Algal Research 56 (2021) 102330

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Algal Research
journal homepage: www.elsevier.com/locate/algal

Update on sesquiterpenes from red macroalgae of the Laurencia genus and

their biological activities (2015–2020)
Ana-Marija Cikoš a, Mladenka Jurin b, Rozelindra Čož-Rakovac b, Dajana Gašo-Sokač a,
Stela Jokić a, Igor Jerković c, *
a
Faculty of Food Technology Osijek, University of Josip Juraj Strossmayer in Osijek, Franje Kuhača 18, 31000 Osijek, Croatia
b
Ruđer Bošković Institute, Bijenička 54, 10000 Zagreb, Croatia
c
Department of Organic Chemistry, Faculty of Chemistry and Technology, University of Split, Ruđera Boškovića 35, 21000 Split, Croatia

A R T I C L E I N F O A B S T R A C T

Keywords: Laurencia genus has been the most promising source of sesquiterpenes (among all macroalgae) including those
Laurencia genus with high degree of halogenation, especially bromination. Related published reviews do not report novel re­
Macroalgae searches included in this study and are not focused exclusively on this genus or sesquiterpenes. The present
Marine natural products (different
review reports novel structures of Laurencia derived sesquiterpenes exclusively in the period of 2015–2020, with
sesquiterpene skeletons)
emphasis on their structural diversity and different skeleton types including chemical biomarkers along with the
Bioactive compounds (cytotoxic, anti-
inflammatory, antibacterial, antifungal, antidi­ methods for their structural analysis. Their cytotoxic, anti-inflammatory, antibacterial, antifungal, antidiabetic,
abetic, anthelmintic, others) anthelmintic activities and others are summarised indicating determined structure – activity relationships along
with ecological role of targeted sesquiterpenes. Furthermore, possible stages of sesquiterpene biosynthesis are
presented for better understanding of their chemodiversity.

1. Introduction miscellaneous triterpenes), around 240 C15 acetogenins (acetogenins

The genus Laurencia (Rhodophyta, Ceramiales, and Rhodomelaceae)
comprise around 140 species distributed throughout the warm sea wa­
ters, particularly from temperate to tropical shores [1]. It has been rich
source of unique specialised metabolites with high degree of haloge­
nation, especially bromination, and wide range of the skeleton types [2].
Within more than 60 species investigated, 700 compounds with unique
structures have been isolated from this genus [3] with sesquiterpenes as
the most abundant terpenes along with diterpenes, triterpenes, steroids,
alkaloids and C15 acetogenins [4]. The comprehensive review of Har­
izani et al. [5] presents the chemical diversity and the bioactivity of the
secondary metabolites isolated from species of the genus Laurencia
including more than 500 sesquiterpenes, about 100 diterpenes (par­
gueranes, isopargueranes, and related diterpenes; labdanes, pimaranes,
and related diterpenes; irieanes and neoirieanes; dactylomelanes;
obtusanes, 15,14-friedoobtusanes, and related diterpenes; prevezanes
and neorogiolanes; miscellaneous diterpenes), about 50 triterpenes
(triterpenes possessing 2,7-dioxabicyclo[4.4.0]decane ring system and
related metabolites; triterpenes possessing 2,8-dioxabicyclo[5.4.0]
undecane ring system; triterpenes possessing symmetry elements;
containing tetrahydrofuran ring and tetrahydropyran ring; acetogenins
containing oxepane ring; acetogenins containing oxocane ring; aceto­
genins containing nine- or ten-membered cyclic ether ring; acetogenins
containing twelve-membered cyclic ether ring; linear acetogenins),
around 30 indols, 5 aromatic compounds, 15 steroids, and 35 miscel­
laneous metabolites. Among them, biologically active metabolites have
been isolated with anticancer [6,7,8], antidiabetic [9], antibacterial
[10], antimalarial [11], anthelmintic [12] and other biological activ­
ities. Harizani et al. [5] reported their cytotoxic activity, antibacterial
and antifungal activity, antiviral activity, activity against parasites and
their vectors, anti-inflammatory activity, miscellaneous biological ac­
tivities, ecological functions, antifeedant activity and toxicity to marine
organismsm, brine shrimp toxicity, and antifouling activity. The pro­
duction of specialised metabolites observed in this genus can be
explained in general as an ecological adaptive response to the environ­
mental changes and oscillations. The specific metabolites are produced
only by certain Laurencia species indicating them as chemical markers.
Several reviews provide information about sesquiterpenes found in
different macroalgae [13,14,15]. Phytochemical and biological prop­
erties of sesquiterpenes isolated from Laurencia genus were presented by

* Corresponding author.
E-mail address: igor@ktf-split.hr (I. Jerković).

