Carroll Et Al 2022 - Marine Natural Products

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REVIEW View Journal
Marine natural products‡

Cite this: DOI: 10.1039/d2np00083k Anthony R. Carroll, *ab Brent R. Copp, c Rohan A. Davis, bd
e
Robert A. Keyzers and Michèle R. Prinsepf
Covering: January to December 2021

Published on 14 February 2023. Downloaded on 2/21/2023 6:39:37 PM.
This review covers the literature published in 2021 for marine natural products (MNPs), with 736 citations (724 for
the period January to December 2021) referring to compounds isolated from marine microorganisms and
phytoplankton, green, brown and red algae, sponges, cnidarians, bryozoans, molluscs, tunicates, echinoderms,
mangroves and other intertidal plants and microorganisms. The emphasis is on new compounds (1425 in 416
Received 23rd November 2022
papers for 2021), together with the relevant biological activities, source organisms and country of origin.
Pertinent reviews, biosynthetic studies, first syntheses, and syntheses that led to the revision of structures or
DOI: 10.1039/d2np00083k
stereochemistries, have been included. An analysis of the number of authors, their affiliations, domestic and
rsc.li/npr international collection locations, focus of MNP studies, citation metrics and journal choices is discussed.
1 Introduction
1 Introduction
2 Marine microorganisms and phytoplankton
2.1 Marine-sourced bacteria This review is of the literature for 2021 and describes 1425 new
2.2 Cyanobacteria compounds from 416 papers, compared to 1407 new
2.3 Marine-sourced fungi (excluding from mangroves) compounds in 420 papers reported for 2020.1 In addition, 41
2.4 Fungi from mangroves known NPs were reported from a marine source for the rst
2.5 Dinoagellates time and 54 known MNPs had their structures revised. Only new
3 Green algae MNP structures or previously reported compounds where there
4 Brown algae has been a structural revision, or a newly established stereo-
5 Red algae chemistry are shown in this review. The review also covers
6 Sponges previously reported MNPs with signicant new bioactivities or
7 Cnidarians ones that have been synthesised for the rst time, but their
8 Bryozoans structures are generally not shown. A † symbol on the identi-
9 Molluscs fying diagram number is used to distinguish structures where
10 Tunicates (ascidians) the absolute conguration has been determined for all stereo-
11 Echinoderms genic centres, axes and/or planes in a compound. Reports of
12 Miscellaneous new MNPs that were identied based solely on a combination of
13 Conclusion
14. Conicts of interest
15. Acknowledgement
16. References
a
School of Environment and Science, Griffith University, Gold Coast, Australia. E-mail:
A.Carroll@griffith.edu.au
b
Griffith Institute for Drug Discovery, Griffith University, Brisbane, Australia
c
School of Chemical Sciences, University of Auckland, Auckland, New Zealand
d
School of Enivironment and Science, Griffith University, Brisbane, Australia
e
Centre for Biodiscovery, and School of Chemical and Physical Sciences, Victoria
University of Wellington, Wellington, New Zealand
f
School of Science, University of Waikato, Hamilton, New Zealand
‡ Electronic supplementary information (ESI) available. See DOI: Trends in new MNPs. The bars represent the total number of
Fig. 1
https://doi.org/10.1039/d2np00083k new MNPs reported each year over the last five years.
This journal is © The Royal Society of Chemistry 2023 Nat. Prod. Rep.
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Natural Product Reports Review
gene cluster information, MS/MS data and/or Global Natural compounds not isolated and no NMR data recorded, have been
Products Social (GNPS)-based molecular networking, with excluded from the review this year. Only a selection of high-
lighted structures (82) is shown in the review. Compound
numbers for structures not highlighted in the review are
Anthony (Tony) Carroll initially
italicised, and all structures are available for viewing, along with
studied the alkaloid and lignan
their names, taxonomic origins, collection locations, and
chemistry of rainforest plants (BSc
biological activities, in an associated ESI document.‡ Access
(Hons) and PhD, Prof. Wal Taylor,
to the curated MNP data held in the MarinLit database2
Sydney University) but marine
provides all the structural and literature data used to prepare
natural products became a major
this review.
focus aer postdoctoral fellowships
Although numbers of new MNPs have increased slightly
at the University of Hawaii with
since 2020, there are decreasing trends in reporting of cyano-
Paul Scheuer and at James Cook
bacteria, mangrove fungi, red algae, sponges and tunicate
University, Australia with John
metabolites over the last few years (Fig. 1). This trend might be
Coll and Bruce Bowden. Fieen
associated with restrictions in domestic and international travel

years as head of natural products
related to the COVID-19 pandemic limiting opportunities for
chemistry for the AstraZeneca/
eld collections.
Griffith University drug discovery project expanded his interests to
include high throughput purication and structure determination
techniques and cheminformatics. Since 2008 he has held a faculty
position at Griffith University, Gold Coast where he is currently
a Professor.
Brent Copp received his BSc (Hons)
and PhD degrees from the Univer- Rob Keyzers carried out his BSc
sity of Canterbury, where he (Hons) and PhD studies at
studied the isolation, structure Victoria University of Wellington.
elucidation and structure–activity His thesis research, carried out
relationships of biologically active under the guidance of Assoc. Prof.
marine natural products under the Peter Northcote, a former
guidance of Professors John Blunt contributor to this review,
and Murray Munro. Two post- focused on spectroscopy-guided
doctoral positions with Jon Clardy isolation of sponge metabolites.
at Cornell and Chris Ireland at the He then carried out post-doctoral
University of Utah were then fol- research with Mike Davies-
lowed with a period spent working Coleman (Rhodes University,
in industry as an isolation chemist with Xenova Plc. In 1993 Brent South Africa) and Raymond
returned to New Zealand to take a lectureship at the University of Andersen (University of British Columbia, Canada) before a short
Auckland, where he is currently a Professor. role as a avour and aroma chemist at CSIRO in Adelaide, Aus-
Rohan Davis received a BSc (Hons) tralia. He was appointed to the faculty at his alma mater in 2009
degree in chemistry and biochem- where he is currently an Associate Professor.
istry from the University of Mel- Michèle Prinsep received her BSc
bourne (1992). He worked as (Hons) and PhD degrees from the
a research assistant on the University of Canterbury, where
AstraZeneca/Griffith University she studied the isolation and
natural product drug discovery structural elucidation of biologi-
program (1994–1996) before cally active secondary metabolites
undertaking PhD studies on from sponges and bryozoans under
ascidian chemistry (1997–2000) the supervision of Professors Blunt
under the supervision of Professors and Munro. She undertook post-
Ronald Quinn and Anthony Car- doctoral research on cyanobacteria
roll. Aer 2 years of postdoctoral with Richard Moore at the Univer-
research at University of Utah with Professor Chris Ireland, he returned sity of Hawaii before returning to
to Griffith University in 2003 where he is currently an Associate New Zealand to take up a lecture-
Professor. His research involves the discovery and development of new ship at the University of Waikato, where she is currently an Associate
bioactive natural products from plants and marine invertebrates. Professor.
Rohan is the manager of NatureBank, an Australian-based bio-
discovery platform.
Nat. Prod. Rep. This journal is © The Royal Society of Chemistry 2023
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Review Natural Product Reports
2 Marine microorganisms and bamemacrolactins A–E 17–21, from the ferment culture of
Bacillus siamensis. Bamemacrolactin C was the most potent
phytoplankton pathogen growth inhibitor and subsequent mechanism of
2.1 Marine-sourced bacteria action (MOA) studies indicated that this MNP targets the
Microbial-derived polyene macrolides are some of the most oxidative phosphorylation pathway in S. scitamineum.10 Der-
effective antifungal agents applied to both crop protection and macozines N–P 22, 23, 24, were isolated from a piezotolerant
human treatments. An anti-infective drug discovery program actinomycete strain Dermacoccus abyssi with dermacozine N 22
utilising marine-derived bacteria identied a cryptic polyene bearing a novel linear pentacyclic phenoxazine motif.11 Genome
biosynthetic gene cluster (BGC) in Actinokineospora sphecio- mining of Fulvivirga sp. revealed a desferrioxamine-like BGC
that contained an unknown gene fulF that is conserved in many
spongiae following genome mining. Activation of this BGC by
applying a variety of fermentation conditions led to the Bacteroidetes species.12 Heterologous expression and feeding
discovery of a new polyene, actinospene 1. This molecule studies identied that fulF functions as a novel acyltransferase
showed a broad spectrum of antifungal activity against several of primary amines, and also resulted in the purication and
plant fungal pathogens as well as pathogenic yeasts with MIC characterisation of desferrioxamine analogues that were named
fulvivirgamides A2, B2, B3, and B4 25–28.12 Chemical investiga-
values ranging from 2–10 mg mL−1.3 New antibacterial tetronate-

based polyketide derivatives, nomimicins A–D 2–5, were iden- tions of a mangrove soil-sourced Isoptericola chiayiensis identi-
tied from a fermentation culture of an Actinomadura strain,4 ed new 2-furanone 29, sesquiterpenoid 30 and benzenoid 31
derivatives, ve new avonoids 32–36, and four other related
whilst chemical examination of an Aquimarina sp. bioactive
broth yielded caprolactin C 6, which, along with its enantiomer metabolites 37–40 that were isolated for the rst time from
(ent-caprolactin C), were synthesised. Both caprolactin C and its nature.13
synthetic enantiomer inhibited the invasion and migration of Two novel lyso-ornithine lipids 41, 42 were isolated from an
A549 lung cancer cells, but only the unnatural compound was arctic Lacinutrix sp.,14 whilst an acyl dipeptide named micro-
found to suppress transforming growth factor-b (TGF-b) monosporamide A 43 was isolated from the fermentation broth
induced epithelial–mesenchymal transition (EMT), thus this of Micromonospora sp. and was shown to display glutamine-
molecule may hold promise as a potential lead candidate for dependent cytotoxicity.15 Another Micromonospora study affor-
ded a new enteromycin-class antibiotic, akazaoxime 44, that
development of new antimetastatic agents.5 The Bacillus genus
yielded a number of new metabolites in 2021 including a dike- possessed an aldoxime functionality. The related congener, A-
topiperazine 7,6 an antimicrobial oxatetracyclo ketone 8,7 76356 45, isolated from a marine source for the rst time, was
bacillibactins E 9 and F 10, which are the rst bacterial side- also reported. The absolute congurations of both molecules
rophores that contain nicotinic and benzoic acid moieties,8 and were assigned by total synthesis, NMR and chiroptical data
the anti-mycoplasma active cyclic lipodepsipeptides, bacilote- analysis. Feeding experiments using 13C-labeled compounds
trins C–E 11–13. This latter study also involved the structure determined that the carbon skeletons present in both 44 and 45
revision of the previously reported bacilotetrin A 14 and baci- are derived from propionate, leucine, and glycine.16
Applying the GNPS molecular networking platform to
lotetrin B 15, 16 that was deemed to be a mixture of two
isomers.9 a Nocardiopsis aegyptia sample resulted in the identication of
four new anthraquinone derivatives, saliniquinones G–I 46–48
and heraclemycin E 49.17 MS/MS-based molecular networking
and follow-up isolation studies yielded the new p-terphenyl
derivatives nocarterphenyls D–H 50, 51–54 from the ferment of
a Nocardiopsis species. The skeleton of nocarterphenyl D was
shown to possess a rare 2,2′-bithiazole scaffold (rst time
identied from nature) whilst the other new congeners con-
tained unusual thioether linked fatty acid methyl ester substi-
tutions. Nocarterphenyl D 50 showed promising activity against
a number of bacteria with MIC values ranging from 1.5 to 6.2
mM.18 A third Nocardiopsis focussed study yielded two polycyclic
thioalkaloids, dassonmycins A 55 and B 56, that both feature
a naphthoquinone[2,3-e]piperazine-[1,2-c]thiomorpholine scaf-
fold.19 New enediyne antibiotics sealutomicins A–D 57, 58–60
were isolated from the deep-sea actinomycete Nonomuraea sp.
with sealutomicin A shown to display potent antibacterial
A biodiscovery project aimed at nding new antifungal activity (MIC 0.05–0.2 mg mL−1) against carbapenem-resistant
agents to treat sugarcane smut (Sporisorium scitamineum) Enterobacteriaceae.20
identied ve new 24-membered macrolactins,
View Article Online
strategy using this marine bacterium and comparative metab-

olite analysis facilitated the discovery of 20 angucycline deriv-
atives including six new highly oxygenated aromatic polyketides
and four new glycosylated derivatives named saccharothrixins
D–I 83–88 and saccharothrixins J–M 89–92, respectively.29
Svalbamides A 61 and B 62, lipodipeptides possessing a pyr-

rolidinone moiety, were identied from a Paenibacillus sp.21
Heterologous production using carotenoid biosynthetic genes
obtained from Planococcus maritimus yielded C30-carotenoids
63, 64,22 and a lipooligosaccharide 65 was identied from
Pseudoalteromonas nigrifaciens.23 Pseudoalteropeptide A 66,
a new siderophoric lipopeptide, was puried from the fermen-
tation broth of Pseudoalteromonas piscicida.24 A revised structure
of the cyclic depsipeptide MA026 67 was established following
extensive physicochemical analysis (HPLC, MS/MS, NMR) and
by total synthesis. The revised structure differed from that
previously reported in 2002 only in the sequence order for two
amino acid residues. Synthetic MA026 showed tight junction
opening activity in a cell-based assay with a similar potency to
that reported for the misassigned NP. Bioinformatic analysis of
the putative MA026 BGC from the Pseudomonas sp. source
supported the absolute conguration assignments for all amino
acid residues.25 New uridine 68 and indole derivatives 69 were
puried and characterised from the fermentation broth of
a Pseudonocardia strain that was obtained from a scleractinian
coral,26 whilst another new indole NP, vibrindole B 70, was Chemical mining of Shewanella algae extracts identied four
identied from a sponge-associated Pseudovibrio denitricans.27 new macrocyclic polyketides 93–96.30,31 Whilst a total of 20
Other Pseudovibrio investigations involved the complete genera of marine-derived bacteria contributed to new chemistry
genome mapping of a sponge-derived isolate, Pseudovibrio reported in 2021, the genus Streptomyces continues to be the
brasiliensis, and the application of a reverse genetics method- predominant source with 120 metabolites. The new MNPs from
ology led to the discovery of a novel family of nonribosomal this prolic genus included two antibacterial spirotetronate
hexapeptides named pseudovibriamides A1–6 71, 72–76 and B1–6 derivatives, lobophorins L 97 and M 98,32 two trioxacarcins
77–82. A combination of MS imaging and biology experiments congeners 99, 100,33 cytotoxic isoquinolinequinones named
showed that this new class of non-surfactant heptapeptides was mansouramycins E–G 101–103,34 a rare benzo[f]isoindole-dione
excreted, promoting motility, and reducing biolm formation.28 alkaloid 104,35 linear azole-containing peptides spongiicolazo-
Genome mining of a Saccharothrix strain led to the identi- licins A 105 and B 106,36 antimycin-type depsipeptides,
cation of a type II PKS BGC (sxn), that encoded several distinct zhaoshumycins A 107 and B 108,37 along with four antimicrobial
subclasses of oxidoreductases, leading the researchers to chlorinated carbazole alkaloids named chlocarbazomycins A–D
hypothesise that this strain had the potential to produce novel 109–112.38
polycyclic aromatic polyketides with unusual redox modica-
tions. Application of the One Strain Many Compounds (OSMAC)
View Article Online
multiple resistant Staphylococcus aureus (MRSA) and Entero-

coccus faecium with MIC values of 4 mg mL−1.43
Four new chlorinated meroterpenoids, merochlorins G–J

