericum beanie
beanie [104].
[104]. This
This compound
compound contains
contains an
an all-carbon
all-carbon [5.5.0]
[5.5.0] spirocyclic
spirocyclic system,
system,
spiro[5.5.0]undec-2-ene-1,5-dione (Figure 69). The cytotoxicity of 147 against the cancer cell linessystem,
extract of Hypericum beanie [104]. This compound contains an all-carbon [5.5.0] spirocyclic HL-60,
spiro[5.5.0]undec-2-ene-1,5-dione
spiro[5.5.0]undec-2-ene-1,5-dione
spiro[5.5.0]undec-2-ene-1,5-dione (Figure
(Figure
(Figure 69).
69). The
69). The cytotoxicity
The cytotoxicity
cytotoxicity of
of 147
of 147
147 against
against the
the cancer
cancer cell
cell lines
cell lines
SMMC-7721, PANC-1, MCF-7, K562, and SK-BR-3 was tested using theagainst
methylthe cancer
thiazol lines
tetrazalium
HL-60,
HL-60, SMMC-7721,
SMMC-7721,
HL-60,method
SMMC-7721, PANC-1,
PANC-1,
PANC-1, MCF-7,MCF-7,
MCF-7, K562,
K562, and
and SK-BR-3
K562, control.SK-BR-3
and SK-BR-3 was
was tested
tested
was tested using
using the
the methyl
methyl thiazol
thiazol
(MTT) with cis-platinum as the positive It exhibited modestusing the methyl
cytotoxicity againstthiazol
K562
tetrazalium
tetrazalium
tetrazalium (MTT)
(MTT)
(MTT) method
method
method with
with
with cis-platinum
cis-platinum
cis-platinum as
as
as the
the
the positive
positive
positive control.
control.
control. It
It
Itexhibited
exhibited
exhibited modest
modest
modest cytotoxicity
cytotoxicity
cytotoxicity
cells with an IC50 16.9 µM.
against
againstK562
against K562cells
K562 cellswith
cells withan
with anIC
an IC50505016.9
IC 16.9μM.
16.9 μM.
μM.
Figure 69. Hyperbeanol C isolated from Hypericum beanie.

Figure
Figure69.
Figure 69.Hyperbeanol
69. HyperbeanolC
Hyperbeanol Cisolated
C isolatedfrom
isolated fromHypericum
from Hypericumbeanie.
Hypericum beanie.
beanie.
Remarkable presentation of the (R)-1,7-dioxaspiro[5.5] undecane framework is found in
Remarkable
Remarkable presentation
Remarkable presentation
presentation of
of the
of the
the (R)-1,7-dioxaspiro[5.5]
(R)-1,7-dioxaspiro[5.5]
(R)-1,7-dioxaspiro[5.5] undecane
undecane framework
undecane framework
framework is
is found
is found
found in
in
in
nor-spiro-azaphilones, thielavialides A−D (148–151), and bis-spiro-azaphilone, thielavialide E (152)
nor-spiro-azaphilones,
nor-spiro-azaphilones, thielavialides
nor-spiro-azaphilones, thielavialides A−D
thielavialides A−D (148–151),
A−D (148–151), and
(148–151), and bis-spiro-azaphilone,
and bis-spiro-azaphilone, thielavialide
bis-spiro-azaphilone, thielavialide EEE (152)
thielavialide (152)
(152)
Molecules 2019, 24, 4165 26 of 37
together with bis-spiro-azaphilone pestafolide A (153) (Figure 70). All these compounds were isolated
together with bis-spiro-azaphilone pestafolide A (153) (Figure 70). All these compounds were
from the endophytic fungal strain, Thielavia sp. PA0001, occurring in the healthy leaf tissue of
isolated from the endophytic fungal strain, Thielavia sp. PA0001, occurring in the healthy leaf tissue
aeroponically grown Physalis alkekengi [105].
of aeroponically grown Physalis alkekengi [105].
Figure 70. Thielavialides A−E (148–152) and pestafolide A (153).