https://doi.org/10.1016/j.algal.2021.102330
Received 6 February 2021; Received in revised form 21 April 2021; Accepted 24 April 2021
Available online 12 May 2021
2211-9264/© 2021 Elsevier B.V. All rights reserved.
A.-M. Cikoš et al.
Al-Massarani [13], while Jesus et al. [15] reviewed haloaryl specialised
metabolites with their biological applications including sesquiterpenes
isolated from different macroalgae. Modzelewska et al. [16] reviewed
anticancer activity of naturally occurring sesquiterpenes. Le Bideau
et al. [14] systematically represented tricyclic sesquiterpenes from ma­
rine origin. The biosynthesis of sesquiterpenes was investigated in detail
mainly for the compounds occurring in plants with wide variety of
skeleton types [17,18], while Miller and Allemann [19] reviewed
sesquiterpene synthases for the better understanding of chemical shifts
occurring during the biosynthesis.
Nevertheless, the discovery of novel and interesting structures has
been occurring in new studies of Laurencia genus and therefore present
review is providing update on Laurencia derived sesquiterpenes. The
present study addresses the following topics: a) exclusively sesquiter­
penes found in the genus Laurencia (as the main producer of sesquiter­
penes among all macroalgae) are targeted in the period 2015–2020 and
presented by different skeleton types; b) the methods of their isolation
(including different extraction solvents) and analysis are systematically
presented; c) their cytotoxic, anti-inflammatory, antibacterial, anti­
fungal and other activites are addressed as well as their ecological roles;
d) the structure influence on bioactivity with the emphasis on cytotox­
icity of targeted sesquiterpenes is presented; e) probable stages of
sesquiterpene biosynthesis are indicated for better understanding of
their chemodiversity as well as general enzymes included in the for­
mation of different sesquiterpene classes (since in other reviews this
topic is not elaborated in detail or not presented, this study covers
broader range of available references); f) the literature references are
updated.
2. Chemical biodiversity of sesquiterpenes from genus Laurencia
Laurencia genus has been the most attractive source of sesquiterpenes
among all marine macroalgae due to its capability of biosynthesizing a
wide variety of structurally diverse sesquiterpenes which are divided
according to their skeleton types to chamigrane, cuparane, laurane,
bisabolane, aristolane, brasilane, eudesmane, snyderane, perforanes and
other skeletons (Table 1). Only new structures reported from 2015 are
further presented in the following figures. In novel papers, sesquiterpene
structures were elucidated on the basis of extensive spectroscopic
analysis including FT-IR, H1-NMR, C13-NMR, H1-H1-COSY, HSQC,
HMBC, and NOESY. The absolute configurations were determined or
proposed based on the biosynthetic grounds by the comparison to
related known sesquiterpenes.
2.1. Chamigrane skeleton sesquiterpenes
Chamigrane-type sesquiterpenes are the most widespread sesqui­
terpenes from the genus Laurencia. Chamigrane skeleton can serve as an
intermediate for formation of novel carbon skeletons. The presence of
both α- and β-chamigrane in marine macroalgae suggests that derived
carbon skeletons are formed by intramolecular cyclization of both cha­
migrane backbones. However, for terrestrial plants related skeletons are
usually formed only from α-chamigrane backbone [20].
Even though there are many reports for chamigrane-type sesquiter­
penes [12,21,22,23,24], recent studies are revealing new undescribed
compounds pointing out the diversity of sesquiterpenes produced by
Laurencia genus (Fig. 1). Kamada et al. [7] reported three undescribed
α-chamigrane sesquiterpenes with ketone functionality from L. majuscula
(7-aldehydelaurencenone B (1), 2-chloro-3-methoxy-α-chamigran-9-one
(2), laureborneone (3)) along with five other known metabolites [1(15)
Z,2Z,4R,8S,9R]-8,15-dibromochamigra-1(15),2,11(12)-trien-9-ol, [1(15)
E,2Z,4R,8S,9R]-8,15-dibromochamigra-1(15),2,11(12)-trien-9-ol, ma'i­
lion [12], laurencenone B [25] and 2-chloro-3-hydroxy-α-chamigran-9-
one [26]. Prior to this study, they reported [27,28] that the population of
L. majuscula produces two major types of halogenated specialised
2
Algal Research 56 (2021) 102330
metabolites: elatol and obtusol belonging to the first type of metabolites,
and [1(15)Z,2Z,4R,8S,9R]-8,15-dibromochamigra-1(15),2,11(12)-trien-
9-ol and [1(15)E,2Z,4R,8S,9R]-8,15-dibromochamigra-1(15),2,11(12)-
trien-9-ol belonging to the second type. The authors discovered the
presence of chamigrane metabolites with ketone functionality in the
compounds 1, 2, 3, laurencenone B and 2-chloro-3-hydroxy-α-chamigran-
9-one. They suggested that newly discovered metabolites can serve as
intermediates in the biosynthetic pathway of specialised metabolite pro­
duction. Recently, undescribed oxygenated sesquiterpenes lau­
remantanones A (4) and B (5) were determined in L. majuscula along with
known compounds (+)-elatol [29], obtusol [23], (+)-laurencenone B and
2-chloro-3-hydroxy-α-chamigran-9-one, as well as dendroidiol [30] and
cartilagineol [31]. The compounds 4 and 5 were formed from α-chami­
grane backbone, while the compounds (+)-elatol, obtusol, dendroidiol,
cartilagineol were formed from β-chamigrane backbone [10]. In the same
year, Kamada et al. [32] discovered (− )-laurencenone D (6) and
(+)-deschloroelatol (7) which were not detected before in the same spe­
cies, along with the previous known compounds (+)-elatol, (+)-lau­
rencenone B, 2-chloro-3-hydroxy-α-chamigran-9-one and cartilagineol
suggesting the unique diversity of halogenated chamigrane sesquiterpenes
and their rearranged analogues in L. majuscula. Red alga L. composita
produced eleven highly halogenated chamigrane sesquiterpenes (com­
positacins A-K (8–18)) and all of the metabolites contained unusual
rearranged compositacin A (8) with specific composition including an
ether bridge involving C-5/C-9 and C-3/C-5 in compositacins B (9) and D
(16) while compositacins B (9) and C (10) were the first chamigranes with
C-10 carbonyl group [33]. The absolute configuration of compositacin B
(9) was determined by ECD calculation, and the absolute configurations of
compositacins A (8) and C–K (10–18) were proposed on the biosynthetic
grounds by comparison to compositacin B (9) and related known sesqui­
terpenoids johnstonol [34] and yicterpene A [35]. It was also suggested
that the structure of the previously reported sesquiterpenoid laurokamin A
should be revised. Hence, the study of Hu et al. [36] revealed the presence
of another compositacins in L. composita, including compositacin L (19),
compositacin M (20) and compositacin N (21), along with known com­
pounds 2,10β-dibromochamigra-2,7-dien-9α-ol [37], 2,10-dibromo-3-
chloro-α-chamigrene [38], obtusane [39], deoxyprepacifenol [40], pre­
pacifenol epoxide [41], pacifidiene, pacifenediol, pacifenol [42], and
yicterpene A. Compositacin L (19) represents the third example of cha­
migranes having C-10 carbonyl group. The study of Chen et al. [43] re­
ported the isolation of 18 compounds from the red alga L. tristicha
including eight new chamigrane-type sesquiterpenes: tristichone A (22),
ristichone B (23), tristichol A (24), tristichol B (25), tristichol C (26),
zristichol D (27), tristichone C (28) and tristichone D (29), along with nine
known compounds, halogenated chamigrene derivatives: 9-(E)-bromo­
methylidene-1,5,5-trimethylspiro[5.5]undeca-1,7-dien-3-one and 9-(Z)-
bromomethylidene-1,5,5-trimethylspiro[5.5]undeca-1,7-dien-3-one [44],
ma'ilione, [1(15)Z,2Z,4S,8R,9S]-8,15-dibromochamagra-1(15),2,11(12)-
trien-9-ol [44], [1(15)E,2Z,4S,8R,9S]-8,15-dibromochamagra-1(15),2,11
(12)-trien-9-ol [44], ma'iliohydrin [45], isorigidol [12], allo-isoobtusol
[46], and majusculone [47]. Philippus et al. [48] used molecular
networking for determination of sesquiterpenes of some algae from Lau­
rencia genus (L. catarinensis, L. dendroidea and L. intricata). An interesting
chemodiversity was observed in L. catarinensis collected from two nearby
islands: L. catarinensis collected in Xavier Island contained three chami­
grane sesquiterpenes including prepacifenol epoxide, johnstonol and
pacifenol along with some C15-acetogenins; L. catarinensis collected in
Arvoredo Island did not contain C15-acetogenins, but contained four
different chamigrane sesquiterpenes including 9-hydroxy-4,10-dibromo-
3-chloro-α-chamigrene [49], 2,10-dibromo-3-chloro-8-hydroxy-β-chami­
grene [49], 4,10-dibromo-3-chloro-7,8-epoxychamigrane [50] and 4,10-
dibromo-3-chloro-7,8-epoxy-5-hydroxychamigrane [51]. These results
indicate that a different chemical composition could be present in the alga
in relation to the collection sites.
A.-M. Cikoš et al. Algal Research 56 (2021) 102330

Table 1
Sesquiterpenes isolated from the species of genus Laurencia.
Laurencia species Determined compounds Extraction Analytical method Bioactivity References
solvent

Chamigrane skeleton sesquiterpenes

L. majuscula 7-Aldehyde-laurencenone B, 2-chloro-3-methoxy- CH3OH FT-IR, 1H and 13C NMR, Cytotoxic activity [7]
1 –1
α-chamigran-9-one, laureborneone H H COSY, HSQC, HMBC,
NOESY
1
Lauremantanones A and B H and 13C NMR, HRESIMS [10]
1
(− )-Laurencenone D and (+)-deschloroelatol H and 13C NMR, HRESIMS Antibacterial activity [32]
1
L. composita Compositacins A-K C2H5OH/ H and 13C NMR, HSQC, – [33]
1 –1
H2O H H COSY, ROESY, HMBC,
HREIMS, LREIMS
1
L. composita Compositacins L-N CH3OH H and 13C NMR, EIMS, Antibacterial and [36]
HREIMS, 1H–1H COSY, DEPT, antifungal activities
HSQC, HMBC, ROESY
1
L. tristicha Tristichone A, ristichone B, tristichol A, tristichol B, tristichol C6H14 H and 13C NMR, HRESIMS, Cytotoxicity, antibacterial [43]
C, zristichol D, tristichone C and tristichone D NOESY, COSY, HMBC and anti-inflammatory
activities

Bisabolane skeleton sesquiterpenes

1
L. composita Laurecomposins A and B CH3OH H and 13C NMR, EIMS, Antibacterial and [36]
HREIMS, 1H–1H COSY, DEPT, antifungal activities
HSQC, HMBC, ROESY

Cuparane skeleton sesquiterpenes

13
L. obtusa α-Bromocuparene and α-isobromocuparene C4H8O2 C NMR, HMBC, ESI-IT – [54]
1
L. johnstonii C2H5OH H and 13C NMR, HREIMS, Anti-acanth-amoeba [55]
HMBC, NOE, COSY activity
1
L. tristicha α-Bromocuparene C2H5OH H and 13C NMR, EIMS – [56]
1
L. nidifica α-Bromocuparene CH3OH H NMR, MS Repellent and insecticidal [74]
activities
L. majuscula Cuparen-3-ol C6H14 NMR and MS Cytoxic activity [57]
1
L. tristicha 4α-Hydroxy-bromocuparene C6H14 H and 13C NMR, HRESIMS, Cytotoxicity, antibacterial [43]
NOESY, COSY, HMBC and anti-inflammatory
activities
1
L. natalensis 8-Deoxyalgoane, 1-deacetoxyalgoane and algoane CH2Cl2/ H and 13C NMR, 1H–1H Anti-inflammatory and [9]
CH3OH COSY, ROESY, HSQC, HMBC, antidiabetic activity
ESIMS, APCIMS
1
L. obtusa 10-hydroxy-cuparaldehyde, 3-hydroxy-15-nor-cuparan-10β- CH2Cl2/ H and 13C NMR, EIMS, Antibacterial and [58]
ol, 2-bromo-3-hydroxy-15-nor-cuparan-10β-ol CH3OH HRESIMS anticandidal activities