129–132, and a dihydronaphthalenedione precursor 133, were
puried and characterised from the cultivation of a Strepto-
myces sp. The most active metabolite, merchlorin I displayed
strong antibacterial activities against Bacillus subtilis, S. aureus
and Kocuria rhizophila with MIC values of 1, 2, and 2 mg mL−1,
respectively.44 Four new a-pyrone derivatives, named germi-
cidins P–S 134–137 were discovered from a sponge-associated
New polyoxygenated polyketides, miharadienes A–D 113,
Streptomyces sp. based on GNPS molecular networking, LC-
114, 115, 116, were isolated from Streptomyces miharaensis, and
DAD-MS proles, and hexokinase II inhibitory activity. Hexo-
113 featured a rare 2,10-dioxabicyclo[5.3.1]undecane scaffold
kinase II is a rate-limiting enzyme in the rst step of the
while 116 contained a unique 5/5 furo[3,4-c]furan motif.39 Three
glycolysis pathway, and has been shown to be expressed at
new g-pyrones 117–119 were identied from the fermentation
a high level in cancer cells (compared with normal human cells)
of the mangrove sediment-derived Streptomyces psammoticus.
thus providing a potential new target for cancer therapy due to
One of the g-pyrones 117 has been previously synthesised but
its critical role in metastatic and tumourigenic processes; ger-
this is the rst report of the molecule from a natural source.40
micidins P–S only weakly inhibited this enzyme.45 Two antibi-
Genome sequencing of a Streptomyces strain uncovered a BGC
otic dixiamycins 138 and 139 from Streptomyces olivaceus
that was linked to the biosynthesis of pentalenolactone-type
displayed activities against seven bacterial strains ranging from
terpenes. Chemical analysis of this actinomycete broth culture
potent to no antibacterial activity.46 Other Streptomyces strains
resulted in the isolation of two new sesquiterpenoids, 1-deoxy-
yielded antaroide 140, a new nine-membered macrolide that
8a-hydroxypentalenic acid 120 and 1-deoxy-9b-hydroxy-11-
was shown to inhibit melanin biosynthesis in murine mela-
oxopentalenic acid 121, both of which were proposed to be
noma cells,47 two antibacterial pyrrolobenzodiazepine deriva-
shunt metabolites of pentalenolactone biosynthesis.41 Genome
tives 141 and 142,48 a new polycyclic tetramate macrolactam,
characterisation studies of another Streptomyces strain, tenta-
koyanamide A 143,49 a new butenolide derivative 144, featuring
tively assigned as S. griseoaurantiacus, led to chemical analyses
an octyl substitution at the g-position,50 two angucyclinone
of the culture broth that yielded three new manumycin-type
derivatives, gephyyamycin 145 and cysrabelomycin 146,51 and
derivatives 122–124,42 whilst chemical analysis of a separate
TMKS8A 147, a new antibacterial chlorinated a-lapachone
Streptomyces strain ferment yielded three new angucycline
derivative, that was identied from the culture extract of
derivatives, actetrophenone A 125 and actetrophenols A 126 and
a Streptomyces strain that was obtained from a sea slug.52 Mar-
B 127, 128. Actetrophenol B contains an unprecedented N-
inoterpins A–C 148, 149 and 150 were isolated from the culture
acetyltryptamine-substituted tetraphene core skeleton and was
broth extracts of two actinomycetes associated with the family
initially isolated as a racemic mixture of atropisomeric isomers
Streptomycetaceae and represent new chemical motifs as they
127 and 128 that were separated by chiral HPLC then analysed
combine quinoline-N-oxides with linear sesterterpenoid side
by ECD to determine their absolute congurations. Acte-
chains.53 New polyene macrolides, pyranpolyenolides A–F 151–
trophenol A 126 was the most active metabolite reported during
156 along with a new cyclic peptide 157 were isolated from
these studies, showing moderate antibiotic activity against
View Article Online
a Streptomyces species. Pyranpolyenolides C–F were identied as

alkene geometric isomers of either pyranpolyenolides A or B
and were proposed to most likely be produced by photochem-
ical conversion during fermentation or NP purication54 A
cryptic trans-acyltransferase PKS BGC (sdl) from Streptomyces
sp. was cloned and transferred into a heterologous host with
chemical investigations of the resulting culture broth leading to
the identication of a new class of polycyclic macrolides named
shuangdaolides A–D 158, 159–161, along with the previously
reported terrestrial-derived metabolite, dumulmycin 162. Gene
inactivation studies identied two biosynthetic intermediates,
shuangdaolides E 163 and F 164, suggesting an unusual
multidomain oxidoreductase that led to the formation of the
rare 2-hydroxycyclopentenone moiety found in this class of
macrolide.55
Through efforts to discover lead compounds against the rare
cancer pseudomyxoma peritonei (PMP) ve new angucyclines,
grincamycins P–T 187–191, from a Streptomyces sp. were identied.
Grincamycin T 191 showed the greatest toxicity towards three PMP
cell lines with IC50 values ranging from 1.4 to 2.7 mM.59 Other new
metabolites reported following Streptomyces fermentation and
chemical investigations include a novel polyene macrolide, hex-
acosalactone A 192,60 a tricyclic diketopiperazine derivative 193,61
the indolizinium alkaloid cyclizidine J 194,62 four aromatic poly-
ketides named wailupemycins M–P 195–198, and two new
hydroxamate siderophores, streptamides A 199 and B 200,63
anthracyclinones named boshramycinones A–C 201–203,64 the
anti-infective cyclodepsipeptide streptodepsipeptide SV21 204,65
nyuzenamides A 205 and B 206 that are bicyclic peptides with
Eight new linear polyketides, piericidins L–R 65–171 and 11-
moderate antifungal and cytotoxic activity,66 and three new polyene
demethyl-glucopiericidin A 172 were identied from
macrolactams 207–209, one of which, 207 was shown to be
a mangrove sediment-derived Streptomyces psammoticus and
unstable under certain heat and light conditions resulting in the
evaluated for cytotoxicity towards six HTCLs; piercidins M–O
formation of 208.67 LC-MS analysis of a Streptomyces sp. extract led
displayed the greatest toxicity with IC50 values < 0.1 mM against
to the prioritisation of this sample for follow-up large-scale
HL-60 cells.56 A genome-directed discovery strategy to identify
fermentation and isolation studies, that afforded three new 20-
new tetrahydroisoquinolines was applied to deep-sea derived
membered macrolides, venturicidins D–F 210, 211, 212. Genome
Streptomyces niveus, yielding the known aclidinomycins A 173
sequencing of this strain revealed the presence of a BGC that
and B 174 along with nine new congeners, aclidinomycins C–K
encoded for glycosylated type I PKS and additional studies showed
175–183. The conguration for two chiral centres in both 173
that the BGC associated with venturicidin biosynthesis (ven) was
and 174 had not been previously assigned but have now been
supported by the proposed biosynthetic pathway and conrmed by
determined by X-ray diffraction (XRD) analysis, enabling their
inactivation of the core PKS gene venK.68
structures to be revised. The new fused scaffold incorporating
As with previous reviews in this series, a number of new
a tetrahydropyran that is part of a distinct 6/6/6/6/5/5 polycyclic
bacterial MNPs were claimed during 2021, but the structures
motif is found in compounds 178, 179–181.57 Malaymycin 184,
presented were not fully consistent with the spectroscopic evidence
a new cyclopentenone-containing tetrahydroquinoline alkaloid,
provided.7,30,31
and mccrearamycin E 185, a geldanamycin analogue bearing
The rst total syntheses of 22 marine bacterial compounds
a rare ring-contracted cyclopentenone moiety, and a C2-
was reported in the literature during 2021, caprolactin C 6,5
symmetric macrodiolide 186 were isolated from Streptomyces
akazaoxime 4 and A-76356 45,16 MA026 67,25 xiamycins D and
malaysiensis. All compounds were evaluated for cytotoxicity
E,69 bacicyclin,70 (+)-pseudonocardide A and (+)-pseudono-
towards ve HTCLs, with 184 the most potent with IC50 values
cardide C,71 nocardiotide A,72 three 2-(p-hydroxybenzyl)-
of 67–70 nM against two cell lines. Furthermore, MOA studies
prodigiosin-based MNPs, along with isoheptylprodigiosin, and
showed that 184 induced cell cycle arrest in the G0/G1 phase in
tambjamine MYP1,73 (+)-spiroindimicin A,74 nesteretal A,75
a C42B (prostate cancer) cell line, caused cell shrinkage and
(+)-03219A,76 enterocin,77 nahuoic acid A,78 piscibactin,79 and
inhibited the expression of the androgen receptor (AR). Malay-
aldgamycin N.80
mycin also suppresses the expression of AR target genes KLK2
Over 80 reviews featuring some aspect of marine bacterial
and KLK3 in the C42B cell line, making it a promising lead
chemistry or biology were published during 2021. This is the
compound for castration-resistant prostate cancer.58
highest number of reviews ever and no doubt reects the impact
View Article Online
produced in large quantities by phytoplankton and a key

component of the global geochemical sulfur cycle, was shown to
be utilised as an osmoprotectant by various Vibrio species,102
mathermycin's cytotoxic MOA involves the targeting of cell
surface phospholipids with a specicity towards phosphatidyl-
ethanolamine,103 while the discovery of an unusual type II PKS
system, which consists of three phylogenetically different
ketosynthase/chain length factor complexes, has been linked to
the generation of cinnamoyl containing lipids belonging to the
youssoufene structure class.104
2.2 Cyanobacteria
A total of 14 peptide-based molecules were reported from cya-
nobacteria during 2021 including the linear lipopeptides

komesuamide 213 and odopenicillatamide 214 from Caldora
penicillata,105 the cyclic depsipeptides trikoveramides A–C 215–
217,106 and cyanobactins trikoramides B–D 218–220107 both
that COVID-19 has had on labs around the world. With lock- from Symploca hydnoides specimens, an antitrypanosomal
downs and lab access restrictions, researchers have clearly linear depsipeptide named kinenzoline 221, whose structure
turned their attention to review articles. Whilst summarising was conrmed by total synthesis,108 and the lipopeptide wen-
each individual review is beyond the scope of this review, changamide A 222 from a Neolyngbya sp. ferment that displayed
a snapshot of 17 standout articles is given below. Review in vitro apoptotic potential towards colon cancer cells.109 The
highlights included those describing advances in phenazine antiparasitic lipopeptide lead, hoshinoamide C 223, was iden-
chemistry over the past decade,81 a catalogue of 1062 terpenoid tied from Caldora penicillata. To determine the absolute
NPs produced by bacteria, entitled “Bacterial terpenome”,82 conguration of the unusual amino acid moiety, 8-amino-4-
overviews of the biology and chemistry of macrolactins83 and methyloctanoic acid, found in 223, two possible diastereo-
thiopeptides,84 how the recording and mining of MS data is mers of hoshinoamide C were synthesised. Hoshinoamide C
transforming NP research,85 N–N bond formation reactions did not exhibit any toxicity against HL-60 or HeLa cells at 10 mM,
involved in NP biosynthesis,86 developing techniques that can but inhibited the growth of the parasites responsible for African
be applied to single cells for accelerating microbial NP sleeping sickness (IC50 2.9 mM) and malaria (IC50 0.96 mM).110
research,87 recent highlights of biosynthetic studies on marine Motobamide 224, a new cyclic decapeptide containing a C-pre-
bacteria products,88 a summary detailing 127 halogenated nylated cyclotryptophan residue, was isolated from a marine
compounds identied from marine actinomycetes (1992– Leptolyngbya sp.; this MNP inhibited the growth of bloodstream
2022),89 use of synthetic biology to elucidate NP BGCs encoded forms of Trypanosoma brucei rhodesiense (IC50 2.3 mM) and
in Streptomyces genomes,90 chemical labelling strategies for NP showed no cytotoxicity against three human cell lines.111
detection and isolation,91 cryptic halogenation reactions asso- In the search for potential new anticancer agents, the
ciated with NP biosynthesis,92 volatile nitrogenous compounds screening of a collection of cyanobacterial extracts was under-
from bacteria,93 the versatile role of condensation domains in taken using a colon tumour cell line (HCT-116). Subsequent
NP biosynthesis,94 importance of microbial NP databases and bioassay-guided fractionation of a Lyngbya cf. confervoides hit
their impact in the multi-omics era,95 diversity, mechanism and extract resulted in the discovery of two new cyclodepsipeptides,
selectivity of polyketide b-branching,96 and an overview of named gatorbulins-1 225 and -2 226.112 Aer detailed biological
natural antiplasmodial lead compounds (648 NPs from various evaluations, gatorbulin-1 was shown to bind to tubulin via
natural sources; 2013–2019).97 a novel mechanism, which highlighted the hydroxamate group
Other marine bacterial research that made noteworthy of 225 as a functionally critical structural motif. A high-
contributions to the eld included the enhanced production resolution X-ray structure of a a/b-tubulin–gatorbulin-1
(3.8-fold increase) of the cytotoxic and antibacterial compound complex conrmed a unique tubulin binding site, the seventh
ohmyungsamycin A that was achieved via adenylation domain to be reported.112 Gatorbulin-1 supply issues were solved via
engineering and optimisation of culture conditions,98 the semi- total synthesis; the discovery of this hydroxamate-containing
synthesis of 18 ilamycin F derivatives, several of which had cyclodepsipeptide derivative has yielded a new lead molecule
improved anti-tubercular activity compared to the MNP,99 for cancer therapy.
research on the biosynthesis of anthraquinone-fused enediynes The new pyrrolinone NP, iheyanone 227, was isolated from
(e.g. dynemicin A) that has delivered insights into the biosyn- a Dapis sp. extract.113 This moiety forms the C-terminal end of
thetic enzymes and pathways associated with this rare chemo- the known antitrypanosomal (T. brucei rhodesiense) linear
type,100 and identication of a C-glycosyltransferase involved in peptide iheyamide A and was identied during previous struc-
the biosynthesis of the pyranonaphthoquinone medermycin.101 ture–activity relationships (SAR) studies to be an important
Dimethylsulfoniopropionate, an organosulfur metabolite constituent of this peptide's antiparasitic phamacophore. To
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determine additional SARs, the rst total synthesis of iheya- isolated from Salileptolyngbya sp.117 Total synthesis of both 236
mide A, iheyanone and analogues was undertaken in 2021.113 and 238 was achieved. The bromoiesol structure class was
Whilst iheyanone 227 showed weaker antitrypanosomal activity shown to selectively inhibit the growth of T. brucei
compared to iheyamide A, synthetic derivatives with longer rhodesiense.117
peptide chains showed improved activity.113
The rst total syntheses of 14 cyanobacterial metabolites

were accomplished in 2021, laingolide A 240,118 kinenzoline
221,108 hoshinoamides A119 and C 223,110 iheyamide A and
iheyanone 227,113 bromoiesol sulfate A 236 and bromoiesol A
238,117 gatorbulin-1 225,112 27-deoxylyngbyabellin A,120 laucys-
teinamide A,121 oscillatoxins E and F,122 and (−)-majusculoic
acid.123 The asymmetric synthesis of four diastereomers of
laingolide A 240 led to the unambiguous assignment of the
stereochemistry for this MNP.
Over 30 reviews featuring cyanobacterial chemistry and/or
biology were published during 2021. Some highlights include
several reviews on cyanobacterial-sourced molecules that display
antiviral activities with a focus on SARS-CoV-2,124,125 the potential of
cyanobacterial compounds for treating neurodegenerative
diseases,126 drug leads derived from Japanese-sourced MNPs,127
a summary of recent advances in hapalindole-type alkaloidal
Six new aplysiatoxin polyketide derivatives were reported in chemistry including biosynthesis, synthesis, and bioactivity per-
2021 including debromooscillatoxins G 228 and I 229 from pectives,128 a comprehensive review of chemistry and pharmaco-
Moorea producens,114 and oscillatoxins J–M 230–233 from logical aspects of cyanobacterial azoline-based oligopeptides,129
a Lyngbya specimen.115 Oscillatoxins J, K and M all exhibited and an overview of toxic compounds produced by cyanobacteria
activities towards potassium channel Kv1.5, which is consid- belonging to the order Nostocales.130
ered a target for new treatments of atrial tachyarrhythmias.115
Cyanobacterial genomes contain a variety of BGCs that 2.3 Marine-sourced fungi (excluding from mangroves)
incorporate fatty acid-derived moieties but predicting or Coral-derived Acremonium sclerotiaenum was the source of 13 new
detecting the encoded MNPs can prove difficult due to current derivatives of the meroterpenoid ascochlorin, acremochlorins A–
lack of knowledge and tools. Stable-isotope-labeling of cyano- M, 241, 242–253, of which all but 250 were chlorinated. Acre-
bacterial fatty acid-derived lipidomes is one strategy for gener- mochlorin A 241 was a potent inhibitor of human dihydroorotate
ating solutions in this eld. Supplementation of Nodularia sp. dehydrogenase, an important enzyme in pyrimidine biosynthesis
cultures with deuterated fatty acids was used to detect NP and suppressed triple-negative breast cancer (TNBC) tumour
signatures in individual strains. This unique strategy resulted in growth in a xenogra model without toxicity.131
the identication of new lactylate-nocuolin A hybrids that were
named nocuolactylates A 234 and B 235. Other minor and
related analogues were also detected but a lack of purity and
limited quantities prevented chemical structures being secured
by NMR spectroscopy.116 New polyhalogenated aryl sulfates,
named bromoiesol sulfates A 236 and B 237, along with their
desulfated analogues, bromoiesols A 238 and B 239 were
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Acremonium persicinum yielded hydroxamate siderophore An OSMAC approach was utilised in the isolation of phenolic
cyclohexapeptides 254–259, which comprise acremonpeptides E derivatives 354 and 355 from two separate Aspergillus strains
and F and their complexes with aluminium and ferric ions and and a known synthetic derivative 356 was obtained as a new
a pentapeptolide, aselacin D 260. The aluminium complexes, MNP from the latter strain also.163 Various other Aspergillus
Al(III)-acremonpeptide E 254 and Al(III)-acremonpeptide F 258 strains contained the polyketides 357–363,164 a meroterpene
exhibited moderate to potent inhibition of two fungal strains.132 364,165 and an indoloditerpene 365.166
Acremopeptaibols A–F 261–266 were obtained from a further
strain of Acremonium,133 and an Acrostalgamus strain was the
source of N-methoxyindolediketopiperazines, acrozines D–G
267–270.134 A molecular networking guided strategy was utilised
in the isolation of amaurones A–I 271–279, polyketide pyrones
from Amauroascus sp. that were susceptible to chemical trans-
formations mediated by environmental stimuli.135 Amphichorda
felina yielded picoline-derived meroterpenoids 280–283, with
the enantiomers isolated as a racemate but separated by chiral