Figure 70. Thielavialides A−E (148–152) and pestafolide A (153).
A very similar [5.5.0] spirocyclic moiety can be found in the structure of pteridic acids C and F
A very similar [5.5.0] spirocyclic moiety can be found in the structure of pteridic acids C and F
(154 and 155, respectively) isolated in 2017 from a culture broth of the marine-derived actinomycete
(154 and 155, respectively) isolated in 2017 from a culture broth of the marine-derived actinomycete
Streptomyces sp. SCSGAA 0027 (Figure 71). While these compounds were seen as potential leads for
Streptomyces sp. SCSGAA 0027 (Figure 71). While these compounds were seen as potential leads for
antibacterial drug discovery, their extensive testing for antimicrobial activity against two gorgonian
antibacterial drug discovery, their extensive testing for antimicrobial activity against two gorgonian
pathogenic fungal strains Aspergullus versicolor SCSGAF 0096 and Aspergullus sydowii SCSGAF 0035;
pathogenic fungal strains Aspergullus versicolor SCSGAF 0096 and Aspergullus sydowii SCSGAF 0035;
a human pathogenic fungal strain Candida albicans SC5314; and two bacterial strains Escherichia coli and
a human pathogenic fungal strain Candida albicans SC5314; and two bacterial strains Escherichia coli
Bacillus subtilis, showed that the compounds had only a weak antimicrobial activity [106].
and Bacillus subtilis, showed that the compounds had only a weak antimicrobial activity [106].
Figure 71. Pteridic acids C and F isolated from Streptomyces sp. SCSGAA 0027 possessing a
Figure 71. Pteridic acids C and F isolated from Streptomyces sp. SCSGAA 0027 possessing a
1,7-dioxaspiro[5.5.0]undecane motif.
1,7-dioxaspiro[5.5.0]undecane motif.
A unique [5.5.0] spirocyclic skeleton formed by a hexahydropyran and a pyrrolo[2,1-c]morpholine
moieties unique
A is found [5.5.0] spirocyclic A
in pollenopyrroside skeleton
(156) andformed
B (157) by a from
isolated hexahydropyran
bee-collected and
Brassicaa
pyrrolo[2,1-c]morpholine moieties is found in pollenopyrroside A (156) and
campestris pollen (Figure 72). The Chinese team who reported these natural products in B (157) isolated from
bee-collected Brassicaacampestris
2010 also proposed pollen
biosynthetic (Figurethat
pathway 72). involves
The Chinese team who
a reaction reported these natural
of 3-deoxy-d-fructose and
products in 2010 also proposed a biosynthetic pathway that involves
5-oxymethyl-2-formyl-pyrrole as the key step. Biological testing of these aldehyde compounds a reaction of
3-deoxy- D -fructose and 5-oxymethyl-2-formyl-pyrrole as the key step. Biological testing
using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method revealed that of these
aldehyde
they possesscompounds using
no cytotoxicity the A549,
against 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
Bel7420, BGC-823, HCT-8, and A2780 cancerous cellbromide lines at
(MTT) method
10 µg/mL [107]. revealed that they possess no cytotoxicity against A549, Bel7420, BGC-823, HCT-8,
and A2780
Anothercancerous
uniquecell lines spirocyclic
[5.5.0] at 10 μg/mLskeleton
[107]. is noteworthy in the context of this review.
Two structurally unique spirocyclic alkaloids 158 and 159 were isolated in 2007 from the halotolerant
Molecules 2019, 24, 4165 27 of 37
B-17 fungal strain of Aspergillus variecolor (Figure 73). Both compounds possessed an intriguing
spirocyclic
Molecules 2018,piperazin-2,5-dione
23, x moiety and exhibited cytotoxic properties [108]. 29 of 39
Figure 72. Pollenopyrroside A isolated from bee-collected Brassica campestris pollen.