Laurane skeleton sesquiterpenes

1
L. okamurai Nanji A CH2Cl2/ H and 13C NMR, LREIMS, – [59]
CH3OH HREIMS, 1H–1H COSY,
HMQC, HMBC
1
L. tristicha Laurinterol C2H5OH H and 13C NMR, EIMS – [56]
L. tristicha and L. CH3OH HPLC-DAD – [68]
okamurai
13
L. obtusa Laurinterol, iso-laurenisol, laurene, 3,7-dihydroxy-dihydro­ C4H8O2 C NMR, HMBC, ESI-IT – [54]
laurene, 11-iodolaurinterol
1
L. nidifica Laurinterol, isolaurinterol, aplysin CH3OH H NMR, MS Repellent and insecticidal [74]
activities
1 13
L. johnstonii C2H5OH H and C NMR, HREIMS, Cytotoxic and anti-acanth- [55]
HMBC, NOE, COSY amoeba activity
1
L. okamurai 3α-Hydroperoxy-3-epiaplysin, debromo-3β-hydroperoxy- C3H6O H and 13C NMR, COSY, PTPB inhibitory activity [75]
aplysin, 3β-hydroperoxyaplysin, isoaplysin, 10-bromoisoalpy­ HMBC, NOESY, HREIMS and antibacterial activities
sin, laurepoxyene, laurokamurene A, isolaurinterol
1
L. heteroclada 2-Bromo-3,5,6-trihydro-1,4-dihydroxy isolaurene CH3OH H and 13C NMR, HREIMS, – [76]
HMQC, 1H–1H COSY, HMBC,
NOESY
1
L. mariannensis Teanol CH3OH H and 13C NMR, HRESIMS, [77]
HMBC, NOESY
1
L. okamurai Laurokamurols A − C C3H6O H and 13C NMR, HREIMS, PTP1B inhibitory activity [78]
HMBC, NOESY, HMQC,
TDDFT-ECD
1
L. nangii Neolaurene CH3OH H and 13C NMR, HRESIMS, Cytotoxic and [79]
NOESY, HBMC antibacterial activities
1
L. tristicha 10-Hydroxyepiaplysinol, epiaplysinol C2H5OH H and 13C NMR, HRESIMS, Antioxidant activity [81]
HSQC, HMBC, NOESY

Aristolane skeleton sesquiterpenes

1
L. complanata Debilone MeOH H and 13C NMR, COSY, – [82]
NOESY, HMBC, HSQC, ESIMS

Brasilane skeleton sesquiterpenes

13
L. obtusa 4-Hydroxy-5-brasilene C4H8O2 C NMR, HMBC, ESI-IT – [54]

Eudesmane skeleton sesquiterpenes

L. obtusa Antifungal and cytotoxic [84]
(continued on next page)

3
A.-M. Cikoš et al. Algal Research 56 (2021) 102330

Table 1 (continued )
Laurencia species Determined compounds Extraction Analytical method Bioactivity References
solvent
1
Eudesma-4(15),7-diene-5,11-diol, teuhetenone, chabrolidione CH2Cl2/ H and 13C NMR, EIMS,
B CH3OH HRESIMS, DEPT, HSQC,
1 –1
H H COESY
1
L. pinnata 1β-B -11-en-4α-ol, 1β-bromo-4α,5α-epoxyselinane, and 1β- CHCl3 H and 13C NMR, EIMS, – [85]
bromoselin-3,11-diene, 1β-bromo-6,8-cycloselin-4(15)-ene, HRAPPIMS, DEPT, HSQC,
1β-bromoselin-4(15),11-diene HMBC, NOE, 1H–1H COSY
1
L. obtusa Eudesma-4(15),11-diene-5,7-diol CH2Cl2/ H and 13C NMR, EIMS, Antibacterial and [58]
CH3OH HRESIMS anticandidal activities

Snyderane skeleton sesquiterpenes

13
L. obtusa β-Snyderol C4H8O2 C NMR, HMBC, ESI-IT – [54]
1
L. obtusa 8-Keto-10-dehydrobromo-γ-snyderol, α-snyderol, β-snyderol,, C4H8O2 H and 13C NMR, HRESIMS, – [89]
8-keto-10-dehydrobromo-β-snyderol, 8-hydroxy-β-snyderol, HSQC, COSY, HMBC
1
L. intermedia Aplysistatin, palisadin B, 3,4-epoxypalisadin A, 2-hydroxylu­ C6H14 H and 13C NMR, HRESIMS, – [93]
zofuranone, 2-hydroxyluzofuranone B HMBC, HSQC,

Other skeletons sesquiterpenes

1
L. johnstonii 3α-Bromojohnstone C2H5OH H and 13C NMR, HREIMS, Anti-acanth-amoeba [55]
HMBC, NOE, COSY activity
1
L. intricata (+)-Cyclocolorenone CH3OH H and 13C NMR, ESIMS Repellent activity [91]
1
L. majuscula Omphalaurediol, rhodolaurenones B and C CH3OH H and 13C NMR, HRESIMS, – [32]
HSQC, 1H–1H COSY, HMBC,
NOESY
L. dendroidea Silphiperfolan-7β-ol CH2Cl2 – – [98]
1
L. snackeyi Snakeol, snakediol CH3OH H and 13C NMR, HRESIMS, Antibacterial activity [99]
1 –1
H H COSY, NOESY

2.2. Bisabolane and cuparane skeleton sesquiterpenes
Bisabolane skeleton includes monocyclic ring structure resulted from
the cyclization of geranyl cation [52]. The recent investigation on L.
composita resulted in two new bisabolane-type sesquiterpenes, named
laurecomposins A (30) and B (31) (Fig. 2). The relative configurations
for both compounds were elucidated, while for laurecomposin A abso­
lute configuration was also given by the modified Mosher's method [36].
Cuparane structure of sesquiterpenes is formed by the cyclization of
bisabolane skeleton between C-6 and C-11. Three methyl groups are in
the aliphatic backbone, one is located at the position 1 and the other two
methyls are at the position 2 [53]. α-Bromocuparene and α-iso­
bromocuparene were found in different Laurencia species such as L.
obtusa [54] and L. johnstonii [55], while α-bromocuparene was obtained
from L. tristicha for the first time by Zhang et al. [56]. Later, α-bromo­
cuparene was also found in L. nidifica (Ishii et al. 2017) and L. majuscula
[57]. L. majuscula also showed the presence of cuparen-3-ol [57]. In
2016, Chen et al. [43] reported one new bromocuparane-type sesqui­
terpene, 4α-hydroxybromocuparene (32) (Fig. 2) isolated from L. tris­
ticha. L. natalensis contained earlier undescribed cuparane
sesquiterpenes including 8-deoxyalgoane (33), 1-deacetoxyalgoane (34)
and algoane (35) [9]. New cuparane-type sesquiterpene, 10-hydroxycu­
paraldehyde (36), and two nor-cuparanes, 3-hydroxy-15-nor-cuparan-
10β-ol (37) and 2-bromo-3-hydroxy-15-nor-cuparan-10β-ol (38), were
isolated for the first time from L. obtusa. Nor-cuparanes, 37 and 38,
isolated in that study are rarely found in marine organisms [58].
2.3. Laurane skeleton sesquiterpenes
Contrary to cuparane-type sesquiterpenes, in laurane-type com­
pounds methyls in the aliphatic portion are placed at the positions 1, 2
and 3. Among all marine organisms, macroalgae belonging to the genus
Laurencia are considered as the main producers of laurane-type sesqui­
terpenes [53].
Recently, nanji A was found for the first time in L. okamurai [59] and
it represents rare dimeric sesquiterpene of the cyclolaurane-type but it
was already detected in L. microcladia [8]. Even though this alga was
studied more times [60,61,62] there was no other report of this com­
pound and possible reason can be the collection time influencing the
metabolism. Previously detected compounds were also found in L.
okamurai [59] including debromolaurinterol [63], laurinterol acetate
[60], laurinterol [64], 3β-Hydroperoxyaplysin, 3α-hydroperoxy-3-epi­
aplysin [65], isolaurinterol [63] and laurokomurenene A [61]. It was
suggested that the compounds debromolaurinterol, laurinterol and iso­
laurinterol can be characteristic specialised metabolites of Laurencia
genus because they were already detected in L. tristicha [66] and L.
intermedia [63] along with the compounds 3β-hydroperoxyaplysin, 3α-
hydroperoxy-3-epiaplysin and laurokomurenene A which can act as
chemotaxonomic markers because they were only detected in L. oka­
murai [61,65]. Laurinterol acetate was found the second time in nature
and it was recorded in L. okamurai so it can be also used as the marker
[60]. L. okamurai and L. tristicha are very similar in morpohology as well
as in the content of specialised metabolites. It can be seen that some
compounds already detected in L. okamurai such as debromolaurinterol,
debromolaurinterol acetate, laurinterol acetate and laurinterol were
detected in L. tristicha as well, along with some previously described
compounds detected only in L. tristicha aplysin [67], aplysinol [60],
debromoaplysinol and aplysinal [67]. Therefore, it can be suggested that
these two algae share the same metabolic pathway and possess closer
genetic affinity. Moreover, laurinterol as the main compound found in
both of the algae can serve as chemotaxonomic marker for these two
species [56]. Zhang et al. [68] provided the overall chemical profiles of
L. tristicha and L. okamurai obtained by high-performance liquid chro­
matography (HPLC). The results showed that both algae are important
sources of laurane-type sequiterpenes due to the presence of laurinterol
as the main sesquiterpene in both species and debromolaurinterol as the
second abundant compound. L. okamurai contained higher content of
laurinterol (14.96–15.42 mg/g), while L. tristicha contained higher
concentration of debromolaurinterol (1.15–1.38 mg/g). Consequently,
laurane-type sesquiterpenes were once again shown as important
chemotaxonomic markers for L. tristicha and L. okamurai. Hence, an
effective new workflow for absolute structure elucidation, in which
crystallographic analysis is iteratively applied together with NMR
analysis was established by Wada et al. [69]. In their study they eluci­
dated the structure of laurinterol by NMR-coupled crystalline-sponge
(CS) method. In the research by Esselin et al. [54] a wide variety of
specialised metabolites were identified from L. obtusa extract, among
them several compounds of laurane-type including laurinterol, iso-
laurenisol [70], laurene [71], 3,7-dihydroxydihydrolaurene [72] and
11-iodolaurinterol [73]. Hence, L. nidifica [74] and L. johnstonii [55]