chromatography.136 Arthrinium strains were the source of pyr-
A LC-MS/MS-based molecular networking approach was
idone alkaloid 284,137 and polyketides 285–289, of which 285,
utilised in the isolation of the cycloheptapeptides 366 and 367,
286 and 289 were obtained as methyl esters (artefacts of isola-
with two further related metabolites isolated in trace amounts
tion) rather than the NP acids. Of the parent acids, that of 289
only so not fully characterised.167 A bivalve mollusc-derived
(arthrinic acid) is a known terrestrial NP but was isolated for the
Aspergillus strain was the source of quinazoline-containing
rst time as a MNP.138 Phenol derivative (3R)-(3′,5′-
indole alkaloids 368–370 and several co-isolated alkaloids dis-
dihydroxyphenyl)butan-2-one 290 was isolated from an Asco-
played various activities, with lapatin A and scequinadoline E
mycota species.139
exhibiting weak a-glucosidase inhibition and quinadoline B
As has been the case in previous years, the genus Aspergillus
and tryptoquivaline L displaying selective activation of the rya-
was the most common source of fungal metabolites in 2021.
nodine receptor in insects.168 Several sediment-derived Asper-
Norditerpene 291 and indone 292 were isolated from Aspergillus
gillus strains yielded a diverse range of metabolites including
aculeatinus,140 A. austroafricanus yielded prenylated indole
a lumazine peptide 371 and a sesquiterpene 372,169 a spiro
alkaloids 293 and 294 and pteridine alkaloids 295 and 296, the
[anthracenone–xanthene] derivative 373, a penicillide analogue
latter of which was obtained for the rst time as a MNP.141
374 and two phthalide derivatives 375, 376,170 and a mer-
Various A. candidus strains yielded p-terphenyls 297,142 298–
oterpene 377.171 An OSMAC approach to cultivation of a so
300143 and indole-diterpene alkaloids 301–303,143 304–307.144
coral-derived Aspergillus strain resulted in the production of
Other Aspergillus strains were the source of viomellein deriva-
cyclopentanone 378–380 and cyclohexanone 381–385 deriva-
tives 308 and 309,145 polyketides 310 and 311 (the latter a known
tives,172 cyclic lipopeptides 386–388 and linear peptides 389–
synthetic derivative but new NP),146 prenylated phenyl-
392,173 whilst another so-coral-derived strain yielded (+)-17-
butyrolactones 312–315,147 phomaligol derivatives 316–319,148
hydroxybrevianamide N 393 and (+)-N1-methyl-17-
320 and 321,149 and highly rearranged ergostanes 322 and
hydroxybrevianamide N 394, which racemised in basic solu-
323.150 Benzophenone 324,151 pinophilin B epimer 325,152 alka-
tion.174 Further Aspergillus strains were the source of an
loid 326,153 and dihydrofuranone derivative 327153 were ob-
azaphthalide derivative 395 and a phthalide derivative 396,175
tained from A. fumigatus strains, whilst other Aspergillus strains
a chromone 397,176 meroterpenoids 398–400 (the last of which is
were the source of phenol derivatives 328, 329,154 oxister-
a structural revision of terretonin E), sesterterpenoids 401, 402
igmatocystins 330–332,155 a sulfonated diphenylether-aminol-
and sesquiterpenoids 403, 404.177
amino acid ester guanidinium salt 333 and its diphenyl ether
A GNPS approach to an extract of Beauveria felina led to
sulfate component 334,156 and sesquiterpenoid lactone 335.157
isolation of 30 cyclo-hexadepsipeptides, which fell into three
Aspergillus oryzae, isolated from a Red Sea sediment, yielded
structural types (destruxins, isaridins and isariins). New des-
asporychalasin 336, a cytochalasin with a 6/6/11 skeleton.158
truxin derivatives felinotoxins A–G 405–411 were amongst these
Aspergillus strains derived from so corals were the source of
compounds. Genome sequencing identied three BGCs, each
cyclic hexapeptides 337–339,159 lipodepsipeptide 340,159 2-
responsible for the biosynthesis of destruxins, isaridins and
pyrone derivatives 341 and 342, cyclopentenone derivative 343
isariins, respectively. Biosynthesis of the nonproteinogenic
and austocystin derivative 344.160 Co-culture of A. sydowii wth
building block (3S)-methyl-L-proline, found in destruxins and
the bacterium Bacillus subtilis induced production of 25 known
isaridins, was characterised. Some of the known peptides
and new metabolites by the fungus including serine sydonate
exhibited weak inhibition of the Zika virus but the clarication
345 and an isomer of macrolactin U 346.161 Furanaspermer-
of the biosynthetic pathway gives opportunities to engineer the
oterpenes A 347 and B 348, meroterpenoids with an unique 6/6/
pathway to potentially generate new anti-Zika virus
6/5/5 pentacyclic skeleton were isolated from a gastropod-
cyclohexadepsipeptides.178
derived Aspergillus terreus strain, along with ve further mer-
Chemical analysis of a sh-gut-derived Chrysosporium sp.
oterpenes 349–353.162
indicated the presence of trace amounts of aza analogues of
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chrysosporazines 412–417, yields of which were not improved The genus Penicillium has again proved a rich source of
by use of a microbioreactor cultivation proling analysis. A marine fungal metabolites. Penicillium chermesinum yielded
precursor-directed biosynthesis strategy utilising supplemen- azaphilones 536–539 and isocoumarin derivative 540,206 nor-
tation with sodium nicotinate did, however, enhance produc- bisabolane derivatives 541, 542 and phthalides 543 and 544
tion of these metabolites plus that of additional analogues 418– were obtained from P. chrysogenum,207 and various strains of P.
421. Cultivation of the fungus on a different medium also citrinum were the source of citrinin analogues 545–549, in
produced an additional analogue 422. All analogues exhibited addition to penicitol A 550 (for which the conguration was
weak to moderate reversal of doxorubicin resistance in a human revised from 14S to 14R),208 polyketides 551 and 552 and steroid
tumour cell line via inhibition of P-glycoprotein and without 553 (the last a known synthetic compound but new NP).209 So
toxicity.179 Benzopyrone 423,180 and tetralone derivative 424,181 coral-derived Penicillium strains yielded deoxyisoaustamide
were isolated from Cladosporium strains. Cochliobolus lunatus derivatives 554–560,210 and azaphilones 561 and 562,211 whilst
yielded 14-membered resorcylic acid lactone 425,182 cytocha- deep-sea sediment-derived strains were the source of phenyl-
lasin derivatives 426–430, including a dimer 426, and a known hydrazone 563–565, and enantiomeric quinazoline 566 and 567
semi-synthetic derivative but new NP, 430, were isolated from derivatives,212 benzamide 568 and 569 and leucine derivatives
570 and 571,213 penicyrone A analogues with an epoxy tetrahy-
a Curvularia strain,183 and a sponge-derived Cymostachys species

yielded cyclic hexadepsipeptide 431,184 and phenol derivatives drofuran ring 572 and 573,213 phenol furanone 574, octanamide
432–437.185 derivative 575 and decanoic acid derivatives 576 and 577.213 An
Dichocetide D 438 is a symmetrical dichlorinated metabolite untargeted metabolomics approach to examination of a P.
obtained from Dichotomomyces cejpii,186 and chlorinated restrictum extract led to isolation of pyran-2-one derivatives 578–
sesquiterpene chlovalicin B 439 was isolated from a Dig- 582, of which 579 was a known synthetic but new NP and 582
itatispora strain.187 Epicoccum nigrum yielded cyclic tripeptide was a known terrestrial NP but a rst time marine isolate214 and
440,188 while several salicaldehyde derivatives 441–444,189 445– P. sclerotiorum yielded azaphilones 583 and 584.215 Sol-
451,190 452–457191 and a diketopiperazine 458,192 were obtained itumergosterol A 585, is an unique 6/6/6/6/5 steroid obtained
from Eurotium strains. Epigenetic manipulation of a Eutypella from P. solitum from deep-sea sediment,216 as were polyketide
species activated a BGC, resulting in isolation of 17 sesquiter- 586 and alkaloids 587 and 588.217
penes, eutypeterpenes A–Q 459–475.193 Penicillium steckii sourced from black band-diseased coral yiel-
Continued investigation of a sh-gut-derived fungus Evlacho- ded new, 589 and 590, and known epithiodiketopiperazines with
vaea sp., (formerly Trichoderma), resulted in the isolation of the an a,b-polysulde bridge that underwent multiple nonenzymatic
cryptic metabolite, N-amino-L-proline methyl ester 476. Isolation interconversions in solution. A further new analogue was present
involved development of a very sensitive, in situ analytical deriva- but not fully characterised. The proposed biosynthetic pathway to
tisation procedure utilising 2,4-dinitrobenzaldehyde and the study these metabolites was supported by a gene cluster mined from the
revealed that 476 is retained in fungal mycelia and only released fungal genome.218 Three pairs of atropodiastereomers were ob-
through disruption by solvent extraction and also that metabolites tained from another strain of P. steckii, comprising heterodimeric
previously obtained from the same fungus and detected in freshly 591 and 592, and homodimeric 593 and 594, bis-isochromans, and
extracted cultures, are in fact artefacts of isolation, produced when isochroman/1,4-benzoquinone conjugates 595 and 596.219 Deep-
media components react with 476.194 Cultures of Fusarium strains sea sediment and sediment-derived Penicillium strains have been
resulted in isolation of the polypropionate derivatives, decempyr- the source of numerous metabolites. Deep-sea-derived compounds
ones A–J 477–486,195 fusarin derivatives 487–492,196 bisindole include chromone derivatives 597–604,220 meroterpenoids 605–
alkaloid enantiomers 493 and 494,197 and oxygenated alkaloid 607,221 p-terphenyls 608–610,222 drimane sesquiterpenes 611 and
dimers 495 and 496.198 612, and polyketides 613–618.223 Sesquiterpene lactone 619,224
Amino acid supplementation of a culture of Lecanicillium resorcinol-long chain fatty acid derivatives 620–624, oxygenated
fusiporum led to isolation of the indole alkaloid lecasporinoid polyene 625, pyridinone derivative 626,225 and poly-
497 and synthesis of a diastereoisomer facilitated assignment of hydroxoxanthones 627–631,226 were also isolated from sediment-
the absolute conguration.199 A fungus of the Lulworthiaceae derived Penicillium strains. Supplementation of a culture of Peni-
family was the source of a sulfated naphthopyrone dimer 498,200 cillium sp. with L-tryptophan yielded indole diterpenoids 632–
and decalin derivatives 499–507 were obtained from a shellsh- 635,227 whilst benzopyran derivative 636,228 N-methyl-4-quinolone
derived Monascus strain, with 504–507 being known synthetic alkaloids 637–641, and citrinin dimer 642,229 were isolated from
compounds but new NPs.201 An anthraquinone 508 was ob- additional Penicillium strains.
tained from a sponge-derived Neosartorya strain, along with the
known MNP tenellic acid C (for which the absolute congura-
tion was determined as 509), a biphenyl ether 510 and diben-
zodioxepinone 511.202 Deep-sea sediment-derived
Paraconiothyrium hawaiiense yielded polyketides 512–518,203
isocoumarin analogues 519–524, and derivatives 525–527 were
obtained from a Paraphoma species204 and Parengyodontium
album was the source of chromanones 528–535.205
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OSMAC manipulation of Pestalotiopsis heterocornis led to Various Trichoderma species have been the source of pro-
production of polyketides 643–650 and ceramide 651,230 a P. harziane 752,254 and harziane 753–755,254 756–762255 diterpene
neglecta culture yielded chromenes 652–655 and chromones 656 derivatives (757, 758 are known compounds but new MNPs) and
and 657,231 (−)-tricinonoic acid 658 and polyketide 659 were harziane lactone 763.256 A range of sesquiterpenes have been
isolated from Phaeosphaeria spartinae,232 and deep-sea obtained from two additional Trichoderma strains including
sediment-derived Phomopsis strains yielded tenellone–macro- bisabolane derivatives 764–773, cadinane derivative 774, cyclo-
lides 660–662,233 and chlorinated azaphilones 663–667.234 Pleo- nerane derivatives 775–779,257,258 and chlorinated trichothecane
sporales strains were the source of phenalenone derivatives 668– derivative 780.258 Trichoderma atroviride yielded biasbolane
670,235 and polyketides 671 and 672.236 Mycophenolic acid sesquiterpenes 781 and 782, steroid 783, and lauric acid deriv-
derivatives 673–675 were obtained from Rhizopus oryzae, (673 is ative 784,259 whilst further sesquiterpenes 785–788, and steroid
a known terrestrial metabolite but new MNP and 675, a known 789 were obtained from T. brevicompactum.260 Peptaibols 790–
synthetic derivative but new NP237). An untargeted metab- 794, consisting of 15 amino acid residues were isolated from
olomics approach to a Rhodotorula mucilaginosa extract resulted another Trichoderma strain,261 and a Xylaria strain yielded
in the isolation of polyol fatty acid esters 676–679. Genome tyrosine derivatives 795–799, phenyl acetic acid derivative 800,
quinazolinone analogues 801 and 802, naphthalenedicarboxylic
sequencing resulted in the identication of the genomic locus