Figure 72. Pollenopyrroside A isolated from bee-collected Brassica campestris pollen.
Another unique [5.5.0] spirocyclic skeleton is noteworthy in the context of this review. Two
structurally unique spirocyclic alkaloids 158 and 159 were isolated in 2007 from the halotolerant B-17
fungal strain of Aspergillus variecolor (Figure 73). Both compounds possessed an intriguing
spirocyclic piperazin-2,5-dione moietyAand
Figure 72. Pollenopyrroside
Figure 72. Pollenopyrroside
exhibited
isolated cytotoxic properties
from bee-collected [108]. pollen.
Brassica campestris
spirocyclic piperazin-2,5-dione moietyAand
isolated from bee-collected
exhibited Brassica campestris
cytotoxic properties [108]. pollen.
spirocyclic piperazin-2,5-dione moiety and exhibited cytotoxic properties [108].
Figure 73. New spirocyclic piperazin-2,5-dione alkaloids isolated from Aspergillus variecolor.
Figure 73.
Figure Newspirocyclic
73. New spirocyclicpiperazin-2,5-dione
piperazin-2,5-dione alkaloids
alkaloids isolated
isolated from Aspergillus variecolor.
from Aspergillus variecolor.
Remarkably, in
Remarkably, in 2018,
2018, aa very
very similar
similar spirocyclic
spirocyclic piperazin-2,5-dione
piperazin-2,5-dione variecolortin
variecolortin B (160) was
Remarkably, in 2018, a very similar spirocyclic piperazin-2,5-dione variecolortin BB (160)
(160) was
was
isolated from
isolated from the marine-derived fungus Eurotium
Eurotium sp. SCSIO F452 (Figure 74). The compound
isolated fromthethemarine-derived
marine-derived fungus
fungus sp. SCSIO
Eurotium F452 (Figure
sp. SCSIO 74). The74).
F452 (Figure compound exhibited
The compound
exhibited different
different antioxidativeantioxidative
and cytotoxicand cytotoxic activities. Interestingly, the same species gave rise to
exhibited different antioxidative andactivities.
cytotoxicInterestingly, the same species
activities. Interestingly, gavespecies
the same rise to agave
compound
rise to
a compound possessing an even more seldomly-occurring spirocyclic moiety; namely, [5.6.0] (vide
apossessing
compound anpossessing
Figure even more
73. New seldomly-occurring
spirocyclic
an spirocyclic
even piperazin-2,5-dione moiety;
alkaloids
more seldomly-occurring namely,
isolated [5.6.0] namely,
frommoiety;
spirocyclic (vide
Aspergillus infra)
variecolor. [109].
[5.6.0] (vide
infra) [109].
infra) [109].
Remarkably, in 2018, a very similar spirocyclic piperazin-2,5-dione variecolortin B (160) was
isolated from the marine-derived fungus Eurotium sp. SCSIO F452 (Figure 74). The compound
exhibited different antioxidative and cytotoxic activities. Interestingly, the same species gave rise to
a compound possessing an even more seldomly-occurring spirocyclic moiety; namely, [5.6.0] (vide
infra) [109].
Figure 74. Spirocyclic piperazin-2,5-dione variecolortin B isolated from the marine-derived fungus
Figure 74. Spirocyclic piperazin-2,5-dione variecolortin B isolated from the marine-derived fungus
Eurotium
Figure 74.sp. SCSIO F452.
Spirocyclic piperazin-2,5-dione variecolortin B isolated from the marine-derived fungus
Eurotium sp. SCSIO F452.
Eurotium sp. SCSIO F452.
The [5.5.0] spirocyclic system occurs very prominently in bioactive meroterpenoids 161a–e and
The [5.5.0] spirocyclic system occurs very prominently in bioactive
fungus Penicillium meroterpenoids 161a–e and
Theisolated
162a–d in 2019 from
[5.5.0] spirocyclic mangrove-derived
system occurs very prominently sp. (Figure
in bioactive 75). Several
meroterpenoids 161a–eof these
and
162a–d isolated in 2019 from mangrove-derived fungus Penicillium sp. (Figure 75). Several
Helicoverpa of these
compounds
162a–d showed
isolated growth
in 2019 from inhibition activity against
mangrove-derived fungusnewly hatched
Penicillium sp.larvae
(Figureof75). Several armigera
of these
compounds
Hubner with showed
IC growth
values inhibition
ranging from 50activity
to 200 againstand
µg/mL, newly
some hatched
notable larvae ofagainst
activity Helicoverpa armigera
Caenorhabditis
Figure 74.
compounds Spirocyclic
showed
50 growthpiperazin-2,5-dione variecolortin
inhibition activity B isolated
against newly from the
hatched marine-derived
larvae fungus
of Helicoverpa armigera
Hubner
elegans with IC50 values
[110].
Eurotium
ranging from 50 to 200 μg/mL, and some notable activity against
Hubner withsp.ICSCSIO F452. ranging from 50 to 200 μg/mL, and some notable activity against
50 values
Caenorhabditis elegans
Workers elegans [110].
ant Carebarella bicolor collected in Panama were found to contain the
of the[110].
Caenorhabditis
The [5.5.0] spirocyclic
histrionicotoxin systemwith
class of alkaloids occurs very prominently
unusual in bioactive meroterpenoids 161a–e
2,7-disubstituted-1-azaspiro[5.5]undecanol and
structures
162a–d isolated76)
163a–i (Figure in [111].
2019 from mangrove-derived fungus Penicillium sp. (Figure 75). Several of these
compounds showed growth inhibition activity against newly hatched larvae of Helicoverpa armigera
Hubner with IC50 values ranging from 50 to 200 μg/mL, and some notable activity against
Caenorhabditis elegans [110].
Molecules 2019, 24, 4165 28 of 37