4
A.-M. Cikoš et al.
Fig. 1. Chamigrane skeleton sesquiterpenes from Laurencia.
revealed the presence of laurinterol, isolaurinterol and aplysin. New
compounds including, debromo-3α-hydroperoxy-3-epiaplysin (39) and
debromo-3β-hydroperoxyaplysin (40) (Fig. 3) were isolated from L.
okamurai along with already known compounds 3β-hydroperoxyaplysin,
isoaplysin, 10-bromoisoalpysin [60], laurepoxyene [65], laurokamur­
ene A and isolaurinterol. The compound 39 was elucidated as debro­
minated analog of 3α-hydroperoxy-3-epiaplysin, while compound 40
was suggested as an epimer of compound 39 at C-3 position, as well
debromo analog of 3β-hydroperoxyaplysin [75]. Undescribed bromi­
nated nonaromatic isolaurene type sesquiterpene identified as 2-bromo-
3,5,6-trihydro-1,4-dihydroxy isolaurene (41) was found in L. heteroclada
[76]. Recently, the structure of teanol (42), undescribed rearranged
brominated cyclolaurane-type sesquiterpene, was reported from
Thailand red alga L. mariannensis (the first report of the genus Laurencia
from Thailand). The relative stereochemistry on the oxolane ring of 42
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Algal Research 56 (2021) 102330
was determined by the NOESY spectrum [77]. Three novel hetero­
dimeric laurane-type sesquiterpenoids, laurokamurols A − C (43–45),
along with eight known related monomeric ones were isolated from the
East China Sea red alga Laurencia okamurai Yamada [78]. The absolute
configurations of new bis-sesquitepenoids, especially their axial
chirality, were determined by extensive spectroscopic analyses and
TDDFT-ECD method. L. nangii was shown as a source of neolaurene (46),
a new 3,4-olefinic laurene type carbon skeleton isolated from a marine
source. Its stereochemistry was determined based on NOESY data [79].
One new laurane-type sesquiterpene, 10-hydroxyepiaplysinol (47) and
known epiaplysinol [80] were isolated from L. tristicha [81].
2.4. Aristolane and brasilane skeleton sesquiterpenes
The aristolane-type sequiterpenes are derivatives of 6,11-
A.-M. Cikoš et al.
Fig. 2. Bisabolane and cuparane skeletons sesquiterpenes from Laurencia.
Fig. 3. Laurane skeleton sesquiterpenes from Laurencia.
cycloeremophilanes. For the first time, debilone (48) (Fig. 4) was iso­
lated from L. complanata that represents the first marine organism as a
source of this compound [82]. Brasilane-type sesquiterpenes possess the
basic structure of octahydro-1,6,6-trimethyl-4-(1-methyl)-1H-indene
[53]. Esselin et al. [54] found one undescribed compound 4-hydroxy-5-
brasilene (49) (Fig. 4), along with known brasilenol and epibrasilenol
[83] in L. obtusa.
Fig. 4. Aristolane and brasilane skeletons sesquiterpenes from Laurencia.
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Algal Research 56 (2021) 102330
2.5. Eudesmane skeleton sesquiterpenes
L. obtusa was the source of eudesmane-type sesquiterpenes that were
reported for the first time and they included undescribed eudesmane
sesquiterpene named eudesma-4(15),7-diene-5,11-diol (50), along with
trinor-sesquiterpene teuhetenone (51) and seco-eudesmane sesquiter­
pene, chabrolidione B (52) (Fig. 5) [84]. Chemical investigation of the
red alga L. pinnata collected from Nanji Island of China [85] resulted in
the isolation and identification of three new eudesmane sesquiterpenes,
1β-bromoselin-11-en-4α-ol (53), 1β-bromo-4α,5α-epoxyselinane (54),
and 1β-bromoselin-3,11-diene (55), and one new 6,8-cycloeudesmane
sesquiterpene, 1β-bromo-6,8-cycloselin-4(15)-ene (56) (Fig. 5)
together with one known eudesmane sesquiterpene, 1β-bromoselin-4
(15),11-diene [86]. Eudesmane derivatives reported in that study are
predominant and rarely reported from this genus, and they may be taken
as chemotaxonomic markers for L. pinnata. One new eudesmane-type
sesquiterpene was isolated from L. obtusa [58] and it was named
eudesma-4(15),11-diene-5,7-diol (57).
A.-M. Cikoš et al.
Fig. 5. Eudesmane skeleton sesquiterpenes from Laurencia.
2.6. Snyderane skeleton sesquiterpenes
Snyderane-type sesquiterpenes are bromo monocyclo-nerodiol de­
rivatives. In 2017, Esselin et al. [54] analyzed the crude extract obtained
from L. obtusa and discovered that its chemical composition is domi­
nated by β-snyderol [87] that was also observed in the study of Sutour
et al. [88]. Hence, Esselin et al. [89] detected an unusual new γ-sny­
derane skeleton in 8-keto-10-dehydrobromo-γ-snyderol (58) (Fig. 5)
that was isolated from L. obtusa. Six known compounds including
α-snyderol and β-snyderol [87], two rearranged derivatives of α-sny­
derol, 8-keto-10-dehydrobromo-β-snyderol and 8-hydroxy-β-snyderol
[90] were also determined. While α- and β-snyderanes are characteristic
for Laurencia genus [5], γ-snyderanes are rare. The authors suggested
that γ-snyderol can be considered as a chemotaxonomic marker in L.
obtuse, but a systematic study of other L. obtusa populations is necessary
[89]. L. snackeyi collected from three different locations (Minna Island,
Sesoko Island and Kayo Coast) revealed the presence of palisadin A,
palisadin B and aplysistatin [91] that were already reported in the
literature [92]. Five halogenated snyderane-type sesquiterpenes,
Fig. 6. Other skeletons sesquiterpenes from Laurencia.
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Algal Research 56 (2021) 102330
aplysistatin, palisadin B, 3,4-epoxypalisadin A, 2-hydroxyluzofuranone
and 2-hydroxyluzofuranone B were for the first time isolated from L.
intermedia [93] even though they were already reported for some other
species such as L. similis [94], L. saitoi [95] and L. luzonensis [96].
2.7. Other skeletons of sesquiterpenes
In addition to all mentioned skeletons, certain found sesquiterpenes
cannot be easily classified into the mentioned groups (Fig. 6, Table 1). A
novel rearranged carbon skeleton, johnstane, was found in L. johnstonii
and represents the first natural sesquiterpene metabolite with that kind
of structure isolated from Laurencia species so far. It was identified as 3α-
bromojohnstone (59) [55]. Aromadendrane skeleton was discovered in
the compound identified as (+)-cyclocolorenone (60) isolated from L.
intricata [91]. Omphalaurediol (61) represents the second example of
marine-derived omphalane sesquiterpenes, while rhodolaurenones B
(62) and C (63) were found as new rhodolaurane-type sesquiterpenes
[32], along with known rhodolaurenone A [97], rhodolaureol and iso­
rhodolaureol [45]. da Silva Machado et al. [98] examined six native
A.-M. Cikoš et al.
populations of L. dendroidea at Southeast Brazilian coast in order to
evaluate the chemical diversity and they reported that a triquinane
sesquiterpene, named silphiperfolan-7β-ol (64), was observed in all
investigated populations. Two new non-halogenated sesquiterpenes,
snakeol (65) and snakediol (66), were isolated from L. snackeyi. The
structure of snakeol (65) is elucidated as the unusual monocyclofarnesol
due to the E configuration of double bond at C-2/C-3, while the most
Laurencia species possess the Z configuration double bond at C-3/C-4
[99].
3. Bioactivity of sesquiterpenes isolated from Laurencia species
Sesquiterpenes from Laurencia species showed different activities:
cytotoxic, anti-inflammatory, antibacterial, antifungal, antidiabetic,
anthelmintic activities and others as well as different ecological roles.
The most actual is cytotoxic activity (expressed as IC50 values) that can
be even compared to the standard compounds such as paclitaxel that has
been used in clinical trials for chemotherapy. However, only a few
studies are available containing comparison and potency of isolated
sesquiterpenes with reference drugs. Targeted sesquiterpenes could be
effective anti-inflammatory agents in comparison to e.g. well-known
anti-inflammatory agent dexamethasone and exhibited moderate to
potent antibacterial and antifungal activity compared to e.g. benzylpe­
nicillin. Further investigations should provide better understanding of
how chemical structure of the compound influences the bioactivity
mechanism. However, many studies have been reporting a variety of
sesquiterpenes from Laurencia species, but without performing bioac­
tivity tests. Furthermore, the bioactivity of Laurecia species has been
often presented for different total extracts as the compounds mixture,
not providing information about specific compound activity and there­
fore this gap is opening new research potential, especially for the most
represented sesquiterpenes. In addition, sesquiterpenes are extremely
important for the chemical defences of macroalgae. However, there is
lack of bioassays in an ecologically relevant manner for instance field
and laboratory assays with natural herbivores that are necessary to
examine the ecological interactions. Their exact role in marine