of a key enzyme involved in the biosynthesis of these metabo- acid 803, and 3,4-dihydroisocoumarin derivative 804.262
lites.238 Phenols 680 and 681 were isolated from Roussoella sia- Isolation of asperspiropene A from a sponge-derived Aspergillus
mensis,239 feeding of anthranilic acid and phthalimide to species led to structural revision and assignment of absolute
a Scedosporium apiospermum culture resulted in production of conguration as 805 and also represents its rst isolation as
diphenylamine derivative 682,240 cyclic decapeptides 683–686 a MNP.263 Drazepinone, originally isolated from ryegrass Lolium
were obtained from Sesquicillium microsporum,241 and so coral- perenne seeds, was reported to have a trisubstituted naphthofur-
derived Symplicium strains yielded steroid derivatives 687– oazepinone skeleton but isolation from a marine-derived Penicil-
690,242 and nortriterpenoids 691–701.243 lium strain led to revision of the structure to enantiomeric new
Epigenetic manipulation of a Spiromastix sp. with sub- MNPs 806 and 807, of which 807 displayed modest inhibition of
eroylanilide hydroxamic acid induced production of sesquiter- protein tyrosine phosphatase 1B (PTP1B) and weak inhibition of T-
penes 702–710.244 Polyketide derivatives 711–714245 and cell protein tyrosine phosphatase.264 Biomimetic synthesis of sar-
phenylspirodrimane derivatives 715,245 and 716–720,246 were ocladione from ergosterol led to its structural revision from con-
obtained from Stachybotrys strains while a Stilbella strain yiel- taining a dihydropyran-4-one moiety to a dihydrofuran-3-one
ded asochlorin analogues 721–724.247 Talaromynoids A–I 725, moiety and also assignment of its absolute conguration as
726, 727–730, 731–733 are highly oxygenated meroterpenoids 808.265 Aperorydine G was isolated as a rst time MNP and its
obtained from Talaromyces purpureogenus, of which 725 and 726 absolute conguration determined as 809,266 and (12S)-12-
possess a 5/7/6/5/6/6 polycyclic ring system and 731, 732 and hydroxymonocerin 810 was also isolated as a new MNP.267 Tri-
733 possess 6/7/6/6/6/5, 6/7/6/5/6/5/4 and 7/6/5/6/5/4 polycyclic quinane (−)-asperaculin A has been synthesised in a 13 step
systems, respectively.248 Other Talaromyces strains yielded process employing biodivergent Baeyer–Villiger oxidation,268 and
polyenes 734–736,249 oxaphenalenone spirolactones 737–741,250 steroid-sterigmatocystin heterodimer asperversin A has been
nonadrides 742–747 251 and polyphenols 748 and 749,252 and prepared by an 11 step asymmetric method.269 Chromanone A was
a Thermomyces strain was the source of polyketides 750 and synthesised from pyrocatechol in two sequences, the shortest of
751.253 which comprised ve steps,270 and cyclohexadepsipeptides exu-
molides A and B were prepared via a method utilising solid- and
solution phases.271 A homodimeric bispyrrolidinoindoline dioxo-
piperazine alkaloid isolated from sponge-derived Aspergillus vio-
laceofuscus has been prepared,272 and synthesis of chlorinated
alkaloids gymnastatin G and dankastatins B and C has also been
achieved.273 Cyclohexenone derivative pleosporol A (and its
stereoisomers) has been prepared from arabinose,274 peniciaculins
A and B and hydroxysydonic acid have been synthesised via an
enantioselective method,275 as have (+)-peniciketals A and B,276,277
and (−)-spiroxin D.278
In silico prediction of SARS-CoV-2 main protease binding ability
for marine fungal compounds predicted wailupemycins H and I,
and cottoquinazoline B to have high nanomolar inhibition for
preventing viral replication,279 and another in silico study indicated
that epolactaene would also inhibit this protease.280 3-Bro-
moascochlorin suppressed small cell lung cancer growth in
a xenogra mouse model without affecting body weight.281
Secoemestrin C displayed weak inhibition of Candida albicans
isocitrate lyase,282 and harzialactone A exhibited weak
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antileishmanial activity.283 Aspulvinone H exhibited weak inhibi- Korea307) or genus (Aspergillus,308,309 Cladosporium,310 Penicillium311).
tion of glutamic oxaloacetate transaminase 1 (GOT1) and the Although not specically on marine fungi, a review on the use of
crystal structure of its complex with GOT1 was determined.284 co-culture for stimulating secondary metabolite production in
Viridicatin and viridicatol displayed photoprotective potential, microorganisms in general contains several marine fungal
absorbing UVB and UVA-II radiation whilst being photostable and examples.312
non-cytotoxic,285 and 6-pentyl-2H-pyrone-2-one showed weak inhi-
bition of settlement of Amphibalanus amphitrite (barnacle)
larvae.286 2.4 Fungi from mangroves
Sequencing of the genome of Aspergillus affinis and compar-
Pyrasplorine A 811 isolated from a rhizosphere sediment-derived
ison with that of closely related Aspergillus species (section Cir-
Aspergillus versicolor is a pyrazinopyrimidine-type alkaloid con-
cumdati) indicated similarity in genome size, GC content and
taining a unique spiro-cyclopentenone ring attached to the pyr-
transporters and that these species are an excellent source of
azino[1,2-a]pyrimidine. Four additional pyrazinopyrimidine
carbohydrate-active enzymes. Although some BGCs are highly
alkaloids pyrasplorines B 812 and C 813, deg-pyrasplorine B 814
conserved amongst the genomes of the section, the A. affinis
and versicoloid A 815 were also reported.313 The assignment of the
genome has some clusters, transporters and genes that appear to

absolute conguration of the spiro centre in pyrasplorine A 811
be strain-specic.287 Examination of a co-culture of Aspergillus
proved challenging since calculated ECD data for both 8′ epimers
sclerotiorum and Streptomyces sp. isolated from hydrothermal
were similar, however the DP4+ calculated 1H and 13C NMR data
vent sediments indicated that notoamide secretion by the fungus
provided denitive evidence to assign 8′R conguration. The
was increased by cyclo(Pro–Trp) produced by the bacterium,
absolute conguration of the known MNP, versicoloid A, has been
leading to the hypothesis that A. sclerotiorum transformed
the subject of several previous studies.314,315 The structure of ver-
cyclo(Pro–Trp) to the biosynthetic precursors of notoamides via
sicoloid A 815 was originally reported without the conguration at
chemical communication.288 Genome sequencing and annota-
C-10 assigned, and subsequently the C-10 conguration was
tion of a Mexican Aspergillus strain, that was the source of an
proposed based on the co-isolation of an analogue whose absolute
array of secondary metabolites including a series of dioxomor-
conguration was assigned through analysis of VCD data. Now
pholines, peptides, and butyrolactones, has revealed that of the
using Marfey's chiral amino acid analysis in conjunction with
67 BGCs identied, ∼60% belong to the non ribosomal peptide
NOESY correlations, the absolute conguration of versicoloid A
synthetase (NRPS) and NRPS-like classes.289 Genome mining of
has been established.313
an A. terreus strain also identied 67 BGCs, including those
The Rhizophora apiculata root endophyte Aspegillus candidus
corresponding to a diverse range of metabolites, reinforcing the
contained seven p-terphenyls, asperterphenyllins A–F 816–
genetic variability and biosynthetic diversity of this strain.290 The
822.316 Asperterphenyllin A exists as a racemic mixture of atro-
mycelia of a Penicillium oxalicum strain were able to catalyse
pisomers. Another Aspergillus sp. isolated from mangrove
biotransformation of progesterone to produce the steroid 7b,15b-
sediment yielded the xanthone derivatives, spinosusones A 823,
dihydroxyprogesterone, whilst the culture broth yielded 15b-
and B 824 and tryptoquivaline alkaloid, asperdiazapinone G 825
hydroxyprogesterone, indicating the likely presence of cyto-
along with ten known MNPs of which sartorypyrone A showed
chrome P450 monooxygenases in the fungus.291 Genomic anal-
weak to moderate antibacterial activity towards a panel of
ysis of a Penicillium steckii culture indicated that it contains
Gram-positive and Gram-negative strains.317 A related alkaloid,
a large number of secondary metabolite clusters, including one
7-hydroxy-3,10-dehydrocyclopeptine 826, was isolated from the
involved in citrinin biosynthesis. Blocking the citrinin biosyn-
mangrove sediment derived Penicillium polonicum. The known
thetic pathway resulted in accumulation of three isoquinoline
MNP cyclopenin, was a co-isolate from this strain and showed
alkaloids.292 Two of the enzymatic oxidative transformations in
moderate inuenza neuraminidase inhibition.318
the biosynthesis of terrein and related metabolites have been
elucidated as early steps in the biosynthetic pathway.293 The
biosynthetic gene cluster tlxA-J for the hexacyclic meroterpenoids
talaromyolides (isolated from Talaromyces purpureogenus) has
been identied by heterologous expression, in vitro enzyme
assays, and CRISPR-Cas9-based gene inactivation, revealing that
the heterodimer of non-heme iron enzymes, TlxJ and TlxI,
catalyses three steps of oxidation in the biosynthetic pathway.294
Amongst the many reviews published on specic aspects of
marine fungi were those on metabolites from endophytic
species,295 and on fungi isolated from sediment,296 or from Sar-
cophyton species,297 those based on compound type isolated
(halogenated compounds298 and bioactive alkaloids299,300), and
several based on metabolite activity type (anti-inammatory and
anti-tumour,301 anti-cancer302 anti-cancer and anti-bacterial,303 anti-
bacterial,304. and anti-microbial305). Other reviews discussed marine
fungi based on their geographical source (Antarctica306 and
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Cladosporium sp. isolated from Cerops tagal roots produced two Table 1 Mangrove plant species yielding fungal isolates (2014–2021)
simple benzoic acid derivatives cladoslides A and B 827 and B 828,
Plant species name Plant type No. papers
a b-carboline cladospomine 829 and a pyridin-2(1H)-one cladoslide
C 830.319 The rst naturally occurring ergosterol purine hybrid 831 Acanthus ilicifolius Mangrove shrub 4
was isolated from Penicillium brefeldianum.320 Aegiceras corniculatum True mangrove 3
Six new 4-quinolone alkaloids oxypenicinolines A–D 832– Avicenna marina True mangrove 6
839, penicinoline F 840 and penicinoline G 841 were isolated Bruguiera gymnorrhiza True mangrove 5
Bruguiera sexangula var. rhynchopetela True mangrove 2
from Penicillium steckii. Oxypenicinolines A–D, all isolated as Ceriops tagal True mangrove 5
racemates, were separated into their enantiomers by chiral Excoecaria agallocha True mangrove 2
HPLC.321 Also reported from another culture of P. steckii were Heritiera littoralis True mangrove 1
the decalin derivatives, penicisteck acids A–D 842–845, and the Hibiscus tiliaceus Coastal plant 1
nitrogenous compounds 846–848. The known MNP co-isolates, Kandelia candel True mangrove 1
Kandelia obovata True mangrove 2
GKK1032C and 4-hydroxy-17R-methylin-cisterol, showed weak Limonium sinense Coastal plant 1
to moderate antibacterial activity against S. aureus.322 Other Lumnitzera racemosa True mangrove 1
Penicillium-derived MNPs reported were phenalenones, ace- Myoporum bontioides Coastal plant 3
neoherqueinones A 849 and B 850, (+)-aceatrovenetinone A 851, Rhizophora apiculata True mangrove 3
(+)-aceatrovenetinone B 852 from Penicillium herquei,323 sorbi- Rhizophora mangle True mangrove 1
Rhizophora mucronata True mangrove 1
cillinoid 853 from Penicillium sp. isolated from the coastal soil
Rhizophora racemosa True mangrove 1
surrounding Hibiscus tiliaceus,324 and penipyrols C–G 854-858 Rhizophora stylosa True mangrove 5
and methyl-penipyrol A 859, a-pyrones isolated from a rhizo- Salicornia sp Salt marsh plant 1
sphere sediment derived Penicillium sp. This extract was chosen Sonneratia caseolaris True mangrove 5
for investigation based on the unusual UV proles of HPLC-UV Thespesia populnea Coastal plant 3
unidentied mangrove Unspecied 35
peaks.325
The chromones, phomochromenones D–G 860–863 were
isolated from the mangrove root endophyte Phomopsis asparagi.
Phomochromenones E and F were obtained as a racemic
mixture and only successfully puried aer being separated as
their diastereomeric Mosher esters and subsequently hydro-
lysed under alkaline conditions.326 Mangrove sediment-derived
Trichoderma atroviride was the source of the simple cyclo-
pentenone acrylic acid derivatives trichodermacid A 864, and
trichodermesters A 865 and B 866,327 while the related cyclo-
pentanes 867 and 868 were reported from Aspergillus avipes
isolated from the pneumatophores of Acanthus ilicifolius.328
All new mangrove fungal-derived MNPs were tested in
a variety of assays but only asperterphenyllin G 822 was
moderately cytotoxic,316 penipyrol C 854 showed weak regener-
ative b-cell effects in zebra sh,325 and aceneoherqueinone A 849
showed weak inhibition of acetyl choline esterase.323 All of the
other new MNPs were inactive in the assays they were tested in.
One review has summarised the chemical diversity and
bioactivity of NPs reported from mangrove-derived Penicillium
species and another discusses the antimicrobial NPs reported
from mangrove fungal epiphytes.329,330
Analysis of MarinLit data2 shows that there have been 294
Fig. 2 150 × 150 SOM of 36 646 MNPs highlighting those reported
papers reporting new MNPs from mangrove fungi since 2014
from (a) all Ascomycota (red isolated from mangrove habitats, blue
but only 92 report fungi isolated from roots or sediment. These other) and (b) mangrove associated Ascomycota (red isolated from
root and sediment studies report fungi associated with 21 aerial parts, blue isolated from roots and sediments).
species of plant of which ve are coastal or salt marsh species,
not mangroves (Table 1).
There are approximately 110 species of mangrove worldwide the free cheminformatics soware Osiris Datawarrior332 using
with 54 considered true mangroves.331 This suggests that the SphereFp (512 substructure fragment dictionary) descriptor)
mangroves remain a relatively untapped resource for new shows no difference in their structural diversity with those re-
fungal biodiscovery. However, a targeted approach to the ported either from other marine fungi or fungi isolated from
isolation and culturing of marine specic fungi is warranted aerial parts of mangroves (Fig. 2). This analysis aligns with the
since a cluster analysis of all mangrove fungi derived MNPs result reported in a recent paper that has further shown that
using a 150 × 150 cell self-organising map (SOM) (generated in
View Article Online
fungal MNPs share over 75% redundancy with NPs isolated and absolute congurations of which have been dened. Use of
from terrestrial fungi.333 the 2D-INADEQUATE NMR experiment with 13C-labelled
compound was crucial for its structure elucidation.339
Non-sulfated water-soluble steroids are rare. Gibbosterol A 882
2.5 Dinoagellates
is a water-soluble sterol isolated from the same Chinese culture of
Resolvins are specialist immunomodulatory regulators that limit A. gibbosum that had previously provided three new SCCCs. The
pro-inammatory responses. Several new resolvins 869, 870 and structure of the compound, including its absolute conguration,
871 with potent anti-inammatory properties were reported from was secured by XRD analysis. Gibbosterol A is a weak to moderate
the diatom Cylindrotheca closterium.334 Two new okadaic acid-type agonist of the human pregnane X-receptor (PXR) via binding at the
glycosides 872 and 873 have been isolated. Their presence was helix-12 region which stabilises the PXR surface, allowing its
observed in contaminated shellsh from Spain, Norway, Canada, binding to the retenoid-X-receptor. Its biosynthesis involving
Ireland and New Zealand.335 Two new amphidinolide N congeners rearrangement of the ubiquitous algal compound b-sitosterol was
874 and 875 are potent cytotoxins isolated from Amphidinium sp.336 also proposed. The acid-catalysed reaction of 882 provided co-
A report of three new amphidiniols 876–878 has suggested that isolated 883, which was inactive in the same assay.340
centrifugation to clarify the culture media is a stressor that
Other compounds were claimed but were only established by