Figure 75. Bioactive [5.5.0] spirocyclic meroterpenoids isolated from mangrove-derived fungus
Penicillium sp.
Workers of the ant Carebarella bicolor collected in Panama were found to contain the
Figure 75.
histrionicotoxin
Figure Bioactive
75. Bioactive [5.5.0]
class [5.5.0]
of spirocyclic
alkaloids meroterpenoids
with
spirocyclic isolated from
from mangrove-derived
mangrove-derived fungus
unusual 2,7-disubstituted-1-azaspiro[5.5]undecanol
meroterpenoids isolated fungus
Penicillium
Penicillium sp.
sp.
structures 163a–i (Figure 76) [111].
Workers of the ant Carebarella bicolor collected in Panama were found to contain the
histrionicotoxin class of alkaloids with unusual 2,7-disubstituted-1-azaspiro[5.5]undecanol
structures 163a–i (Figure 76) [111].
Figure 76. Alkaloids 163–i of the histrionicotoxin class isolated from ant Carebarella bicolor.
Figure 76. Alkaloids 163–i of the histrionicotoxin class isolated from ant Carebarella bicolor.
An interesting group of natural products representative of this spirocyclic system are periplosides
(164),An interesting group
a spiro-orthoester
Figure 76. Alkaloids
of natural products
group-containing representative
pregnane-type
163–i of the histrionicotoxin
of this
glycosides
class isolated
spirocyclicthe
discovered
from ant Carebarellain
system are
bicolor. course of
periplosides (164), a spiro-orthoester group-containing pregnane-type glycosides discovered
phytochemical investigation of the root bark of Periploca sepium (Figure 77). The [5.6.0] spirocyclic in the
course
12. of phytochemical
[5.6.0] Spirocyclic
orthoester investigation
System
core is distinctly of the root bark of Periploca sepium (Figure 77).
modified with a steroid unit on one hand (R1 ) and with an oligosaccharideThe [5.6.0]
2
moiety on the other (R ). The compounds were evaluated for their inhibitory activities against the
An interesting group of natural products representative of this spirocyclic system are
periplosides (164), a spiro-orthoester group-containing pregnane-type glycosides discovered in the
course of phytochemical investigation of the root bark of Periploca sepium (Figure 77). The [5.6.0]
Molecules
Molecules 2018,
2018, 23,
23, xx 31
31 of
of 39
39
Molecules 2019, 24, 4165 29 of 37
spirocyclic
spirocyclic orthoester
orthoester core
core is
is distinctly
distinctly modified
modified with with aa steroid
steroid unit
unit on
on one
one hand
hand (R
(R11)) and
and with
with an
an
oligosaccharide moiety on the other (R 22). The compounds were evaluated for their inhibitory
oligosaccharide moiety on the other (R ). The compounds were evaluated for their inhibitory
proliferation of T-lymphocytes. As a result, one specific compound (periploside C), the most abundant
activities
activities against
against the
the proliferation
proliferation ofof T-lymphocytes.
T-lymphocytes. As As aa result,
result, one
one specific
specific compound
compound (periploside
(periploside
glycoside containing a spiro-orthoester moiety found in the plant, exhibited the most favorite selective
C),
C), the
the most
most abundant
abundant glycoside
glycoside containing
containing aa spiro-orthoester
spiro-orthoester moiety
moiety found
found in
in the
the plant,
plant, exhibited
exhibited
index value (SI = 82.5). The inhibitory activity and the SI value appear to depend on the constitution of
the
the most favorite selective index value (SI = 82.5). The inhibitory activity and the SI value appear to
most favorite selective index value (SI = 82.5). The inhibitory activity and the SI value appear to
the saccharide chain [112].
depend
depend on on the
the constitution
constitution of
of the
the saccharide
saccharide chain
chain [112].
[112].
Figure
Figure 77.
Figure 77. General structure
77. General
General structure of
structure of [5.6.0]
of [5.6.0] spirocyclic
[5.6.0] spirocyclic orthoester
spirocyclic orthoester periplosides.
orthoester periplosides.
periplosides.
The remarkable,
The from a structural perspective, spirolide G (165),(165),
was isolated from DanishDanish
strains
The remarkable,
remarkable, from
from aa structural
structural perspective,
perspective, spirolide
spirolide G G (165), was
was isolated
isolated from
from Danish
of toxigenic
strains dinoflagellate Alexandrium ostenfeldii. The toxicological profile of this compound was
strains of
of toxigenic
toxigenic dinoflagellate
dinoflagellate Alexandrium
Alexandrium ostenfeldii.
ostenfeldii. The
The toxicological
toxicological profile
profile of
of this
this compound
compound
evaluated
was [113]. Interestingly, in addition to the spirocyclic [5.6.0] moiety in question, spirolide G (165)
was evaluated
evaluated [113].
[113]. Interestingly,
Interestingly, in
in addition
addition toto the
the spirocyclic
spirocyclic [5.6.0]
[5.6.0] moiety
moiety in
in question,
question, spirolide
spirolide
contains
G two others; namely, a [4.4.0] and a [4.5.0] motif (Figure 78).
G (165)
(165) contains
contains two
two others;
others; namely,
namely, aa [4.4.0]
[4.4.0] and
and aa [4.5.0]
[4.5.0] motif
motif (Figure
(Figure 78).
78).
Figure 78. Spirolide G isolated from toxigenic dinoflagellate Alexandrium ostenfeldii.