ecosystem and the mechanisms of macroalgal chemical defences against
herbivores and competitors should be studied more, since very little data
are available.
3.1. Cytotoxic activity
Cytotoxic activity was the most studied among Laurencia-derived
sesquiterpenes which resulted with new findings of potential antitumor
agents. The structure of tested sesquiterpenes exhibited a significant
influence on the promotion of activity against wide variety of tested cell
lines. The composition of chamigrane-type sesquiterpenes revealed that
β-chamigrane type sesquiterpenes (elatol, obtusol, [1(15)
Z,2Z,4R,8S,9R]-8,15-dibromochamigra-1(15),2,11(12)-trien-9-ol, [1
(15)E,2Z,4R,8S,9R]-8,15-dibromochamigra-1(15),2,11(12)-trien-9-ol,
dendroidiol and cartilagineol) showed much stronger activity against
three tested cancer cell lines (HeLa, MCF-7 and P-388; IC50 ≤ 1.0 μg/
mL), while α-chamigrane sesquiterpenes (laureborneone, lau­
remantanones A and B) showed activity against only two types of cell
lines (HeLa and P-388; IC50 ≤ 5.0 μg/mL) [7,10]. Among all tested
isolated sesquiterpenes, 7-aldehydelaurencenone B showed the stron­
gest activity against HeLa cell line (IC50 = 7.83 μg/mL) and P-388 cell
line (IC50 = 8.98 μg/mL) that can be attributed to the presence of
aldehyde group when compared to laurencenone B (17) that did not
show any activity. Therefore, the authors suggested that the cytotoxicity
of laureborneone, [1(15)Z,2Z,4R,8S,9R]-8,15-dibromochamigra-1
(15),2,11(12)-trien-9-ol, [1(15)E,2Z,4R,8S,9R]-8,15-dibromochamigra-
1(15),2,11(12)-trien-9-ol might be due to the presence of the vinyl
bromide [7].
It was shown that the presence of hydroxyl and exo-methylene
moieties are important for biologically active sesquiterpenes due to the
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Algal Research 56 (2021) 102330
enhancement of the cytotoxicity against various cancer-derived cell
lines (colon, glioblastoma, breast, ovarian, lung, skin, prostate, neuro­
blastoma, pancreas, and murine glioblastoma) [8,100,101]. Barcellos
Marini et al. [6] showed that (− )-elatol and obtusol exhibited the most
promising activity against Colo-205 cell line with IC50 values of 1.2 ±
1.4 μg/mL and 2.5 ± 1.3 μg/mL. Due to the multidrug resistance in
tumors after successful chemotherapy, new antitumor substances should
be found with high tumor cell selectivity resulting in apoptosis. Hence,
elatol and obtusol showed a remarkable apoptotic process in the treat­
ment against Colo-205 cell line, but authors suggested that other
methodologies should be used for the confirmation of this process [6].
Not only the structure of sesquiterpenes influences the cytotoxic
activity intensity, but also the applied concentration against cancer cell
lines. It was observed that laurinterol showed dose-dependent inhibition
of the metabolic activity of breast cancer cell lines. When crude extract
of L. johnstonii was applied against the same cells, the reduced metabolic
viability was also observed in breast cancer explants. The cytological
effects of the crude extract (IC50 value for Vero cells was 26.18 μg/mL
and 28.05 μg/mL for MCF-7 cells) were similar to those induced by
paclitaxel which served as positive control, while activity of laurinterol
(IC50 = 15.68 μg/mL for Vero cells; IC50 = 16.07 μg/mL for MCF-7 cells)
was similar to cisplatin, suggesting different molecular damage mech­
anisms that should be studied in detail [102]. Eudesma-4(15),7-diene-
5,11-diol (49), teuhetenone (50) and chabrolidione B (51) were tested
against MCF-7 cells and the results were compared to cisplatin. Teuhe­
tenone (50) exhibited the highest cytotoxic activity against MCF-7 (IC50
= 22.8 ± 0.18 μM) when compared to cisplatin (59 ± 0.045 μM) [84].
Neolaurene (45) showed the strongest cytotoxic activity among all
tested compounds against HeLa, MCF-7 and P-388 cells with MIC values
of 125.0, 175.0 and 125.0 μg/mL, respectively [79]. 4,10-Dibromo-3-
chloro-7(14)-chamigrene, α-isobromocuparene and cuparen-3-ol were
isolated from L. majuscula and tested against three cancer cell lines HCT-
116 (human colon cancer cells), PC-3 (human prostate cancer cells) and
HepG2 (human hepatocellular carcinoma cells). α-Isobromocuparene
showed the best activity against HCT-116 cell lines (IC50 value of 46.70
μg/mL), cuparen-3-ol against PC-3 cells (IC50 value of 60 μg/mL), while
4,10-dibromo-3-chloro-7(14)-chamigrene was best active against
HepG2 cells (IC50 52 μg/mL), but when compared with cisplatin which
served as positive control they did not exhibit significant activities (IC50
values for cisplatin were 3.78, 1.50 and 1.65 μg/mL, respectively) [57].
3.2. Anti-inflammatory activity
The studies have shown that marine-derived halogenated specialised
metabolites can be considered as effective anti-inflammatory agents
[103,104]. Chen et al. [43] evaluated anti-inflammatory activities of
compounds isolated from L. tristicha by measuring their ability to sup­
press N-formylmethionyl-leucyl-phenylalanine/cytochalasin B (fMLP/
CB)-induced superoxide anion (O−2 •) generation, as well as elastase
release in human neutrophils. When the concentration of 20 μM was
applied, tristichol A 24 and allo-isoobtusol exhibited significant inhibi­
tion towards generation of fMLP/CB, while elastase release was signif­
icantly inhibited when tristichol A 24, [1(15)Z,2Z,4S,8R,9S]-8,15-
dibromochamagra-1(15),2,11(12)-trien-9-ol and allo-isoobtusol were
used. (− )-Elatol (IC50 16.5 ± 1.1 μg/mL) was the most active for the
inhibition of production of nitric oxide among other isolated com­
pounds, obtusol (IC50 33.2 ± 1.0 μg/mL) and cartilagineol (IC50 > 100
μg/mL), from L. dendroidea. Also, (− )-elatol reduced tumor necrosis
factor-α at 100 μg/mL (53.01 ± 2.49%) and 20 μg/mL (35.05 ± 1.92%)
with an IC50 of 189.8 ± 3.6 μM.
3.3. Antimicrobial activity
Kamada et al. [32] tested a wide range of halogenated chamigrane-
type sesquiterpenes and their rearranged analogues, as well as some
metabolites belonging to omphalane and rhodolaurane skeletons (elatol,
A.-M. Cikoš et al.
laurencenone B and 2-chloro-3-hydroxy-α-chamigran-9-one, cartilagi­
neol, (− )-laurencenone D (6), and (+)-deschloroelatol (7), omphalaur­
ediol (60), rhodolaurenones B (61) and C (62), rhodolaurenone A,
rhodolaureol and isorhodolaureol). The compounds elatol, cartilagineo,
rhodolaurenones B 61 and C 62, showed bactericidal activity against all
three clinical pathogens, Escherichia coli, Salmonella typhi and Vibrio
cholera (MIC value 100 μg/mL; MBC value 250 μg/mL). Neolaurene (45)
isolated from L. nangii showed good antibacterial activity against E. coli,
S. typhi, Staphylococcus aureus and V. cholera with LC50 values of 12.5,
7.5, 7.5 and 12.5 μg/mL, respectively [79]. The compounds isolated
from L. tristicha in the study by Chen et al. [43] were evaluated against
Enterobacter aerogenes, Serratia marcescens and Yersinia enterocolitica.
When compared to the standard antibiotic ampicillin at the dosage of
100 μg/disk (inhibition zone 5 mm), only 9-(Z)-bromomethylidene-
1,5,5-trimethylspiro[5.5]undeca-1,7-dien-3-one showed a good anti­
bacterial activity against S. marcescens at the dosage of 100 μg/disk
(inhibition zone 8 mm), while other compounds (tristichol A 24, ma'i­
lione, [1(15)E,2Z,4S,8R,9S]-8,15-dibromochamagra-1(15),2,11(12)-
trien-9-ol, ma'iliohydrin and allo-isoobtusol) displayed lower activities.
When tristichone A (22) and ristichone B (23) were tested against
multridrug-resistant bacteria such as E. coli, Klebsiella pneumoniae, Pro­
teus mirabilis, Pseudomonas aeruginosa, Enterococcus faecalis and
S. aureus, only ristichone B (23) exhibited activities with MICs in the
range of 0.08–0.15 mM. Hence, tristichone A (22) displayed significant
anticandidal activity against Candida albicans and Candida tropicalis
(MICs = 8.27 and 10.13 μM, respectively) when compared to positive
control amphotericin B (MICs = 4.63 and 5.27 μM, respectively) [58].
Snakeol (64) and snakediol (65) isolated from L. snackeyi were tested for
their antibacterial activity and it was showed that they exhibited strong
activity against S. typhi with MIC/MBC ratio of 2.79, as well against
E. coli with MIC/MBC ratio of 3.02 and 2.76, respectively. It was sug­
gested that these antibacterial activities could be due to the presence of
hydroxyl group at C-1 position in the monocyclofarnesol-type structure
[99]. Laurecomposins A (29) and B (30), preintricatol and gossonorol
were evaluated for antibacterial activity against Gram-positive bacteria
S. aureus and Gram-negative bacteria P. aeruginosa. Tested compounds
were not active towards Gram-negative P. aeruginosa, but they were
active against Gram-positive S. aureus with MICs ranging from 10.9 to