prompts release of the compounds from the dinoagellate into the MS-methods and their structures are not shown here.341–343
surrounding liquid.337 Karenia brevisulcata is a well-documented The total synthesis of limaol has been achieved,344 while the
producer of potently toxic metabolites, with two new relative and absolute congurations of formosalide A 884 and B
brevisulcenal-type sulfated esters 879 and 880 being sourced from 885 have been established following their syntheses.345 Two
a New Zealand isolate of the dinoagellate.338 groups have independently synthesised and determined the full
A new super carbon-chain compound (SCCC), benthol A 881, stereostructure of amphirionin-2 886.346,347 The role of synthesis
has been reported from an undescribed eukaryote that is unrelated in solving congurational relationships within marine poly-
to any known clade. The hybrid polyether/polyol structure of this cyclic ethers has been reviewed.348 A review of the toxic metab-
potent antimalarial polyketide has 35 chiral centres, the relative olites produced by Karenia brevisulcata has been published,349
as have reviews of models of food chain webs of ciguatera in
Australia,350 and the effects of okadaic acids and dinophysis-
toxins on sh.351
The molecular target of the azaspiracids (AZAs), and their
corresponding mode of action, has been claried. The AZAs
cause anion dysregulation by affecting target volume regulated
anion channels; they are the rst compounds to be found to do
so, making them important biochemical probes to study these
cellular ion channels.352 Regulatory limits on various dinoa-
gellate toxin concentrations in shellsh exist, but within the
AZA-class, currently only AZA-1, AZA-2 and AZA-3 are monitored.
Treatment of these three compounds with blue mussel hepa-
topancreas caused production of numerous other AZAs,
including several new congeners as detected by MS, therefore
monitoring of the three parent compounds alone may be
insufficient as a food safety measure.353
A recent study has shown that gambierone from Gamber-
idiscus cheloniae is not as toxic as other ciguatera compo-
nents.354 Brevetoxin PbTx-2 has differential effects against
human and dinoagellate thioredoxin reductases, suggesting it
is a key endogenous regulator of this enzyme in K. brevis.355
The structure of goniodomin B has been revised to 887
following further NMR analysis; it is formed from parent
goniodomin A depending on the solvent's cationic composi-
tion.356 Two independent studies have probed saxitoxin
biosynthesis by correlating toxin production to the stxA4 gene
copy number in both toxin producing and non-producing
strains of Alexandrium minutum, A. pacicum and Gymnodi-
nium catenatum.357,358 An analytical study of saxitoxin, okadaic
acid, domoic acid and microcystin content in the excreta and
tissues of cetaceans either stranded or unintentionally caught
in nets over an 18 year period in Southern California has been
used to establish models of food-chain transmission of these
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important metabolites.359 Another study has investigated how anti-inammatory and anti-thrombotic properties have been
the diatom neurotoxin b-N-methylamino-L-alanine is magnied proled within the Irish microalga Chlorococcum sp. SABC
through the food chain through molluscs, via crustaceans to 012504, marking this strain a potentially valuable resource for
carnivorous gastropods. The absence of bacteria producing b-N- nutraceutical development.371
methylamino-L-alanine in the gut of gastropod Nevertia didyma
suggests detection of the neurotoxin in the mollusc is evidence
of trophic transfer.360 A comparison of 313 polar metabolites 4 Brown algae
within 21 phytoplankton species has shown that the bulk
community metabolome is reective of the producing algal Two cresol lipids 894 and 895 were obtained from an Egyptian
community. These results show that the algal community Sargassum, while an Indian Turbinaria yielded three furanones
composition can have a large effect on the carbon economy of 896–898, respectively.372,373 A different species of Indian Turbi-
the local ocean surface.361 A computational study that combines naria was the source of three macrolides 899–901, while a Dic-
the speed of low-level calculations with the accuracy of expen- tyopteris from Oman provided two brominated phthalates 902
sive DFT methods in complicated molecules has used the highly and 903 and a cinnamic acid 904, respectively.374,375 Diterpe-
exible dinoagellate compound belizentrin as a test case. noids are commonly encountered in brown algae. Bifucaria
Assessment of the outputs showed that the commonly used DP4 bifurcata from Ireland was the source of four linear diterpenoids
analysis provided the wrong conclusions regarding the relative 905–908 and extensive DFT and optical methods were used to
conguration of portions of the molecule, while the more rapid establish their relative and absolute congurations.376 Indian
J-DP4 algorithm provided the correct result.362 Marienneine is specimens of Padina and Sargassum provided ve dolabellanes
a blue/green pigment responsible for the green colouration of 909–913 and one xenicane 914 diterpenoid, respectively.377,378
oysters, but whose structure has eluded chemists for over Five new hydroazulene-containing pachydictyol diterpenoids
a century. Produced by the diatom Haslea ostrearia, REDOX 915 and 916–919 were reported from a Chinese Dictyota sp.
studies coupled with Raman spectroscopy have shown that the Complexation with a rhodium auxiliary allowed the absolute
non-toxic oxidised state is responsible for the blue/green colour, conguration to be determined for the parent compound. All
and that the pigment is stable in this form, making mariennine the isolates showed weak to moderate cytotoprotective effects
a stable and food-safe colourant for food applications; its against oxidative stress caused by H2O2 exposure in neuronal-
identity still remains a mystery.363 like PC12 cells.379
3 Green algae
Four new ceramides 888 and 889–891 from Ulva lactuca are
predicted to have antiviral bioactivity based upon in silico
studies,364 while a new brominated biphenyl aldehyde 892 and
an iodinated phenolic aldehyde 893 were reported from a Saudi
Arabian Avrainvillea amadelpha.365
Ten new diterpenoids 920–929, mostly belonging to the
secospatane class, were obtained from a Spanish Rugulopteryx
okamurae,380 while an Australian Cystophora provided a series of
new sterols 930–935.381
A review of the chemistry of the Ochrophyta genus Turbinaria
has been published,382 as has a review of Ochrophyta poly-
phenols as modulators of metabolic disorders.383 Sargahy-
The total synthesis of the thiazole-containing antimicrobial droquinoic acid is a major meroterpenoid component of
peptide pagoamide A isolated from Derbesia sp. has been re- Sargassum serratifolium. A recent study has shown hypothalamic
ported simultaneously by two groups, conrming the structure injection of the acid in mice fed a high fat diet resulted in
assigned.366,367 A review of the use of invasive algal species, weight loss without a change in food intake by elevating ther-
especially chlorophytes, as sources of valuable marine bioac- mogenic signalling pathways via UCP1, therefore the acid has
tives has been published.368 The bioactivity of two related nor- potential as an anti-obesity lead.384 Eleganone, a linear diter-
terpenoids has been reported in different publications. Lolio- penoid found from B. bifurcata, showed moderate reversal of 6-
lide isolated from Codium tomentosum has been found to have hydroxydopamine-induced cellular damage, thereby providing
neuroprotective effects, preventing the 6-hydroxydopamine- a mitochondrial protective effect. This bioactivity was achieved
induced death of neurological cells, by inhibition of oxidative by reducing the downstream effects of oxidative stress and
stress and NF-kB and thereby having a potential role as a ther- inhibiting NF-kB.385 Another diterpenoid, dilkamural, is
apeutic for Parkinson's disease.369 In an alternative application, produced by the invasive brown alga R. okamurae and has
epi-loliolide isolated from Ulva lactuca is a regulator of p53 antifeedant properties that may explain why the alga is not
signalling to control DNA damage and hence could be a photo- predated upon by herbivores within the seaweed's new
protective agent against UV-B.370 A series of unusual lipids with geographical range.386 Fucoxanthin is a common carotenoid
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component of many seaweeds, including the edible Sargassum Two new sesquiterpenoids 952 and 953 were obtained from
horneri. A study has shown that pre-treatment of PC12 neuronal Asian specimens of Laurencia heteroclada and L. tristicha,
cells with fucoxanthin prevented oxidative damage caused by respectively,396,397 while a Red Sea Laurencia was the source of
methamphetamine administration, and regulated Nrf2 trans- ve halogenated diterpenoids and norditerpenoids 954–958.398
location. These ndings suggest fucoxanthin could have a role Bandokorols A 959 and B 960 are polyether-type triterpenoids
as an antidote to methamphetamine toxicity.387 A combination from a Japanese collection of Chondria armata.399
of GNPS-molecular networking and bioassay-guided fraction- Additional oxygenated triterpenoids were obtained from
ation has shown that individual fatty acids isolated from Sac- Laurencia viridis collected from the Canary Islands. Laurokanols
charina latissima and Laminaria digitata are inactive by A–E 961, and 962–965 are unusual spiro-ketal containing tricy-
themselves, but mixtures were synergistically active against the clic triterpenoids, while yucatecone 966 is a biosynthetically
swine helminth parasite Ascaris suum.388 Investigation of the unusual epimer of thysiferol. A comprehensive computational
phlorotannins and pigments of intertidal rock-pool Sargassa- approach was used to investigate the structural rearrangements
ceae algae from Brittany has shown that the smaller, more within the biosynthetic pathway to these molecules.400 Other
dense individuals are located in lower pools but with higher Rhodophyta-derived compounds were also claimed but these
levels of biosynthetic pigments to compensate for protection are inconsistent with the spectroscopic data provided and their
against irradiation, and that phlorotannins did not appear to structures are not shown here.401
play a photoprotective role and their content and distribution is
more reective of taxonomy rather than source location.389 The
factors relating to induction of phlorotannin production are not
well understood. A study of the temporal effects of herbivore
(sea snail Littorina littorea) predation upon Fucus vesiculosus has
shown that tannins have a role as an inducible chemical
defence upon grazing by the snails, and that grazing has
differential temporal effects upon the stress response of the
alga.390
5 Red algae
A Japanese Laurencia yielded two new C15 acetogenins 936 and The total synthesis of three C15 acetogenins from Laurencia,
937,391 while a Soliera was the source of new aromatic polyketide and of diterpenoid glycoside peyssonnoside A, have been ach-
938.392 An ethanolic extract of a Chinese L. tristicha was the ieved.402,403 A review of new Laurencia-derived sesquiterpenoids
source of 4-isopropylbenzaldehyde-containing products, from 2015–2020 has been published,404 as has a review of red
presumably formed by condensation with acetophenone, as algal compounds with potential as anti-acne treatments.405 A
exemplied by 939. The other six compounds 940–945 review of developments in synthetic methodology to produce
comprised three enantiomeric pairs. LC-MS analysis of an the important neuromodulatory compound kainic acid was also
additional methanolic extract of the alga indicated the presence published.406 Two separate reports have identied anti-
of the compounds, suggesting that they are true metabolites of angiogenesis activity for red algal compounds. The edible
the plant and not artefacts of isolation. The presence of three seaweed Laurencia undulata contains large amounts of D-iso-
racemic mixtures within the extract suggests the formation of oridoside that was shown to inhibit HIF-1a, with the down-
these compounds is either from a non-stereoselective enzymatic stream effect of down-regulating VEGF. This makes the alga
production or via non-enzymatic processes.393 a potential anti-tumour functional food.407 Additionally, a tri-
brominated biphenyl ether inhibits matrix metalloproteinase-9
to block cell migration and invasion in models of human
tumours.408
A metabolomics study using IR, GC-MS and NMR spectros-
copy has characterised the fatty acid composition of the edible
alga Solieria pacica, highlighting the signicant presence of
cyclopropanyl and cyclopentenyl lipids.409 Additionally, GC-MS
screening of secondary metabolites coupled with Bray–Curtis
statistical similarity analysis of numerous Plocamium speci-
Four ureido-bromophenols 946–949 were obtained from mens from Antarctica has identied 15 different chemotypes
Rhodomela confervoides,394 while two pyrrolidine alkaloids 950 across six haplotypes. The functional role of the genetic and
and 951 came from Acanthophora spicifera.395 The Rhodophyta metabolic diversity remains to be resolved, but it could explain
are a common reservoir of terpenoid chemistry, with ve
separate accounts of new isoprene-derived metabolites in 2021.
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chemoecological roles for the metabolites in deterring synthesis of homophymamide A was also achieved. During the
herbivory or encroachment.410 analysis of the constituent amino acid absolute congurations
using Marfey's method, racemisation of the terminal Lys
residue during derivatisation has led to a cautionary note for
6 Sponges assignment of peptides that contain a ureido linkage.424
Macrolides 991 and 992 have been reported from Clathria
There was a signicant downturn in reports of sponge-derived vulpina and 993 and 994 from C. procera, although in the latter
compounds in 2021, with a ∼20% drop in new metabolites publication, the authors showed a lack of due diligence and
from phylum Porifera when compared to 2020.1 Two long chain referred to their isolates as procerolides, a name already coined
fatty acid butenolides 967 and 968 were obtained from to describe ascidian-derived hydroxy-butenolides.425,426 Neo-
a Chinese specimen of Hippospongia,411 while a new sphingoid petrosiasins A 995 and B 996 are bis-quinolizidine alkaloids
glycoside 969 was reported from a dredged Oceanapia.412 A from a Neopetrosia,427 while a series of renierate 997–999 and
dredged Cladocroce sp. (245 m, Japan) was the source of renieramycin 1000 alkaloids were sourced from a Vietnamese
sphingosine calyxoside B 970. To elucidate the position of the Haliclona.428
ketone moiety, the authors derivatised the carbonyl as an oxime
Four new 3-alkylpyridinium dimer alkaloids, neo-

and then used a Beckmann rearrangement to generate two petrosidines A–D 1001, 1002–1004 were reported from an
amide isomers and this facilitated LC-MS analysis to specify the Indonesian N. chaliniformis. Although only weakly active against
ketone position along the lipid chain.413 HeLa/Fucci2 uorescently labelled cells, time lapse imaging of
the bioassays to assess the antiproliferative effects of 1001
shows it causes an increase in the cell cycle duration, and that it
inhibits the cellular mitochondrial membrane potential and
hence perturbs cellular bioenergetics.429
Methyl lipid glyceroether 971 and alkylated phenol ether 972

were obtained from Aaptos aaptos and Luffariella variabilis,
respectively.414,415 A linear polyketide 973 was isolated from
a Vietnamese Hippospongia,416 while methylated polyketides
were obtained from a symbiotic consortium of Plakortis sym-
biotica and Xestospongia deweerdtae 974 and 975, and from
Callyspongia diffusa 976 and 977, respectively.417,418 Three new
chromanones 978–980 came from Hyrtios erecta.419 Originally an
ascidian-derived compound, the structure of etzionin 981 has
been revised following its re-isolation along with related dike-
topiperazines clioetzionins A 982 and B 983 from Cliona
celata.420 An unusual fused g-lactam 984 was reported from
Aplysina aerophoba,421 while new hydantoin-containing alka-
loids 985–988 were obtained from Aaptos aaptos and Hemi-
mycale sponges.414,422
Thorectandrin A 989 is a brominated tryptophan-derived
alkaloid isolated from Thorectandra choanoides, collected in
the Great Australian Bight. The sponge extract was selected for
further examination based upon GNPS-based MS screening,
which also revealed a cluster of related metabolites. When
considering the biosynthesis of 989, a putative indoleamine 2,3-
Psammocindoles A–C 1005–1007 were reported from Psam-
dioxygenase (IDO) was suggested as transforming several co-
mocinia vermis,430 while the isolation of amakusamine 1008,
isolated aplysinopsin metabolites into a series of thorectan-
a weak inhibitor of osteoclast formation, from a Psammocinia
drin congeners, including highly reactive Michael acceptors
sponge, was accompanied by its total synthesis.431 A series of
that underwent chemical transformation during extraction to
bis-indole alkaloids 1009–1014 were found from a South Korean
produce various artefacts. This work could lead the way to the
Spongosorites,432 while damirines A 1015 and B 1016 are rear-
use of Thorectandra metabolites as IDO-susceptible pro-drugs
ranged staurosporine-type alkaloids from a Damiria collected in
for in vivo immunotherapeutic applications.423
Thailand;433 the latter compounds should not be confused with
Surprisingly, there was only one report of a new sponge-
the common damirone pyrroloiminoquinone alkaloids
derived peptide in 2021. Homophymamide A 990 was ob-
commonly reported from Latrunculid sponges.
tained from a dredged (200 m) specimen of Homophymia sp.,
A cultured specimen of Tedania anhelans was the source of
collected at Sango-Sone seamount, Japan and showed moderate
racemic spondomine, that was resolved into its dextrorotatory
inhibitory activity against carboxypeptidase B. The total
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1017 and laevorotatory 1018 forms by chiral HPLC. The struc- the isolates, conrming their structures. Two pairs of the
tures of the compounds, including absolute conguration, were metabolites were obtained as non-separable epimeric mixtures
secured by NMR, XRD and computational methods, and were 1034/1035 and 1036/1037 respectively; keto–enol tautomerisa-
supported by a semi-synthesis that provided both the target NPs tion of these pairs in solution led to a mix of all four stereo-
but also four additional stereoisomers. All the semi-synthetic isomers within two days. Several of the isolates showed
compounds exhibited weak to moderate cytotoxicity against moderate to potent inhibitory activity against various bacterial
K562 cells, and in addition signicantly promoted angiogenesis strains, although no clear SAR was observed.442
in a zebrash model. The authors used deuteration experiments
and computational modelling to probe the role of acid catalysis
in the formation of these dimeric compounds.434
Myrindole A 1019 from a Myrmekioderma sp. is a highly
proton-decient bis-indole alkaloid, making its structure
elucidation extremely challenging. The structure of 1019 was
nally secured using a combination of standard 2D-NMR
experiments but ultimately required the use of 1H–15N-HMBC Only one nucleoside, neopetroside C 1041 was reported from
and 1,n-ADEQUATE spectra, and also the use of chiroptical sponges in 2021.443
spectroscopy and chemical reduction. The substitution pattern As always, isoprene-derived isolates are a dominant class of
of the pyrazine ring in myrindole A is unprecedented.435 sponge metabolite. Mero-sesquiterpenoids were reported from
Tedaniophorbasins A 1020 and B 1021 are inherently uo- the genera Hippospongia 1042–1044, Dactylospongia 1045–1048
rescent alkaloids from Tedaniophorbas ceratosis.436 The rst and Dysidea 1049, respectively,416,444–447 while there was only one
thiazide-containing NP, neopetrothiazide 1022 has been re- report of sponge-derived mero-diterpenoids, from Astroclera
ported from Neopetrosia sp. collected from Palau. Given the willeyana 1050–1052.439
highly proton-decient nature of its carbon skeleton, the LR- Several reports of new sesquiterpenoids were published in
HSQMBC experiment optimised to detect four- and ve-bond 2021. New bisabolane-type sesquiterpenoids were obtained
correlations was crucial to elucidate its structure. Neo- from Chinese Halichondria 1053–1060 and Plakortis 1061–1066
petrothiazide is a weak to moderate inhibitor of PAX3-FOXO1- sponges, respectively,448,449 and also from a North Sulawesi
driven luciferase but with only a small therapeutic window Axinella specimen 1067.450 More heavily rearranged sesqui-
given its weak cytotoxicity.437 terpenoids were reported from Persian Ircinia 1068 and Indo-
nesian Lamellodysidea 1069 sponges.451,452 Enantiomeric
(+)-1070 and (−)-1071 spongiterpenes are likely artefacts of
isolation from a Spongia sp. collected in China.453
Surprisingly, very few diterpenoids were reported in 2021. A
new dolabellane 1072 came from a Luffariella sponge,415 while
a dredged Antarctic Dendrilla sponge yielded spongian diter-
penoid 1073 that was inactive in antifouling assays.454 A further
rearranged spongian diterpenoid 1074 was obtained from
a Saudi Arabian Spongia along with several oxidised and linear
sesterterpenoids 1075–1077, respectively.455 Other linear ses-
terterpenoids were obtained from further Luffariella sponges
collected in China 1078–1090, and Japan 1091 and 1092; the
latter study made use of chemical reduction using AD-mix to aid
in structure elucidation.456,457 Two unrelated polycyclic ses-
terterpenoids 1093 and 1094 were isolated from a South Korean
Haliclona sp.458 Scalarane-class sesterterpenoids are particularly
Sponges of the genera Stylissa and Astroclera were the sour- prevalent in sponge extracts. New examples came from Lend-
ces of stylissaol A 1023 and dimer N(1)-methylisoageliferin enfeldia 1095–1101, and Dysidea 1102–1122 sponges,
1024, respectively.438,439 Bromotyrosine-derived alkaloids were respectively.459–461 The structures of additional scalarane
reported from a Greek Aplysina 1025–1028, Vietnamese Ecione- congeners were claimed but are unrealistic based upon
mia acervus 1029 and an Egyptian Pseudoceratina arabica 1030, biosynthetic grounds and are not shown here.462,463
respectively.421,440,441 Bromotyrosines are also commonly Known for over 40 years, arguably one of the most famous
encountered in Suberea sponges. A Solomon Islands Suberea MNPs is manoalide. With hundreds of publications and patents
clavata yielded eight new bromotyrosines, subereins 1–8 1032– on members of this important anti-inammatory sesterterpene
1039 that predicated a structural revision of two known stu- class, there is a strong knowledge base regarding the structural
larin alkaloids 1031 and 1040. Subereins-2 and -3 were sepa- diversity within manoalide terpenoids. Isolation of 10 new
rated using supercritical CO2 chromatography, while chemical manoalides 1123 and 1124–1132 has facilitated their structural
interconversion of known 11-epi-stularin-3 1031 yielded ve of revision, in particular characterising their congurational
relationships. With such a diversity of stereoisomers available,
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SAR studies indicated that the 24R, 25S congeners are the most (7616 extracts) against the barber's pole worm (Haemonchus
potent bioactives in the class.464 contortus) has been published. HTS against this nematode
resulted in 58 hit extracts (∼0.8%) showing >70% inhibitory
activity.498 In a separate study, hexachlorinated dipeptide dysi-
denin (Citronia sp.) inhibits the motility and morphology of H.
contortus.499 A MOA study of madangamine A has shown it exerts
its anti-proliferative effects by increasing the concentration of
LC3-II and p62 autophagic proteins, resulting in increased
lysozyme size and pH in a manner similar to chloroquine,
New pregnane sterols 1133–1136 were reported from a Pal- making this a lead structure towards treatments for lysozymal
auan Epipolasis.465 Other sterols were obtained from Dysidea disorders.500 Three sponge-derived merosesquiterpenoids
1137–1144, Xestospongia 1145, Halichondria 1146–1148, and (smenospongine, ilimaquinone, dactylospontriol) have been
Echinoclathria 1149 sponges,465–469 while a new theonellasterol found to induce mitochondrial apoptosis, and also show
1150 extends the membership of the 4-methylidene class of activity in ex vivo models of colorectal cancer.501 Furospinulosin-
1 is not considered cytotoxic in its own right (IC50 > 100 mM), yet
sterol commonly found from genus Theonella.470 An unusual