Figure
Figure 78.
78. Spirolide
Spirolide G
G isolated
isolated from
from toxigenic
toxigenic dinoflagellate
dinoflagellate Alexandrium
Alexandrium ostenfeldii.
ostenfeldii.
Referring back to the chemical investigation of the marine-derived fungus Eurotium sp. SCSIO F452
Referring
discussed aboveback
Referring back to
to the
the chemical
in connectionchemical investigation
investigation
with compounds of
of the
the marine-derived
belonging marine-derived
to fungus Eurotium
fungussystem,
the [5.5.0] spirocyclic Eurotiuman sp.
sp. SCSIO
SCSIO
intriguing
F452
[5.6.0] spirocyclic compound 166 (Figure 79) was also isolated from the same species [109]. This isan
F452 discussed
discussed above
above in
in connection
connection with
with compounds
compounds belonging
belonging to
to the
the [5.5.0]
[5.5.0] spirocyclic
spirocyclic system,
system, an
a
intriguing
intriguing [5.6.0]
[5.6.0] spirocyclic
compound 166
166 (Figure
(Figure 79)
79) was
was also
also isolated
isolated from
from the
the same
same
case of one species giving rise to a diversity of spirocyclic frameworks, underscoring the significance of species
species [109].
[109].
This
This is
is aa case
spirocycles case of
of one
in the one species
species
natural giving
giving
product rise
rise to
realm. to aa diversity
One diversity of
particular of spirocyclic
spirocyclic
example frameworks,
spirocycle underscoring
frameworks,
of such underscoring
diversity the
the
derived
significance
significance of
of spirocycles
spirocycles in
in the
the natural
natural product
product
from a single organism is discussed in Section 13 below. realm.
realm. One
One particular
particular example
example of
of such
such spirocycle
spirocycle
diversity
diversity derived
derived from
from aa single
single organism
organism isis discussed
discussed inin Section
Section 1313 below.
below.
Figure 79. A [5.6.0] spirocyclic compound isolated from marine-derived fungus Eurotium sp.
Figure
Figure 79.
79. A
A [5.6.0]
[5.6.0] spirocyclic
compound isolated
isolated from
from marine-derived
marine-derived fungus
fungus Eurotium
Eurotium sp.
sp. SCSIO
SCSIO
SCSIO F452.
F452.
F452.
Molecules 2019, 24, 4165 30 of 37
Molecules 2018,
Molecules 2018, 23,
23, xx 32 of
32 of 39
39
A [5.6.0] spirocyclic moiety is recognizable in the new sesquiterpene dimer vieloplain G (167)
A [5.6.0]
A
isolated [5.6.0]
in 2019spirocyclic
spirocyclic moiety
from themoiety isXylopia
roots ofis recognizable
recognizable in
vielanain the new
the
(Figure new sesquiterpene
80).sesquiterpene dimer
dimer
This compound vieloplain
vieloplain
showed G (167)
G (167)
considerable
isolated in
isolated in 2019
cytotoxicity 2019 from
from
against the roots
the
DU145 roots of
cellsof Xylopia
Xylopia
with vielana
an ICvielana (Figure 80).
(Figure 80). This
This compound
compound showed
showed considerable
considerable
50 value of 9.5 µM [114].
cytotoxicity against DU145 cells with an IC value of 9.5 μM
cytotoxicity against DU145 cells with an IC50 value of 9.5 μM [114].
50 [114].
Figure 80.
Figure Vieloplain G
80. Vieloplain G isolated
isolated from Xylopia vielana
from Xylopia containing
containing aaa [5.6.0]
vielana containing [5.6.0] spirocyclic
[5.6.0] spirocyclic scaffold.
spirocyclic scaffold.
scaffold.
Figure 80. Vieloplain G isolated from Xylopia vielana
13. [6.6.0]
Spirocyclic System
System
This type of spirocyclic framework is exceedingly rare in the natural product domain, with only
This type
This type of
of spirocyclic
spirocyclic framework
framework is is exceedingly
exceedingly rare
rare in
in the
the natural
natural product
product domain, with
with only
only
one example of unique 1-oxaspiro[6.6]tridecane 168, a spirocyclic nortriterpenoiddomain,
Spiroschincarin A
one example
one example ofof unique
unique 1-oxaspiro[6.6]tridecane
1-oxaspiro[6.6]tridecane 168,168, aa spirocyclic
spirocyclic nortriterpenoid
nortriterpenoid Spiroschincarin
Spiroschincarin A
A
isolated from the fruit of Schisandra incarnate (Figure 81) [115].
isolated from
isolated from the
the fruit
fruit of
of Schisandra
Schisandra incarnate
incarnate (Figure
(Figure 81)
81) [115].
[115].
Figure 81.
Figure 81.
Figure Spiroschincarin A
81. Spiroschincarin
Spiroschincarin A isolated
A isolated from
isolated from the
from the fruit
the fruit of
fruit of Schisandra
of Schisandra incarnate.
Schisandra incarnate.
incarnate.
14. Plant Species Distinctly Rich in Diverse Spirocyclic Natural Products