26.8 μg/mL. The results were compared with MICs obtained for positive
controls including tobramycin, kanamycin sulfate, chloramphenicol and
erythromycin (2.0, 16.0, 8.0 and 0.5 μg/mL, respectively) [36]. The
tested halogenated sesquiterpenes, elatol and obtusol, isolated from L.
dendroidea were tested for antimycobacterial activity of Mycobacterium
bovis and M. tuberculosis H37 Rv culture. Obtusol displayed higher ac­
tivity with IC50 of 31.4 ± 0.8 μg/mL for M. bovis and IC50 of 97.1 ± 1.4
μM, whereas elatol was not able to inhibit mycobacterial growth [105].
Laurinterol and aplysin isolated from L. johnstonii were evaluated
against nine strains of M. tuberculosis that causes tuberculosis. Laur­
interol inhibited eight out of nine strains of M. tuberculosis with MICs
≤100 μg/mL, but when compared with rifampicin, the most common
drug for tuberculosis, MICs were much lower than for laureinterol and
aplysin (0.1–32 μg/mL). The strain M. tuberculosis CIPTIR-F296 was the
most susceptible for both compounds and when compared with rifam­
picin (MIC = 32 μg/mL), MIC value for laurinterol was the lowest (MIC
= 25 μg/mL). Authors suggested that for this activity the hydroxyl group
in laurinterol was more relevant than the bromide atom and the for­
mation of an ether bond between the aromatic ring and the cyclopentane
fragment in aplysin [106].
Eudesma-4(15),7-diene-5,11-diol (49) and chabrolidione B (51)
exhibited a good antifungal activity against C. albicans, C. tropical,
Aspergillus flavus and A. niger with MIC values ranging from 2.10 μM to
6.7 μM, while positive control amphotericin B showed MIC 4.6–5.4 μM
[84]. Compositacins A-K (8–18) were evaluated against eight microor­
ganisms including Microsporum gypseum, Trichophyton rubrum,
C. albicans, C. glabrata, C. parapsilosis, Cryptococcus neoformans and
A. fumigatus. Only compositacin G (14) exhibited significant antifungal
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Algal Research 56 (2021) 102330
activity against M. gypseum with MIC80 value of 4 μg/mL, while com­
positacins B–D (9–11), I–K (16–18) and deoxyprepacifenol displayed
moderate antifungal activity [33]. Four bisabolane sesquiterpenes iso­
lated from L. composita exhibited significant inhibitory activity against
Microsporum gypseum with MIC values of 4.0, 8.0, 8.0 and 4.0 μg/mL for
laurecomposins A (29) and B (30), preintricatol and gossonorol,
respectively. The results were compared with positive controls including
itraconazole, ketoconazole, fluconazole and voriconazole that inhibited
M. gypseum with MICs values of 2.0, 1.0, 8.0 and 0.125 μg/mL, respec­
tively [36].
3.4. Other reported bioactivities
As it was stated that the halogenation of sesquiterpenes leads to more
active compounds in terms of cytotoxicity and anti-inflammatory ac­
tivity, Garcia-Davis et al. [55] conducted bromination of inactive laur­
interol and isolaurinterol to observe the influence on antiparasitic
activity against Acanthamoeba castellanii. The bromination resulted in
four halogenated derivatives 3α-bromojohnstone (58), 8-bromoaplysin,
8,10-dibromoisoaplysin and 13-hydroxy derivative which exhibited
better activity than the natural sesquiterpenes with IC50 values of
18.804 ± 0.198, 24.559 ± 1.105, 22.818 ± 1.896 and 29.937 ± 2.918
μg/mL, but showed lower activity when compared to the reference
compounds chlorhexidine (IC50 = 1.526 ± 0.45 μg/mL) and vor­
iconazole (IC50 = 0.33 ± 0.1 μg/mL) which are used for the treatment of
Acanthamoeba infections. Among them, 3α-bromojohnstone (58) was
the most active compound with IC50 value of 18.804 ± 0.198 μg/mL.
Arberas-Jimenez et al. [107] aimed to investigate the potential of
laurinterol isolated from L. johnstonii against Negleria floweri that is
known as brain eating amoebae and it can cause infection called primary
amoebic meningoencephalitis (PAM). The results showed that laur­
interol induced cell death in the treated amoebae and it was able to
eliminate it with the concentration IC50 of 13.42 μM, but it was not as
active as the commonly used therapeutic agent against N. floweri known
as amphotericin B (IC50 = 0.12 μM).
Debromo-3α-hydroperoxy-3-epiaplysin (38) and debromo-3β-
hydroperoxyaplysin (39) were evaluated for the protein tyrosine phos­
phatase 1B (PTP1B) enzyme inhibitory activity. The compound 39
exhibited significant PTP1B inhibitory activity with IC50 value of 13.0
μg/mL with oleanolic acid as the positive control (IC50 = 1.3 μg/mL),
while its epimer 38 was inactive. Authors suggested that the R-config­
uration at C-3 position may be significant for the activity [75]. Later, Li
et al. [78] also evaluated dimeric bis-lauranes laurokamurols A − C
(42–44) for their PTP1B activity and they exhibited significant inhibi­
tory activity with IC50 values of 8.1, 12.5 and 6.1 μM, respectively,
compared with oleanolic acid (IC50 = 3.3 μM). The potent PTP1B
inhibitory activities of these compounds could provide a direction for
further function-oriented synthesis of such compounds towards new
antiobesic or antidiabetic drug discovery.
Three tested compounds, 8-deoxyalgoane (32), 1-deacetoxyalgoane
(33) and algoane (34) isolated from L. natalensis showed greater anti-
inflammatory activity against xanthine oxidase than the commercial
inhibitor allopurinol, especially algoane (34) with IC50 value of 3.091
μM when compared with IC50 value of 3.543 μM for allopurinol. 1-
Deacetoxyalgoane (33) and algoane (34) possess two hydroxyl groups
and they were more active for the inhibition of α-glucosidase (AG) and
dipeptidyl peptidase IV (DPP IV) with IC50 values of 36.167 ± 2.48 μM
and 79.023 ± 3.84 μM for the inhibition of AG and 43.365 ± 3.27 μM
and 23.941 ± 1.70 μM for the inhibition of DPP IV. 8-Deoxyalgoane (32)
contains only one hydroxyl group and it was the least active compound
(IC50 values of 82.843 ± 1.98 μM for the inhibition of AG and 58.523 ±
3.32 μM for the inhibition of DPP IV). Hence, all three compounds
exhibited higher activity than acarbose (IC50 value of 306.84 ± 2.15 μM
for the inhibition of AG), known as commercial α-glucosidase inhibitor.
Also, algoane (34) was noted as the most promising antidiabetic agent
due to its activity close to the commercial inhibitor of
A.-M. Cikoš et al.
dipeptidylpeptidase IV (IC50 value of 2.923 ± 0.18 μM for the inhibition
of DPP IV). These findings were confirmed when all three compounds
were subjected to molecular property analysis for the prediction of po­
tency and bioavailability. All three molecules displayed good results for
LogP and Topological Surface Area (TPSA), known as two main in­
dications for the prediction of oral bioavailability of drugs, also the
positive results against the enzyme inhibitory targets and nuclear re­
ceptor ligands were obtained [9]. Although stereochemistry of the
compounds did not show any significant effect on cytotoxic activity
[108], it was observed that the enantiomers of elatol exhibited differ­
ences in acetylcholinesterase (AChE) inhibitory activity. While
(+)-elatol did not exert significant effect on the enzyme activity,
(− )-elatol were the most active tested sesquiterpene with 78.5% of AChE
inhibition. Other compounds that exhibited significant activity were
dendroidiol with inhibition of 72.9% and cartilagineol with 61.3% of
inhibition [109]. Authors also presented a molecular docking of
(− )-elatol that showed the importance of interactions with specific
residues, thus corroborating the inhibitory effect of AChE. In the study
where 11 laurane-type sesquiterpenes obtained from L. tristicha were
evaluated for their antioxidant activity by scavenging effect on hydroxyl
free radical using electron paramagnetic resonance (EPR), it was shown
that the 1,10-epoxy moiety was crucial for the activity since the com­
pounds having this moiety exhibited better activity. The compounds
that possess Br at phenyl ring, as well as the compounds with acetyl
group connecting to 1-OH showed less activity, but the phenolic hy­
droxy group significantly enhanced the activity [81].
3.5. Ecological role of sesquiterpenes
Even though the literature has been reporting mostly bioactivities of
sesquiterpenes, several authors reviewed and investigated the ecological
role of sesquiterpenes [110,111,112]. Namely, macroalgae have been
producing sesquiterpenes as the protection against enemies or for
feeding and reproduction. They have developed a range of defensive
mechanisms, both physical and chemical, as an answer to the extreme
conditions and competition for space, light and nutrients [113]. How­
ever, the predictions of toxic or deterrent effects are difficult to make
based only upon the chemical structures of particular metabolites. The
effects can vary greatly among the compounds that differ only slightly in