spiro-sterol 1151 was also reported.415 New stellettin 1152–1157 it induced apoptosis of spheroid MDA-MB-231 TNBC cells
and rhabdastin 1158 and 1159 triterpenoids came from Stelletta exposed for 24 or 48 h, but had no activity in standard 2D-
and Rhabdastrella sponges, respectively.471,472 A Negombata adherent assays run for longer (72 h) time periods. Use of
sponge yielded nor-triterpenoid 1160; other structures were a reversed phase protein assay veried the differential effect
claimed but are inconsistent with the spectroscopic data against spheroid cells vs. standard models.502
provided and are not shown here.473 A series of nor- Reviews of MNPs from Indonesia and Tonga have focussed
tetraterpenoids 1161–1164 were isolated from a Vietnamese predominately upon sponge-derived compounds.503,504 The
Clathria.474 chemistry of the sponge family Hymedesmiidae,505 and the
The rst total synthesis of various plakorsin and ancorino- genera Callyspongia,506 Latrunculia,507 Petrosia,508 Phorbas,509 and
side lipids have been reported,475,476 as has the synthesis of Reniera,510 has been reviewed. Sponge alkaloids, primarily those
polyketide peroxides muqubilin and several negombatoper- with cytotoxic activity, that were published between 1987–2020
oxides.477 The total synthesis of geodiamolide H has been ach- have been reviewed,511 as have sponge-derived compounds with
ieved,478 while the production of four potential stereoisomers antimalarial/antiprotozoal activity.512 Reviews of sponge-derived
has called for the structural revision of characellide B, although terpenoid endo-peroxide compounds, and of (iso)malabaricane
no alternative structure was proposed.479 The structure of tau- triterpenoids, respectively, have been published.513,514 A review
mycin A 1165 has been revised following its synthesis.480 has summarised the use of sponge- and sponge symbiont-
Although its total synthesis has been accomplished numerous derived compounds for cosmetic applications.515
times, a new synthetic approach to produce halichondrin B A critical review examining the relationships between sponge
utilises a reverse strategy to form the cyclic ethers, shortening taxonomy, metabolite distribution, geographical location has
the overall synthetic route.481 Two different reports from the corroborated a number of suggested chemotaxonomic rela-
same authors have called into question the structures proposed tionships, with several classes of metabolite and taxa showing
for aaptolines A and B, but no alternatives have been a strong correlative relationship. Moreover, the conserved
provided.482,483 The structure of njaoamine I has been revised to metabolite diversity within various taxa, including under-
1166 following its synthesis using a ring closing alkyne studied species, suggests the latter could be important reser-
metathesis reaction.484 Two separate groups have reported the voirs of untapped chemical diversity.516
total synthesis of various oxo-aplysinopsin alkaloids.485,486 Other A comprehensive examination of Verongiid chemistry in the
compounds that have been synthesised include hyrtioserag- period 1960–2020 has also explored metabolite diversity.
amine A,487 7-hydroxylamellarin A,488 and ma'edamines C and Geographic and calculated physico-chemical properties were
D.489 Three Dysidea-derived merosesquiterpenoids have been assigned to all structures, and a meta-analysis of these used to
synthesised,490 while three groups have independently revised characterise groupings within the metabolite distribution.
the structure of dysiherbol A to 1167; the latter two groups also Links were made using statistical tools (for example bipartite
report the total synthesis of dysideanone B.491–493 The structure network analyses, similarity networks) between compounds of
of halioxepine 1168 has also been revised following its similar structure to link with predicted pharmacokinetic prop-
synthesis,494 while the structures of diterpenoid metabolites erties. This work sets a platform for similar investigations in the
cyclobutastellettolide B and hamigeran M have been conrmed future, as well as highlighting the importance of statistical
following their rst total syntheses.495,496 Poly-chlorinated methods in MNP research.517
steroids clionastatins A 1169 and B 1170 have been produced The fatty acid proles of ve North Atlantic deep sea marine
synthetically for the rst time, leading to their structure sponges (order Tetractinellida), that are considered to have high
revision.497 symbiotic microbial abundances, have been examined. Bacte-
A protocol to prioritise anthelmintic samples from the rial fatty acid biomarkers dominated the proles. Detailed
Australian NatureBank marine invertebrate extract collection analysis of the fatty acid proles and 13C isotopic composition
suggests that fatty acid proling can be used to
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chemotaxonomically distinguish deep sea sponge species, and hosts, even in sponges with low microbial abundances. More-
that the sponges acquire fatty acid precursors from their over, geographically, and phylogenetically distinctive sponges
symbiont microbiomes.518 A separate study of one Caribbean harboured similar bromotyrosine alkaloid compositions, irre-
Scopalinid and ve Axinellid sponge phospholipids has sug- spective of the microbial communities they contain. This
gested minimal seasonal variation. Hierarchical cluster analysis nding appears to be independent of the tight correlation
of the data indicated that fatty acid composition is descriptive between the sponge microbiome and metabolome, hinting at
of species but did not provide insight at the family or order a deeper relationship within the invertebrate holobiont.525
levels; brominated fatty acids were a common subclass
detected.519
A large study of 43 individual Latrunculid sponges has 7 Cnidarians
assessed variability of pyrroloiminoquinone metabolites, an
important and commonly encountered class of MNP from this S8 was isolated from a Taiwanese collection of Sinularia humilis
family, with distinctive species-dependent proles across over and the structure conrmed by XRD.526 A number of simple
200 individually detected metabolites.520 A MS-based protocol lipids and quinonoid MNPs were reported from cnidarians
including dendronephthyones A–C 1171–1173 isolated from
for discovery of proline-rich cyclic peptides has been described.

The method utilises a biomimetic enzymatic synthesis to a Vietnamese collection of Dendronephthya mucronata,527
provide standards for the analysis, showing that proline-rich a simple epoxy-derivative of exibilisquinone 1174 from
peptides are much more common in marine sponges than southern Taiwan specimens of Sinularia scabra,528 the related
isolation studies would suggest.521 The abundance of arginine hydroquinone sarcotenuhydroquinone 1175 from Sarcophyton
and the non-proteinogenic amino acid homoarginine, tenuispiculatum (cultured specimens),529 and a series of terpe-
including its enantiomeric excess, have been examined in four noid amide derivatives of spermidine and spermine sinular-
sponge species using stable isotopic dilution methodology. The amide A–G 1176, 1177, 1178 and 1179–1182 isolated from
concentration of homoarginine, which was found to be exclu- Sinularia sp.530 Sinularamide C exhibited weak inhibition of
sively L-congured, can in fact exceed that of L-arginine in some casitas B-lineage lymphoma proto-oncogene B with a potential
species of sponge. The role of this amino acid in sponge hol- role of enhancing the adaptive and innate immune system with
obiont biosynthesis remains a mystery.522 GC analysis of implications for antitumour immunotherapies. Three
extracts of the Caribbean sponge Hyrtios proteus with multiple compounds reported from the marine environment for the rst
detector types has shown that naturally occurring brominated time, puried from extracts of Sarcophyton trocheliophorum,
polyphenolics, including para-dioxins, are more abundant than include a known leachate from plastic pipes 1183, a phenol
brominated persistent organic pollutants. Comparative analysis previously reported from terrestrial plants 1184 and the wax
using the octopus Octopus maya, that is a possible human food 1185.531 The structure has been conrmed and absolute
source, as a model predator showed the sponge contained ∼30 conguration established for the meroterpenoid chabrolo-
times more of the natural brominated compounds than the naphthoquinone B 1186 via total synthesis that used a chiral
pollutants. This study highlighted the role marine animals may pool approach.532 Investigation of the seasonal variation of fatty
have in biomagnication of halogenated compounds in the acids in Vietnamese tropical specimens of Sinularia exibilis
trophic chain.523 identied no variation in poly-unsaturated fatty acid (PUFA)
A study has compared the geographic and phylogenetic content, consistent with their role as a structural factor of coral
distribution of a cryptic Ribosomally synthesised and Post- cell membranes, while saturated fatty acid content increased
translationally modied Peptide (RiPP) halogenating enzyme during the summer months, attributed to energy storage
in widespread sponge metagenomes across the Pacic and lipids.533 The species contains zooxanthellae symbionts – the
Atlantic oceans. More than 50 copies of BGCs encoding for RiPP observation of no clear relationship between PUFA content and
halogenases across multiple bacterial taxa were detected in light intensity showed there was no contribution from the
various sponge holobionts, highlighting the cosmopolitan symbiont to the seasonal increase in fatty acid content.
nature of the BGC, which is at odds with the cryptic nature of Sesquiterpenes reported from cnidarians in 2021 included
the halogenated RiPPs they would produce. The BCGs were calamusins J 1187 and K 1188, isolated from Sarcophyton
found in all sponge samples with highly diverse microbiomes glaucum collected in the Red Sea,534 a polycyclic mer-
but were absent from other less microbially diverse invertebrate osesquiterpenoid 1189 and six asteriscanes 1190–1195, from
hosts. This study therefore highlights the conservation of MNP Sinularia humesi (Ximao Island, China),535 new examples of
biosynthetic potential across large geographical areas and sesquiterpenes containing nardosinane or rearranged nardosi-
symbiotic producers.524 nane skeletons 1196–1204 from Xisha Island collections of
In a separate multi-omics study, the distribution of bromo- Lemnalia sp.,536 and linardosinenes D–G 1205–1208 from Lito-
tyrosine alkaloids from phylogenetically distant sponges phyton nigrum,537 neolemnanes 1209 and 1210 from Paral-
collected from the Indo-Pacic (Guam, Solomon Islands) and emnalia thyrsoides,538 and 1211–1215 from Lemnalia sp.,539,540 an
Atlantic (Florida Keys, Puerto Rico) was examined. A statistically aristolane 1216 from Lemnalia sp.,540 three cadinene-type 1217–
robust correlation between metabolome and microbiome 1219 and a eudesmane-type 1220 from Cespitularia sp.541 and
across the sponge specimens was detected, suggesting the key two rearranged cardinane-type sesquiterpenes 1221 and 1222,
role microbes play in dening the metabolic diversity of their isolated from Sinularia brassica.542 The absolute congurations
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of shagenes A 1223 and B 1224 were established following earlier, a Taiwanese collection of Cespitularia sp. also afforded
asymmetric synthesis of what were enantiomers of the MNPs.543 verticillane-type diterpenes 1268–1275, amide 1276 and three
An asymmetric total synthesis of the clovane sesquiterpene norditerpenes 1277–1279.541 Semisynthetic modication of
rumphellclovane E has also been reported.544 Of a large set of dolabellatrienone and a related dolabellane diterpene from
sesquiterpenes isolated from a Canary Islands collection of Eunicea sp. identied analogues with weak to moderate antiviral
Palythoa aff. clavata, none exhibited activity against amoeba activity towards Zika and Chikungunya virus'.554 Virucidal
(IC50 > 10 mM)545 while some exhibited weak activity, with effects were observed for the most active compounds. A diverse
modest selectivity indices, towards Leishmania spp. and Trypa- set of cembranoids, rearranged cembranoids and biscem-
nosoma cruzi.546 As with each year, the dominant number of branoids were reported from Lobophytum, Sinularia and Sar-
metabolites reported from cnidarians are diterpenoids. Bebry- cophyton species of so corals in 2021. Lobophytum crassum was
cin A 1225, sourced from Bebryce grandis, was identied as the source of lobocrassin I 1280 (Southern Taiwan)555 while
a weakly active (IC50 1.1 mM) growth inhibitor of P. falciparum Ximao Island, South China Sea was the site of collection that led
Dd2 strain, blocking parasite maturation at the schizont life to the isolation of a further nine new cembranoids 1281–1289
stage.547 and a set of known related metabolites including durumolide J
1290, lobolide A 1291, and 20-acetylsinularolide C 1292 and
lobocrasol 1293.556,557 XRD played a role in securing the absolute

conguration of the new 1280 and known (durumolide J and
lobolide A) cembranoids while that of 20-acetylsinularolide C
was reassigned based upon Mosher's method of analysis. In the
case of lobocrasol, XRD allowed for correction of conguration
of four stereogenic centres.
Specimens of Sinularia siaesensis (Ximao Island, South China