14. Plant
14. Plant Species
Species Distinctly
Distinctly Rich
Rich in
in Diverse
Diverse Spirocyclic
Spirocyclic Natural
Natural Products
Products
Some cases when the same plant or microorganism gave rise to secondary metabolites with several
Some cases
Some cases when
when thethe same
same plant
plant or
or microorganism
microorganism gavegave rise
rise to
to secondary
secondary metabolites
metabolites with
with
structurally-diverse spirocyclic frameworks were discussed above. However, one recent example
several structurally-diverse
several structurally-diverse spirocyclic
spirocyclic frameworks
frameworks were were discussed
discussed above.
above. However,
However, one one recent
recent
published in 2019, describing a chemical investigation of monoterpenoid indole alkaloids isolated from
example published in 2019, describing a chemical investigation of monoterpenoid
example published in 2019, describing a chemical investigation of monoterpenoid indole alkaloids indole alkaloids
the roots of Gelsemium elegans (also briefly discussed in Section 8 of this review), stands out from the
isolated from
isolated from the
the roots
roots of
of Gelsemium
Gelsemium elegans
elegans (also
(also briefly
briefly discussed
discussed inin Section
Section 88 of
of this
this review),
review), stands
stands
standpoint of hitherto unprecedented skeletal diversity [116]. In particular, the following spirocyclic
out from
out from the
the standpoint
standpoint of of hitherto
hitherto unprecedented
unprecedented skeletal
skeletal diversity
diversity [116].
[116]. InIn particular,
particular, the
the
frameworks were encountered among the natural products isolated from this species: [4.5.0]—featured
following spirocyclic frameworks were encountered among the natural products
following spirocyclic frameworks were encountered among the natural products isolated from this isolated from this
in 19-oxogelsevirine (169), gelsevirine (170), and koumimine (171); [4.7.0]—featured in gelsedethenine
species: [4.5.0]—featured
species: [4.5.0]—featured in in 19-oxogelsevirine
19-oxogelsevirine (169),
(169), gelsevirine
gelsevirine (170),
(170), and
and koumimine
koumimine (171);(171);
(172); and a unique [4.8.0] system—featured in humantenine (173) and 19,20-epoxyhumantenine (174)
[4.7.0]—featured in
[4.7.0]—featured in gelsedethenine
gelsedethenine (172);
(172); and
and aa unique
unique [4.8.0]
[4.8.0] system—featured
system—featured in in humantenine
humantenine
(Figure 82).
(173) and
(173) and 19,20-epoxyhumantenine
19,20-epoxyhumantenine (174) (174) (Figure
(Figure 82).
82).
Molecules 2019, 24, 4165 31 of 37
Figure
Figure 82. Structurally
Structurallydiverse
diverse spirocyclic
spirocyclic frameworks
frameworks isolated
isolated from
from aa single
single plant
plant species
species
(Gelsemium elegans).
15. Conclusions
15. Conclusions and
and Perspectives
Perspectives
Spirocyclic scaffolds
Spirocyclic scaffoldsare areomnipresent
omnipresent in the
in natural products
the natural domain.
products By analyzing
domain. the diversity
By analyzing the
of spirocyclic systems reported for natural products in the literature, one can
diversity of spirocyclic systems reported for natural products in the literature, one can appreciate appreciate an uneven an
distribution of such motifs according to the spirocycle type: certain motifs
uneven distribution of such motifs according to the spirocycle type: certain motifs are more are more abundant than
others andthan
abundant someothers
are rather
and scarce,
some exemplified by onlyexemplified
are rather scarce, a handful ofby naturally
only a occurring