the chemical structure as it was noticed that halogenation in red algal
metabolites did not enhance their feeding deterrent effects. Debro­
moaplysinal, known as one of common laurane-type sesquiterpene,
exhibited moderate antifouling activity (EC50 = 1.00 μg/mL), but
pacifenol (EC50 = 2.36 μg/mL) and 2,10-dibromo-3-chloro-9-hydroxy-
α-chamigrene (EC50 = 2.51 μg/mL) exhibited weak activity. These re­
sults were compared to the positive control CuSO4 with EC50 = 0.18 μg/
mL [114]. Also, Al-Lihaibi et al. [115] compared their results for anti­
fouling activity with CuSO4 (EC50 = 0.34 μg/mL) and the results indi­
cated that 2,10-dibromo-3-chloro-7-chamigrane isolated from L. obtusa
showed potent activity against larvae of Balanus amphitrite with EC50 =
0.14 μg/mL. Protopapa et al. [116] evaluated several sesquiterpenes
isolated from different species of Laurencia genus and among them only
perforenol exhibited promising antifouling potential (IC50 value 0.5 μM)
with bromosphaerol serving as a benchmark (IC50 value 0.6 μM) against
the barnacle Amphibalanus amphitrite and at the same time it did not
exhibit ecotoxicity against non-target organisms. Liposoluble terpenes
can mediate different alga-herbivore interactions as it was shown in the
study by Nocchi et al. [117] where elatol (9) isolated from L. dendroidea
attracted Aplysia brasiliana and revealed its potential as a chemical
mediator in the interaction between Laurencia and Aplysia. They showed
for the first time with the combination of experiments that elato can
serve as chemical cue attracting A. brasiliana which is very important for
the maintenance of associations and biodiversity. Another study exam­
ined the chemical defense in L. dendroidea by direct grazing by
A. brasiliana, as well as water-borne chemical cues from conspecific
neighbors grazed by A. brasiliana. The results revealed that grazing by
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Algal Research 56 (2021) 102330
A. brasiliana induced the anti-herbivory chemical defences in L. den­
droidea and showed significant changes in the sesquiterpene metabo­
limic profile by increasing its content. Hence, they showed that L.
dendroidea can perceive waterborne chemical signals released by
neighboring grazed conspecifics [118].
L. intricata can be promising source of bioactive metabolites that can
be used as potential biocontrol agents for stored-product insects. It was
established that (+)-cyclocolorenone (59) can act as natural insecticide
due to its strong repellent activity against the maize weevil Sitophilus
zeamais (EC50 2.0 μg/mL), and it showed the same activity as pyrethrin
(EC501.7 μg/mL) known as natural insecticide [91]. Laurinterol isolated
from L. nidifica also showed a strong repellency against the maize weevil
with ED50 value of 12.65 μg/cm2 and it was showed as good insecticide
against termite Reticulitermes speratus (LD50 2.2 μg/insect) even though
it exhibited lower activity than the commercial insecticides (rotenone,
fenitrothion and pyrethrins with LD50 values of 0.110, 0.025 and 0.013
μg/insect, respectively) [74]. These are promising results that can help
for the development of environmentally-friendly natural pesticides
without toxic residues and disturbances in the environment, also lethal
effects on non-targeted organisms will be avoided but further research
and evaluation of structure-activity relationship are needed. Anti­
lesihmanial activity of (− )-elatol and obtusol was tested against the
insect-stage promastigotes of Leishmania mazonensis and they exhibited
in vitro and in vivo leishmanicidal activity with IC50 values of 6.2 μg/mL
and 9.7 μg/mL, respectively. The values were lower than the reference
drug potassium antimony (III) tartrate hydrate (IC50 0.9 ± 0.2 μg/mL)
[23].
4. Biosynthesis of sesquiterpenes
Sesquiterpenes represent a large group of natural organic compounds
whose identification is still expanding due to broad structural diversity
(ca. 300 specific C15-hydrocarbon skeletons) that represent a challenge
for the structure elucidation and synthesis [19]. For instance, only
among tricyclic sesquiterpenes, 54 different skeletal types (284 com­
pounds) were reported by Le Bideau et al. [14] pointing out large che­
modiversity. Several of these compounds were specific only for the
marine organisms and they could not be found in the terrestrial plants.
In distinction from monoterpenes which were mostly halogenated
[119], tricyclic sesquiterpenes showed limited halogenation, but the
most of halogenated molecules were found in the genus Laurencia.
Ružička and Stoll [120] first pointed out that the sesquiterpenes can
be formed from a common intermediate farnesyl pyrophosphate (FPP),
and previously it was considered that the intermediate was an activated
derivative of acyclic alcohol farnesol. While geranyl pyrophosphate
(GPP) is synthesized in the plastids, FPP is synthesized in the plant
cytosol from acetyl-CoA [121], but this observation has not been
experimentally determined in red algae where some of methylerythritol
phosphate (MEP) pathway enzymes were plastidial, but others appeared
to be localized in the cytosol or other organelles [122]. de Oliviera et al.
[123] reported the presence of MEP pathway in Laurencia dendroidea,
but there are no studies reporting the presence of mevalonate (MVA)
pathway in this specie. In further research, de Oliviera et al. [124]
indicated high diversity of chemical modifications of sesquiterpene
precursors resulting with a wide variety of carbon skeletons. However,
the biogenetic routes can be different when vascular plants and algae are
compared due to their phylogenetic distance.
4.1. Sesquiterpenes biosynthesis stages
The enzymes known as prenyltransferases are responsible for the
elongation of hydrocarbon chains by adding isopentenyl pyrophosphate
(IPP) units to dimethylallyl pyrophosphate (DMAPP). IPP units can be
formed by MVA and/or MEP pathways. After the initial condensation of
IPP and DMAPP, GPP is formed, while another 1′ -4 condensation of IPP
yields FPP, crucial for sesquiterpene biosynthesis [125].
A.-M. Cikoš et al.
The conversion into the cyclic terpene carbon skeletons is stimulated
by terpene synthases, also known as terpene cyclases and the pyro­
phosphate group is eliminated and the carbocations are generated.
Hence, formed carbocations can undergo the cyclization, but first the
isomerization of the initial carbocation to an intermediate capable of
cyclization is needed due to the impossibility of direct cyclization of (E)
configuration of double bond of terpene synthases substrates. The
cyclization can occur by the addition of the stabilized cationic centre to
Fig. 7. Proposed mechanisms for the initial cyclizations of FPP and formation of typical Laurencia sesquiterpene skeletons.
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Algal Research 56 (2021) 102330
one of the carbon-carbon double bonds in the substrate [125]. Specif­
ically, for sesquiterpenes, FPP is converted to nerolidyl pyrophosphate
(NPP). This initial isomerization is crucial for generating the interme­
diate with the proper reactivity and conformational flexibility to over­
come the stereochemical barrier for direct cyclization and allow the
formation of cyclic products. During the isomerization, ionization of FPP
to the transoid cation-pyrophosphate anion occurs that is subjected to
several transformations [126]. As can be seen in Fig. 7, the initial
A.-M. Cikoš et al.
cyclization of (E,E)-FPP (66) to sesquiterpenes can occur by six alter­
native pathways. Without the initial isomerization of FPP, two ways of
ionization of farnesyl cation (67) are possible, either 1,10-cyclization to
(E,E)-germacradienyl cation (68) or 1,11-ring closure to (E,E)-humulyl
cation (69). As mentioned before, the isomerization of 66 to both en­
antiomers (3S)- or (3R)-NPP (70), depending on the specific sesquiter­
pene synthase, via 71 is obligatory for common 1,6-cyclization to
bisabolyl cation 72 or a less common cycloheptenyl cation 73 by 1,7-
cyclization that requires (Z)-configured olefinic double bond. The in­
termediate cation (71) created by diphosphate extrusion from (70) can
serve as the precursor for 72 and 73, (E,Z)-germacradienyl cation (74)
obtained by 1,10-cyclization and (E,Z)-humulyl cation (75) formed by
1,11-ring closure that further generates the stereoisomers of 68 and 69
[127]. Sesquiterpenes are present with wide range of skeleton types, but
chamigrane, bisabolane, laurane and cuparane are the most represented
among macroalgae belonging to Laurencia genus. Thus, their probable
formation is presented in Fig. 7 from bisabolyl cation which is the main
precursor of these skeleton types. Bisabolyl cation 7 leads to the for­