Sea) afforded the cembranoid-related norditerpene sinus-
iaetone A 1294 and polyoxygenated cembranoids 1295 and
1296.558 XRD was used to establish absolute conguration of
1294 and 1295 while Mosher's method was used to assign that
of 1296 and the previously reported MNP exibilisin C 1297. The
Of six new examples of diterpene glycosides 1226–1231 iso-
structures of humilisins A–F 1298–1303, isolated from speci-
lated from Lemnalia bournei, the former two compounds
mens of S. humilis collected from Ximao Island, South China
exhibited weak antibacterial activity towards S. aureus and
Sea, encompass cembranoids and rearranged cembranoids.559
Bacillus subtilis.548 Several groups reported new examples of
It is interesting to note that the structure of (+)-humilisin A
casbane- or cabane-related diterpenoids, including sinucrassins
reported from this so coral is the dextrorotatory antipode of
A–K 1232–1242 isolated from Sinularia crassa,549 sinuereper-
the metabolite noted earlier [(−)-humilisin A, 1286] isolated
oxides B 1243 and C 1244, 5-deoxy-10-oxo-11,12-dihy-
from a Ximao Island collection of Lobophytum crassum.557 So
drodepressin 1245 and sinueracasbanones A–D 1246–1249 from
corals of the genus Sinularia were also the sources of cem-
S. erecta,550 and two sets of casbane-related and casbane-
branoid querciformolide F 1304, isolated from S. querciformis,560
diterpenoids from S. nanolobata (1250–1252),551 and S. erecta
and norcembranoid sinulariadiolide B 1305, from S. multi-
(1253–1255), respectively.552 XRD was used to characterise the
ora.561 Although evaluated in a wide range of anti-
structures and assign absolute conguration of a number of
inammatory, antimicrobial and antitumour bioassays,
these new MNPs (1243–1255) as well as the previously reported
almost all of the cembranoid and biscembranoid MNPs isolated
casbane 10-oxo-11,12-dihydrodepressin 1256.552 Five rearranged
from Sarcophyton genus so corals in 2021 (sarcotenusenes A–
serrulatane diterpenes, litosetoenins A–E 1257–1261, isolated
C, 1306–1308, from specimens of cultured S. tenuispiculatum;529
from Litophyton setoensis feature an unusual tricyclo[3.0.4]
cherbonolides M 1309 and N 1310, from a Taiwanese collection
decane core.553 Of six new diterpenes isolated from Xisha Island
of S. cherbonnieri;562 sarcoconvolutums A–E, 1311–1315, from
specimens of Lemnalia sp., including four decalins bio-
Red Sea specimens of S. convolutum;563 ximaoglaucumins A–F,
oranates A–D 1262–1265, a serrulatane given the trivial name
1316–1321, from a South China Sea collection of S. glaucum;564
euplexaurene D 1266 and an aromadendrane-type named
ximaosarcophytols A 1322 and B 1323, from S. trocheliopho-
cneorubin K 1267; 1262–1267 were weakly antibacterial while
rum;565 diterpenes 1324–1328 and an unusual cyclobutene
1266 was inactive.540 In addition to four sesquiterpenes noted
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biscembranoid 1329, from Taiwanese samples S. tortuosum;566 28 new examples of briaranes, gemmolides A–Z2 1355–1382,
ximaolides H–L, 1330–1334, from Yalong Bay, Hainan-sourced some of which were weakly active in the bioassay or exhibited
specimens of S. tortuosum567) were considered inactive using cytotoxicity to bone marrow macrophages.584 Known metabolite
this review's criteria (ESI‡). Weak cytotoxicity and inhibition of junceellolide D was found to be the most active compound
release of superoxide anion and elastase from stimulated (although still classied as a weak inhibitor) in the extract. A
neutrophils was observed for 1329. The investigation of S. large set of eunicellin diterpenoids klyaccilins B–T 1383–1401
glaucum564 also led to the isolation and characterisation of were isolated from a Ximao Island collection of Klyxum acci-
a previously reported568 cembranoid sarcophytolol, the struc- dum, with structure and absolute conguration of B, C, F, O and
ture of which was corrected to 1335. Further investigation of the S (the latter reported as a NP for the rst time) being secured by
literature for related compounds led to the conclusion that the XRD analysis.585 The eunicellin multioralin 1402, a co-
two previously reported structures of sarcotrocheliol (originally metabolite with a cembranoid noted earlier, and known euni-
isolated in 2015 from S. trocheliophorum569 and “corrected” in cellin sclerophytin E both inhibited barnacle cyprid settlement
2019 using XRD570) were in fact incorrect and are represented by in vitro.561 Taiwanese collections of Asterospicularia laurae yiel-
1335. Stunningly, examination of the XRD cif le used to ded examples of xenicane diterpenes asterolaurins N–R 1403–
“correct” the structure in 2019 clearly shows the structure of 1407, none of which exhibited cytotoxicity towards a panel of
“sarcotrocheliol” to be 1335, representing a sad indictment on HTCLs.586,587 In addition to a weakly cytotoxic xenicane, xenio-
the lack of rigour by the authors and the journal peer review lide O 1408, a new gorgostane derivative 1409 was characterised
process. from an extract of the Red Sea so coral Xenia umbellata.588 Of
a further 13 sterols reported in 2021, including ehrensteroids
A–F 1410–1415 from a Vietnamese collection of Sarcophyton
ehrenbergi,589 cholestane 1416 from cultured specimens of
Sinularia sandensis,590 secosterols verrucellols A–D 1417–1420
from Verrucella umbraculum (Yongxing Islands),591 gorgostane
1421 and ergostane 1422 from Red Sea collections of Hetero-
xenia fuscescens592 and 1423 and 1424 from Sinularia brassica
(Vietnam),542 only verrucellols A–C exhibited biological activity,
Further examination of the biological activities of puried being weakly active as immunosuppressive agents. A
so coral-derived cembranoids has identied antioxidant and biosynthesis-inspired synthesis of pinnigorgiols B and E has
cytotoxic properties of sinularin,571–573 that 5-epi-sinuleptolide is been reported, with the methodology incorporating an elegant
antiproliferative towards pancreatic tumour cells inducing acyl radical cyclisation/hemiketalisation cascade that formed
apoptosis and cell cycle arrest574 and that crassolide, in models two rings and three contiguous stereogenic centres in one
related to the autoimmune disease antiphospholipid syndrome, step.593
can suppress dendritic cell maturation and downstream T cell Genome mining of the branching stony coral Acropora mil-
responses.575 Four new examples of briarane-type diterpenoids, lepora identied a predicted protein sequence AmAMP1 that
2-butyryloxybriarane B-3 1336, 9-acetylbriarenolide S 1337, shared some resemblance to known coral and jellysh antimi-
briarenolide W 1338 and 12-isobriarenolide P 1339, were iso- crobial peptides and for which homologues could be identied
lated from a Yucatan Peninsula collection of Briareum asbesti- in a range of other corals.594 The mature peptide contains six
num.576 In addition, the previously reported MNP briarane B-3 cysteine residues making it related to the Shk group of sea
was also isolated, with the authors using a combination of anemone neurotoxins. Synthesised peptides derived from the
VCD, which is the rst reported use of this technique to study protein sequence demonstrated activity towards both Gram-
this class of NP, and XRD to provide further conrmation of the positive and Gram-negative bacteria. The discovery, develop-
absolute conguration recently determined using 1H NMR ment, and utilisation of sea anemone neurotoxins in general,595
residual chemical shi anisotropy.577 Collections of B. stechei and specically regarding sticholysin toxins,596 have been
(synonymous with B. excavatum) afforded a range of reviewed. Sticholysin II, and likely also its isoform sticholysin I,
structurally-related diterpenes including briarenols L 1340 (Ie induce maturation of dendritic cells through a toll-like receptor
Island),578 O 1341, P 1342 (aquaculture),579 U 1343, V 1344 (Ie 4/myeloid differentiation primary response gene 88-dependent
island),580 W 1345, X 1346, Y 1347 and Z 1348 (aquaculture)581 pathway,597 and that sticholysin II shares similar abilities to act
and briastecholides A–C 1349–1351 (Ie Island).582,583 A large as an immunostimulant to those of the evolutionarily distinct
number of known briaranes were also isolated during these pore-forming peptide listeriolysin O (bacteria Listeria mono-
studies – of note were the assignment of absolute conguration cytogenes).598 Kunitz-type peptides from the sea anemone
to briarenol G 1352 and solenolide C 1353 using XRD578,582 and Heteractis crispa protect neuronal cells from the toxic effects of
the reassignment of the structure of solenolide B 1354 to now 6-hydroxydopamine.599 The search for new insulin-like peptides
incorporate a b-oriented 12-acetoxy group.580 Biological has identied the tentacles of the sea anemone Oulactis sp. as
screening for inhibitors of receptor activator of NF-kB ligand a new source.600 A peptide, synthesised based upon the tentacle
(RANKL)-induced osteoclast differentiation, in combination transcriptome, did not bind to insulin or insulin-like growth
with GNPS molecular networking, led to the characterisation of factor receptors but did show weak activity towards voltage-
gated potassium and sodium channels. A systematic search of
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published genomes and transcriptomes of cnidarians for making use of Matteson homologation methodology, has
homologues of the blue protein rpulFKz1, originally described afforded the MNP and a small set of related analogues, some of
from the jellysh Rhizostoma pulmo, has identied a family of which exhibit weak cytotoxicity towards the HCT-116 cell line.610
pigment precursors called the rhizostomins specically associ- Reviews describing SAR studies of aplyronine A,611 dolastatin
ated with jellysh in the order Rhizostomeae.601 Not all 10,612 and cyclodepsipeptides of the aurilide family613 were
precursors were associated with blue pigmented organisms, published in 2021. Investigation of the chemical diversity of the
suggesting that the proteins may be responsible for other Australian nudibranch Ardeadoris rubroannulata afforded,
colours, possibly by modication of the protein/chromophore, amongst others, the 9Z 1429 and 9E 1430 isomers, facilitating
or that they confer photoprotection or act in other, as yet correction of the previously proposed structure of pu'ulenal to
unknown roles. that of the 9Z isomer and assignment of the 9E isomer as the
new MNP isopu'ulenal.614 Spongian-15-one diterpene 1431 was
reported from a South China Sea collection of the nudibranch
8 Bryozoans Glossodoris atromarginata, with the study also establishing the
The synthesis of the C-1–C-16 fragment of bryostatins with 4- absolute conguration of the previously reported diterpene
1432.615 Both compounds were isolated from mantle tissue of
methoxybenzyl protection at the 7-hydroxyl group has been

achieved as a starting point for the synthesis of simplied the nudibranch. A total of 11 new spongian-16-one diterpenes
analogues (bryologues), particularly a diuorinated analogue.602 were reported from Australian collections of Goniobranchus
The antimicrobial activity of several of the brominated indole aureopurpureus 1433–1437 and Goniobranchus sp. 1438–1443.616
alkaloids securamines has been assessed and they were shown The absolute congurations of both 1433 and 1436 were
to be selective inhibitors of Gram-positive strains with secur- secured by XRD analysis. In all cases, the diterpenes were iso-
amines E and I displaying weak inhibition of two and three lated exclusively from mantle tissue of the nudibranchs. A series
strains respectively, whilst securamine H exhibited moderate of polymeric MNPs, molleamines A–E 1444–1448 were isolated
inhibition of four strains.603 A review of the four total syntheses from the Pleurobranch mollusc Pleurobranchus forskalii.617
of hinckdentine A has been published604 and a new application Molleamine C was identied as being capable of blocking
of diffusion ordered NMR spectroscopy (DOSY) for molecular acetylcholine-induced calcium inux while electrophysiology
weight determination of NPs used the recently discovered experiments determined it to be a weak partial antagonist of
alkaloids convolutamines K and L in comparsion to volutamine a3b4 and a6/a3b4 nAChR's. A Brazilian collection of the nudi-
F to illustrate the utility of the methodology.605 branch Roboastra ernesti was the source of tambjamines M–O
1449–1451, identied during a metabolomics-driven MS/MS
study with the structures conrmed by synthesis.618 A side-
9 Molluscs chain desacetyl analogue of the sesquiterpene ansellone A
(nudibranch Cadlina luteomarginata) exhibits activity in an HIV
Three sesquiterpenes, aplydactylonins A–C 1425, 1426 and 1427 latency-reversing agent assay with similar potency to the NP
were isolated from the sea hare Aplysia dactylomela, with the while methylether or des-oxy analogues were devoid of
structure and absolute conguration of aplydactylonin A activity.619 The NP chemistry of shell-less molluscs of the genus
secured by XRD analysis.606 Aplydactylonin B was weakly cyto- Onchidium, covering 1978 to 2020, has been reviewed.620 The
toxic, inducing cell death via both apoptosis and necrosis. The muricid gastropod Chicoreus ramosus was the source of benzo-
structure of (+)-srilankenyne 1428, previously reported from chromenone 1452,621 while cuttlesh Sepia pharaonis afforded
Aplysia oculifera, was conrmed, and the absolute conguration spiropharanone 1453,622 the octopus Cistopus indicus yielded
assigned by asymmetric total synthesis.607 the unusual bislactones cistobislactones A 1454 and B 1455,623
and terpenoids 1456–1458 were isolated from the squid Uro-
teuthis duvaucelli.624 Two new saxitoxin analogues, M5-
hemiaminal 1459 and M6-hemiaminal 1460, were isolated as
likely metabolites of paralytic shellsh toxins from the scallop
Patinopecten yessoensis.625
Synthesis of the proposed structures of bathymodiolamides
An elegant stereoselective synthesis, using a one-pot three- A and B, originally isolated from the deep-sea hydrothermal
component bisaldol coupling to set the absolute conguration vent mussel Bathymodiolus thermophilus, gave products that
of seven stereocentres, has afforded a contiguous precursor that exhibited discrepancies in NMR data and in vitro cytotoxicity
undergoes retro-Claisen fragmentation to afford dolabriferol C proles.626
(seahare, Dolabrifera dolabrifera) under mild conditions.608 The The seasonal and location variations of levels of cyclic imine
ease of formation of the MNP from the precursor suggests the toxins in northern Adriatic Sea mussels, oysters, scallops and
isolated metabolite could be an artefact. Further investigation edible ascidians,627 gymnodimine A in Spanish molluscs,628
of the SAR of the Aplysia kurodai MNP aplyronine A has identi- lipophilic toxins in shellsh from SE China,629 and Southern
ed that analogues of just the side-chain are themselves actin Gulf of California,630 and okadaic acids and pectenotoxin-2
depolymerisers and that biotin-tagged examples bind to toxins and associated algal species in a lagoon in Sardinia,631
actin.609 A new route to doliculide (Dolabella auricularia), have been reported. The distribution of other mollusc/bivalve
View Article Online
related toxins including tetrodotoxin in shellsh in southern Li504 1468 and Li520 1469, the sequence and molecular
England,632 and Central and Northern Adriatic Sea,633,634 and modelling of which identied similarity with the active site
domoic acid in mussels (Turkey),635 and bivalves (NW Spain),636 motif of disulde-associated oxidoreductases.649 The latter
have also been described. Brevetoxins have been reported in peptide was able to assist the oxidative folding of a-conotoxin
French Mediterranean mussels for the rst time.637 Further ImI, affording improved yield of the natively folded protein.
biological investigation of puried toxins have identied that
pinnatoxin G cytotoxicity is mediated via its interaction with
nAChR's,638 that 3D imaging can be used to reveal that 3H-
labeled pinnatoxin G reaches the brain and crosses the
placental barrier in rat embryo and human perfused cotyledon
models,639 and that okadaic acid-induced changes to the insect
alimentary canal resembles those observed in rodent models
and makes the insect more susceptible to bacterial infection.640
The complete genome assembly of C. betulinus has been re-