handful of compounds.
naturally
The most widespread are the [5.5.0], [4.5.0], and [4.4.0] spirocycles. In
occurring compounds. The most widespread are the [5.5.0], [4.5.0], and [4.4.0] spirocycles.terms of associated bioactivities
In terms
discovered and reported for spirocyclic products, these are mostly limited to
of associated bioactivities discovered and reported for spirocyclic products, these are mostly limited the usual profiling in
the context of antiproliferative, anti-inflammatory, and antimicrobial activities.
to the usual profiling in the context of antiproliferative, anti-inflammatory, and antimicrobial However, the strong
connections
activities. of spirocyclic
However, frameworks
the strong to the
connections of natural product
spirocyclic domain to
frameworks andthetheir emerging
natural product privileged
domain
motif status in the synthetic drug discovery argues in favor of the need
and their emerging privileged motif status in the synthetic drug discovery argues in favor of for more thorough panel
the
profiling of all newly-discovered natural products, as novel and hitherto
need for more thorough panel profiling of all newly-discovered natural products, as novel and unprecedented bioactivity
leads could
hitherto be discovered.
unprecedented Certain scarcely-populated
bioactivity areas of the
leads could be discovered. spirocyclic
Certain natural product
scarcely-populated space
areas of
can be specifically developed into synthetic libraries and investigated for
the spirocyclic natural product space can be specifically developed into synthetic libraries andbioactivity. More spirocycles
appear to have
investigated been discovered
for bioactivity. More in the last 5–10
spirocycles appearyears, withbeen
to have an apparent
discovered advent
in theof plant
last 5–10species
years,
giving rise to several types of spirocyclic frameworks in the course of their
with an apparent advent of plant species giving rise to several types of spirocyclic frameworks in the chemical investigation.
The spirocyclic
course natural product
of their chemical discovery,
investigation. The therefore,
spirocyclicappears
naturalto be on the
product rise andtherefore,
discovery, is likely toappears
inspire
new
to bescaffolds
on the for risedrug
and design
is likely andtoscreening
inspire newlibrary development.
scaffolds for drug design and screening library
development.
Funding: This research was funded by the Ministry for Science and Education of the Russian Federation under
the Federal
Funding: Target
This Program,
research “High-Priority
was funded Areas forfor
by the Ministry Research
Science and
andDevelopment in Science
Education of the Russianand Technology
Federation for
under
Russia in 2014–2020,” grant number (RFMEFI57718X0285).
the Federal Target Program, “High-Priority Areas for Research and Development in Science and Technology for
in 2014–2020,”The
Acknowledgments:
Russia grantauthors
numberare indebted to Dmitry Dar’in of Saint Petersburg University for helpful
(RFMEFI57718X0285).
discussions regarding this work.
Acknowledgments: The authors are indebted to Professor Dmitry Dar’in of Saint Petersburg University for
Conflicts of Interest: The authors declare no conflicts of interest.
helpful discussions regarding this work.
Conflicts
Referencesof Interest: The authors declare no conflicts of interest.
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© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
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Molecules 2019, 24, 4165; doi:10.3390/molecules24224165 www.mdpi.com/journal/molecules