mation of chamigrane and bisabolane skeleton types of sesquiterpenes
including the conversion of α-bisabolane precursor via the oxidation and
nucleophilic attack by bromide resulting in halidrine derivative which
yields bisabolane sesquiterpenes. On the other hand, the formation of
γ-bisabolane precursor yields α- and β-chamigrane derivatives by the
enzymatic cyclization of γ-bisabolane derivative [128]. Hence, laurane
type sesquiterpenes are also derived from bisabolyl cation intermediate
followed by the ring closure, alkyl shift and then aromatization of the
cyclohexane ring [65]. Cuparane type sesquiterpenes are derived via
protonation of γ-bisabolane followed by the cyclization to cuparane
cation which subsequently yields sesquiterpenes with cyclopropane ring
[56,129]. Interestingly, cuparane cation can be the precursor for for­
mation of laurane type sesquiterpenes by the methyl migration of
cuparane cation [130].
The final stage of sesquiterpene biosythesis includes complex re­
actions and transformations including oxidation, alkyl and hydride
shifts, deprotonation, isomerization, conjugation and additional cycli­
zations where the parent carbon skeletons are enzymatically mediated
to form carbocationic intermediates and at the end they are converted to
numerous distinct terpene metabolites. However, most of these metab­
olites are cyclic so the synthases utilize a very similar carbocationic
reaction mechanism which is employed by prenyltransferases. Depro­
tonation of the cation to an olefin or capturing by a nucleophile (H2O)
marks termination of the reaction cascade [121,125].
4.2. The enzymes involved in sesquiterpene biosynthesis
Sesquiterpene synthases are highly active enzymes which are
responsible for generating different structures of sesquiterpenes as it was
shown with only two sesquiterpene synthases from Abies grandis,
δ-selinene and γ-humulene synthases, capable of synthesizing up to 52
different sesquiterpenes [131]. The formation of multiple products by
terpene synthases is the consequence of their reaction mechanism,
including the emerging of carbocationic intermediate from which many
products can be formed. It is necessary to consider their level of activity,
as well as their subcellular location [125]. Sesquiterpene synthases need
to eliminate the pyrophosphate group (PP) of FPP so that the carboca­
tion can be created and then neutralized to relatively simple structure or
it can undergo to various rearrangements resulting in complex di- and
tricyclic structures [121].
The catalytic mechanism of synthases can be divided into two pha­
ses, the metal ion binding and pyrophosphate cleavage and carboca­
tionic reaction cascades followed by the final reaction products. In the
first phase, divalent metal (Mg2+) initiates the formation of an ion pair
between pyrophosphate and farnesyl cation due to the cleavage of C–O
bond in FPP with the attachment of three metal ions at the top of the
active site. The binding of these metal cations, that coordinates
diphosphate group of the substrate, are controlled by two metal ion
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Algal Research 56 (2021) 102330
binding sites in all sesquiterpene synthases. The farnesyl chain in the
active site accepts reactive conformation by binding three Mg ions. The
second phase includes the reactions of sesquiterpene synthases leading
the carbocation through complex cyclization cascades that include
additional carbocationic and neutral intermediates. After the initial
ionization, the enzymes act as passive catalysts that simply guide the
intermediates through the reaction cascades [19].
There are specific sesquiterpene synthases responsible for each
sesquiterpene class. This great variety is well represented in the work by
Cane [126] where he reviewed the enzymatic formation of sesquiter­
penes including the description of wide variety of sesquiterpenes cy­
clases, such as bisabolane, trichodiene, bergamotene, humulene,
caryophyllene, pentalenene, aristolochene, and patchoulol synthases.
Also, the mechanisms of formation of cyclic sesquiterpenes and their
precursors along with their stereochemistry were represented. Sesqui­
terpene cyclases are among the most naturally occurring versatile cat­
alysts responsible for the formation of more than 15 distinct
sesquiterpene carbon skeletons in Laurencia species [132]. de Oliviera
et al. [124] unveiled the genes related to the biosynthesis of α-bisabo­
lane synthase which is responsible for the biosynthesis of bisabolane-
type sesquiterpenes. Moreover, the genes coding pentalenene synthase
and δ-cadinene synthase which are involved in humulene- and cadinyl-
type sesquiterpenes biosynthesis were detected. The biosynthesis of
germacrene-type sesquiterpenes involves the enzymes germacrene-A
synthase and oxidase, aristolochene synthase [126] as well as 5-epi-aris­
tolochene-1,3-dihydroxylase which use germacrene A as intermediate as
demonstrated by Rising et al. [133]. Also, Scheuer [134] suggested that
the biosynthesis of elatol, the major specialised metabolite found in
Laurencia dendroidea, involved the enzymatic addition of bromochloride
at bisabolonium ion prior to the cyclization to chamigrane derivative. It
has been suggested that red algal terpene synthase genes are evolu­
tionarily more closely related to microbial terpene synthase genes than
to typical plant terpene synthase genes [135].
5. Conclusion
The present review encompasses sesquiterpenes isolated exclusively
from Laurencia genus in the period 2015–2020 and they were classified
into the groups by their skeleton structure to chamigrane, cuparane,
laurane, bisabolane, aristolane, brasilane, eudesmane, snyderane and
other skeletons including those with high degree of halogenation,
especially bromination. Among them, chemical markers were found. It
was shown that Laurencia sesquiterpenes exhibit cytotoxic, anti-
inflammatory, antibacterial, antifungal, antidiabetic and anthelmintic
activities and others including different ecological roles. The most actual
is cytotoxic activity that can be even compared to e.g. paclitaxel used in
clinical trials in chemotherapy. Targeted sesquiterpenes could also be
effective anti-inflammatory agents. The explored structure-activity re­
lationships were presented, but further research in necessary. There is
lack of bioassays in an ecologically relevant manner for instance field
and laboratory assays with natural herbivores that are necessary to
examine the ecological interactions. Possible general biosynthetic
pathways of targeted sesquiterpenes were presented, but more detail
research of their formation is necessary since the biogenetic routes can
be different when vascular plants and algae are compared due to their
phylogenetic distance.
Laurencia sesquiterpenes chemical diversity, along with their bio­
activities, leads to more attention of scientists for further exploration of
these interesting, easy accessible red algae that are distributed around
the world. Due to the fact that the novel sesquiterpene structures are still
being detected, this might lead to the new discoveries that can be
directed towards investigation of biological potential (particularly for
anticancer activity) as well as bioavailability of the most promising
sesquiterpenes.
A.-M. Cikoš et al.
CRediT authorship contribution statement
Ana-Marija Cikoš: Methodology, Visualization, Writing-Original
draft preparation. Mladenka Jurin: Writing-Original draft prepara­
tion, Visualization. Rozelindra Čož-Rakovac: Project administration;
Resources. Dajana Gašo-Sokač: Supervision. Stela Jokić: Conceptual­
ization, Supervision. Igor Jerković: Conceptualization, Supervision,
Writing-Original draft preparation.
Funding
This work was supported by the Croatian Government and the Eu­
ropean Union (European Regional Development Fund—the Competi­
tiveness and Cohesion Operational Programme - KK.01.1.1.01) through
project Bioprospecting of the Adriatic Sea (KK.01.1.1.01.0002) granted
to The Scientific Centre of Excellence for Marine Bioprospecting-
BioProCro. Therefore please add as the acknowledgement: "We would
like to thank the Croatian Government and the European Union (Euro­
pean Regional Development Fund—the Competitiveness and Cohesion
Operational Programme - KK.01.1.1.01) through project Bioprospecting
of the Adriatic Sea (KK.01.1.1.01.0002) granted to The Scientific Centre
of Excellence for Marine Bioprospecting-BioProCro for funding of this
research.
Author contributions
All authors contributed to the conceptualization and design of the
review, as well as drafting and revising it.
Declaration of competing interest
The authors declare no conflict of interest.
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