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Figure 3. Cyclohelminthol X (8) from Helminthosporium velutinum plant.

Figure 5. Structures of fungi-derived illudins M and S.

Figure 7. Structures of antiparasitic, fungus-derived (−)-ovalicin (15) and fumagillin (16).

The most structurally simple, naturally occurring spirocyclic lactone, 1,7-dioxaspiro[4.4.0]nonane

Studies of secondary metabolite structures in endophyte fungus Penicillium purpurogenum

Studies of secondary metabolite structures in endophyte fungus Penicillium purpurogenum

microorganisms (Mycobacterium spegmatis (ATCC70084), Staphylococcus aureus (ATCC25923), and

Figure 18. Spirocyclic mycotoxins produced by P. aethiopicum.

Figure 20. Structure of herbicidal hydantocidine isolated from Streptomyces hygroscopicus.

Figure 22. Examples of naturally occurring spirooxyindoles.

A structurally unique [4.4.0] spiroheterocyclic system is represented by a series of highly

A structurally unique [4.4.0] spiroheterocyclic system is represented by a series of highly

Molecules 2018, 23, x 12 of 39

Figure 27. 1,6-Dioxaspiro[4.4]nonane secondary metabolite isolated from entomogenous fungus

Figure 28. Bipolaricins from phytopathogenic Bipolaris sp. fungus.

Molecules 2018, 23, x 14 of 39

Figure 32. New spirocyclic triterpenoids isolated from Leonurus japonicas.

Figure 34. Structurally novel triterpenoids isolated from Belamcanda chinensis.

New biologically active sesquiterpenoids 83–85 possessing an all-carbon [4.5.0] spirocyclic

hepatoprotective activities against APAP-induced HepG2 cell damage [62].

Molecules 2018, 23, x 16 of 39

Perhaps the most clinically advanced natural natural spirocyclic

Figure 37. Anti-ring worm drug griseofulvin (GrisovinTM

Figure 38. Examples of natural [4.5.0] spirocyclic lactones.

Molecules 2019, 24, 4165 16 of 37

Figure 39. Abyssomycins from Actinobacteria.

Figure 39. Abyssomycins from Actinobacteria.

Figure 42. Lambertollols A and B.

Figure 46. Abiespiroside A isolated from Chinese tree Abies dalavayi.

Figure 46. Abiespiroside A isolated from Chinese tree Abies dalavayi.

Figure 47. Pathylactone

Figure 49. Natural spirocyclic tetrahydrofurans.

Figure 50. Enantiomers of [4.5.0] spirocyclic dihydrofuran 8,9-dehydrotheaspirone reported in

Figure 53. Erectile function-potentiating toxin featuring a [4.5.0] spirocyclic motif.

FigureFigure 54. [4.5.0]

Figure 55. Alkaloid (±)-pandamarine isolated from Pandanus amaryllif olius.

Another example of nitrogen-containing [4.5.0] spirocyclic system is provided by surugatoxin

A [4.5.0] spirocyclic system is recognizable in spirostaphylotrichins which are spirocyclic γ-lactams

Molecules 2018, 23, x 24 of 39

Figure 60. Fomlactones A–C possessing a [4.6.0] spirocyclic moiety.

Figure 61. Enantiopure

a 7-oxabicyclo[4.2.1]nonane motif and a trans/cis/cis/cis-fused 5/5/7/6/5 pentacyclic ring system.

Another recent example (reported in 2019) of a [4.6.0] spirocyclic system is provided by

Finally another [4.6.0] spirocyclic

Figure 64. Structure of [4.6.0] spirocyclic seconoriridone A.

Figure 64. Structure of [4.6.0] spirocyclic seconoriridone A.

Molecules 2019, 24, 4165 24 of 37

Figure 69. Hyperbeanol C isolated from Hypericum beanie.

Molecules 2018, 23, x 28 of 39

Figure 70. Thielavialides A−E (148–152) and pestafolide A (153).

Figure 72. Pollenopyrroside A isolated from bee-collected Brassica campestris pollen.

Molecules 2019, 24, 4165 28 of 37

Figure 78. Spirolide G isolated from toxigenic dinoflagellate Alexandrium ostenfeldii.

14. Plant Species Distinctly Rich in Diverse Spirocyclic Natural Products

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