ported, identifying 133 conopeptide genes.650 Biological inves-
tigation of a4/7-conotoxin Bt1.8, identied in the transcripts of
C. betulinus, identied it as a selective potent inhibitor of both
rat and human a3b2b3 and a3b2 nAChR's.651 Homology
Investigation of the levels of endocannabinoids e.g. N- modelling combined with free-energy perturbation has been
arachidonoyl ethanolamine and 2-arachidonoyl glycerol in the used to classify nAChR selective a4/7-conotoxin LvIA mutants,
green mussel Perna viridis has found the latter to be present in suggesting it outperforms the more commonly used molecular
higher levels in unattached mussel and that exposure to mechanics-generalised born/surface area method as a tech-
synthetic lipid reversibly inhibited attachment.641 Dietary nique to predict potency- and selectivity-enhancing mutations
competition for eicosapentaenoic acid (EPA)-producing dia- of a-conotoxins.652 Investigation of engineered variants of a-
toms between the cultivated Pacic Oyster Crassostrea gigas and conotoxin LvIB identied the inuence of residues Gln141,
fouling Mytilus galloprovincialis was used to explain the obser- Asn184 and Lys186 on a7 nAChR species selectivity.653 Xylene-
vation of a negative relationship between EPA and docosahex- linked cysteine [2,4] modied analogues of a-conotoxin TxIB
aenoic acid content in the oysters and the presence of fouling have enhanced serum stability and show selectivity towards a6/
organisms.642 The metabolite prole of the purple colour of a3b2b3 nAChR's654 while an alkyne variant, replacing cysteine
oyster (C. gigas) shell includes xanthurenic acid, porphyrins and [1,3], of a-conotoxin Vc1.1 failed to inhibit a7 and ha9a10
high molecular weight acid-soluble pigments, the latter of nAChR's but was a GABAB R selective agonist and also reversed
which have characteristics of ommochrome natural mechanical allodynia in vivo.655 a-Conotoxins promote the
pigments.643 proliferation of C6 glioma cells in vitro.656 Synthesised 3/4- and
Relevant reviews of the chemistry of Conus molluscs pub- 3/6-, but not 3/7-, loop-size variants of a-conotoxins GI and MI
lished in 2021 include coverage of non-peptidic small mole- are potent inhibitors of muscular nAChR's.657 Both the a4/7-
cules,644 a review of 60 examples of post-translationally modied conotoxin CIC (venom of C. catus) and an N-terminus trun-
conopeptides,645 and a review of the medicinal chemistry of a- cated mutant selectively inhibit a3b2 and a6/a3b2b3 nAChR,
conotoxins that antagonise the a9a10 nAChR.646 suggesting the N-terminal tail can accommodate structural
The venom of the worm-hunting cone snail Conus imperialis changes without any effect on observed receptor activity.658 a4/7-
contained new MNPs conazoliums A 1461 and B 1462 and Conotoxin LvIF, a 16-residue synthesised peptide based upon
known genuanine, with the former and latter NPs found to act genomic DNA clone data derived from C. lividis also exhibits
as pheromone mimics of sexually mature mating polychaete potent inhibition of ra3b2 and ra6/a3b2b3 nAChR's.659 The 17-
worms.647 Metabolomics identied deep-water specimens (−150 residue peptide a4/7-conotoxin Lv1d (C. lividis) demonstrates in
to −210 m) to contain the three described MNPs, while shal- vivo analgesic effects.660 A crystal structure of a4/7-conotoxin
lower water specimens (−30 to −60 m) did not. Conazolium A OmIA (C. omaria) with Lymnae stagnalis acetylcholine binding
was only weakly active as an nAChR antagonist. protein, at 2.47 Å resolution, has identied principal interac-
Conosteroids A–E 1463–1467 were isolated from the hypo- tions between His5 and Ala7 of the conotoxin with C-loop
branchial gland of C. geographus.648 All compounds exhibited residues Tyr185–Tyr192 and the conotoxin disulde and
diverse effects on mouse root ganglion cells in cell-based high- Cys188–Cys189.661 A 26-residue conotoxin belonging to the A-
content screening – further exploration of a synthetic analogue superfamily, identied from a cDNA library of C. striatus,
identied it as a negative allosteric modulator of GABAA R with exhibits in vivo analgesic activity,662 while synthetic cal14.2b
in vivo activities. Genome mining of C. lividus and subsequent (Californiconus californicus) exhibited insulinotropic activities in
peptide synthesis afforded two tetrapeptide mature peptides
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vitro and in vivo suggesting potential roles in the treatment of Glycosylated derivatives of lamellarin D generally exhibit potent
Type 2 diabetes.663 u-Conotoxins characteristically inhibit N- cytotoxicity towards HTCLs and inhibition of the catalytic
type voltage-gated calcium channels and in the specic case of function of topoisomerase I, though it was found the level of
u-conotoxin MVIIA, have application in the treatment of biological activity was dependent upon the monosaccharide
neuropathic pain. A new example, u-conotoxin Bu8 (C. bullatus) used, its position on the alkaloid scaffold and the degree of
is twice as active in vitro as MVIIA, is potently active in in vivo glycosylation.679 The biological data determined for some of the
models and based upon NMR structure analysis and SAR of derivatives identied a disconnect in cytotoxicity vs. enzyme
mutants and Bu8/MVIIA hybrids, exhibits a different target inhibition, suggestive of the presence of other targets/MOA.
binding mode vs. MVIIA.664 Local administration of u-con- Conformational and cytotoxicity evaluation of a small set of
otoxins MVIIA and GVIA has identied activity against post- ascidiacyclamide analogues that vary in amino acid residues at
surgical pain and oxaliplatin-induced neuropathy in in vivo positions 1 and 5 has identied that the use of the non-
testing while neither exhibited activity in a cisplatin-induced proteogenic tert-leucine residue at position 5 locks the peptide
neuropathy model.665 u-Conotoxin CVIF was inactive in these in to a square form, as opposed to a folded, conformation.680 In
pain models. The 3D structure of the I superfamily conotoxin some cases, the square form peptides exhibited mildly
GXIA, originally isolated from C. geographus venom, has been enhanced cytotoxicity. The invasive fouling ascidian Ascidiella
investigated by NMR, identifying a triple stranded b-sheet aspersa contains the previously reported MNP 3,7,11,15-
structure reminiscent of tarantula toxins.666 Conantokins are g- tetramethyl-hexadecan-1,19-disulfate that was found to exhibit
carboxyglutamate-rich peptides that antagonise the N-methyl-D- hemolytic activity towards sheep erythrocytes and was toxic to
asparate receptor, with potential roles in overcoming opiate scallops.681 Of a set of ve ascidian-derived meroterpenoids
dependence. A conantokin-T variant, con-T[M8Q] exhibits (epiconicol, cordiachromene A, didehydroconicol, methox-
potent activity in mouse models of morphine-dependence.667 yconidiol, conidione), epiconicol was identied as being of
most interest as a potential antifouling agent, inhibiting
Amphibalanus amphitrite larval settlement at 10 mg mL−1
10 Tunicates (ascidians) without any attendant mortality to the cyprids.682 Further
Five bicyclic carboxylic acids, 1470–1474, were isolated from investigation of the biological effects of known ascidian MNPs
a South Korean Sea collection of the ascidian Didemnum sp.668 has identied plakinidine D and 3,5-diiodo-4-
Compounds 1471 and 1473 are stereoisomers of previously re- methoxyphenethylamine to be weak inhibitors of colony
ported aplidic acids. Of note was the nding that 1473 and 1474 formation of Chinese hamster V79 cells,683 with other studies
embody a bicyclic core of opposite absolute conguration to the identifying the latter phenethylamine analogue to also be
other co-metabolites. Weak antibacterial activity against S. capable of blocking several potassium channels.684 Pyrimidine
aureus was observed for 1471. Known MNP rubrolide A exhibi- substituted variants of meridianin C were less active than the
ted weak antibacterial activity towards Gram-positive bacteria, MNP at inhibiting GSK-3b but were more active in improving
whereas new hydrated analogues rubrolides V 1475 and W 1476 glucose uptake implying the presence of other signalling
were devoid of activity.669 Both wakayin and the 16-hydroxy-17- protein targets.685 A single oral dose rat drug metabolism study
oxindole variant 1477 exhibited weak GI50 values towards the of meridianin C has identied N/O-glucuronidation, O-sulfation
NCI-60 cell line panel.670 A MS binding assay and subsequent and a range of hydroxylation metabolites.686 Taking inspiration
bioassay-directed fractionation afforded the sterol sulfate syc- from the mildly antibacterial ascidian MNPs the eusyn-
osterol A 1478 as a moderate inhibitor of a-synuclein stelamides, a series of barbiturate-scaffolded synthetic mimics
aggregation.671 of antimicrobial peptides were prepared and comprehensively
evaluated for antimicrobial properties, identifying one partic-
ular analogue with in vivo efficacy in a mouse model of neu-
tropenic peritonitis.687
The association of ascidians and microorganisms with
respect to MNP chemistry has been reviewed.688,689 Ulithiacy-
clamide was present in an enriched bacterial sample, while
both it and patellamide E were identied in unenriched
samples obtained from photosymbiont Prochloron didemni cells
separated from Indonesian collections of Lissoclinum patella.690
Syntheses of ascidian metabolites 19-bromoisoeudistomin A precursor gene was PCR-amplied from the enriched sample,
U,672 ritterazine B,673 (−)-rossinone A,674 (−)-herdmanine D675 identifying coding sequences for both cyclic peptide MNPs.
and siladenoserinol D676 have been reported. Examination of BGCs associated with the biosynthesis of palmerolides in the
the cellular effects of synthetic biselide A using image-based Antarctic ascidian Synoicum adareanum have been linked to the
phenotypic screening identied that the macrolide can be novel verrucomicrobium “Candidatus Synoicihabitans
added to the growing list of MNPs that target microtubules and palmerolidicus”.691,692
microtubule dependent structures.677 The phosphorylated lipid
phosphoeleganin (Sidnyum elegans) is a weak reversible inhib-
itor of PTP1B and acts as an insulin-sensitising agent in vitro.678
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11 Echinoderms The biological activities of the sea urchin pigment echino-

chrome A have been reviewed,711,712 while new activities with
New quinonoid MNPs were reported from crinoids, including respect to atopic dermatitis,713 brosis and inammation,714
naphthopyrones 1479 (Colobometra perspinosa)693 and delica- and protection against UVB-induced photoaging715 have been
pyrons A–E 1480–1484 (Comanthus delicata)694 and phenanthrol- reported. Bioassay-directed fractionation of an extract derived
perylenes gymnochrome H 1485 and gymnochrome A mono- from the starsh Asterias amurensis has identied the saponin
sulfate 1486 (Hypalocrinus naresianus).695 The porphyrin 1487 thornasteroside A as having cholesterol-binding activity.716 A
was isolated from extracts of the brittle star Ophiura sarsii, survey of starsh and brittlestars collected from various sites
representing the rst report of the compound as a MNP.696 The around the UK has found common sunstars to always contain
structure proposed for a molecule isolated from the sea urchin quantiable levels of saxitoxins, with high to very high levels
Salmacis bicolor was inconsistent with the reported NMR data – concentrated in female gonads.717 The structures and biological
the publication should be retracted.697,698 New examples of activities of sea cucumber-derived triterpene glycosides (2017–
steroidal aglycone and disaccharide (microdiscusol G 1488 and 2021) have been reviewed.718 Mining the genome of Apostichopus
microdiscusoside A 1489, isolated from Asterias microdiscus)699 japonicus led to the identication of 30 enzymes responsible for
and triterpene glycosides (pacifcusosides A–C 1490–1492, from
saponin biosynthesis.719 Frondoside A is active in in vitro

Solaster pacicus)700 were reported from Arctic and Far Eastern models of Parkinson's disease, attenuating dopaminergic neu-
collections of starsh. The latter glycoside exhibited weak rodegeneration and reducing a-synuclein aggregation,720 and
cytotoxicity. Metabolites reported from sea cucumbers included the saponin exhibits selective cytotoxicity towards cell lines with
one example of a cerebroside, holospiniferoside 1493 isolated high levels of MYC oncogene expression and inhibits xenogras
from a Red Sea collection of Holothuria spinifera,701 and in mice.721 Molecular dynamics simulations have been used to
a diverse array of glycosides: HSEA-P1 1494 and HSEA-P2 1495, investigate the interactions of selected triterpene glycosides
from Thai specimens of Holothuria scabra,702 coloquandrano- with model erythrocyte membranes, identifying two different
side A 1496 from a South China Sea collection of Colochirus mechanisms of either pore formation or the formation of
quandrangularis,703 echinoside B methyl ether 1497 from Hol- phospholipid and cholesterol clusters in the outer and inner
othuria atra,704 chitonoidosides A, A1, B, C, D, E, E1, F, G and H membrane leaets.722 The small molecule MNP 2-butoxyte-
1498–1507 from Far Eastern specimens of Psolus chito- trahydrofuran, puried from Holothuria scabra, suppresses Ab
noides705,706 and kurilosides A3, D1, G, H, I, I1, J, K and K1 1508– aggregation in a model of Alzheimer's disease via interaction
1516, isolated from Thyonidium kurilensis (Far Eastern Kurile with heat shock factor 1 which leads to upregulation of
Islands).707 HSEA-P1 and HSEA-P2 exhibited weak inhibition of autophagy-related genes.723 The pharmacokinetic, tissue distri-
a-synuclein aggregation and in a C. elegans model, rescued a- bution and excretion proles of two cholestane-sulfates, puri-
synuclein-mediated dopaminergic neurodegeneration. ed from Cucumaria frondosa, were investigated in Balb/c mice,
reaching serum peaks at about three hours, were almost
completely excreted within nine hours and accumulated in the
liver.724
12 Miscellaneous
Two structurally intriguing diaryheptanoid dimers zosterabi-
sphenones A 1517 and B 1518 were isolated from Northern
Germany collections of the seagrass Zostera marina.725 The
structures contain an unusual keto tautomer of a catechol
subunit, the stability of which was ascribed to what would be
unfavourable steric interactions for the hypothetical aromatic
tautomer. Zosterabisphenone B exhibited weak cytotoxicity
Levels of the bitter amino acid pulcherrimine in ovaries of
towards the HCT-116 cell line. Gibberellane diterpenes enhoi-
the sea urchin Hemicentrotus pulcherrimus vary with the annual
dins A 1519 and B 1520 were also isolated from extracts of
reproductive cycle, increasing in maturing ovaries as oogenesis
a seagrass (Enhalus acoroides) collected from Xincun Bay, South
proceeds in the cooler months, decreasing aer spawning in
China Sea.726
spring.708 The short-term palatability of the ovaries as a shery
The hyphenated MS imaging technique incorporating trap-
product in some parts of Japan was attributed to lower seawater
ped ion mobility spectrometry (MALDI-2-TIMS-MSI) has been
temperature. The structures and biological activities of sphin-
used to explore the anatomical distribution of different sterols
golipids reported from Asteroidea and Holothuroidea classes of
within the sterol-auxotrophic atworm Waminoa sp.727 The
echinoderms has been comprehensively reviewed.709 Ganglio-
worm hosts Symbiodiniaceae and Amphidinium dinoagellate
sides puried from the sea urchin Strongylocentrotus nudus
algae – the nding of distribution differences in the host tissue
exhibit neuritogenic effects by targeting tyrosine-kinase recep-
suggests the transfer of sterols to the atworm plays a greater
tors TrkA and TrkB and activating MEK1/2-ERK1/2-CREB and
role than simply being a likely source of energy. Immunohis-
PI3K-Akt-CREB pathways.710
tochemistry using anti-TTX antibodies was used to investigate
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the anatomical distribution of tetrodotoxin in ribbon worm

Cephalothrix cf. simula, nding that the toxin is concentrated in
cells associated with the circulatory and excretory systems.728 LC
uorometric and LC-MS/MS techniques were used to explore
temporal and spatial variation in saxitoxin and tetrodotoxin
family toxins in tissue samples of the crab Zosimus aeneus at
a single reef in Japan.729 The relative concentrations varied with
location, with higher saxitoxin content in specimens from the
NW reef zones. The authors noted crab stomach content con-
tained spicules from Lissoclinum sp. ascidians in saxitoxin-rich
zones while spicules from Trididemnum sp. ascidians domi-
nated in saxitoxin-poor zones.
Fig. 3 Location of researchers who are authors of new MNP papers

2017–2021. Circle size proportional to number of authors in each

location.
2017–2021 (using Scopus), the most striking change that has

occurred over the last decade is the increasing dominance of
studies reported out of China, a trend well underway in the
2010s but now very much matured. Of the 2261 papers
reporting new MNPs in the last ve years, nearly half (1116)
have Chinese corresponding authors. This proportion has
doubled over the last decade. Furthermore, of the 6870 authors
Deep-water sh from Gambier Islands, French Polynesia that have contributed to new MNP papers, 2702 have a Chinese
contained detectable levels of ciguatoxins, identifying them as affiliation, with scientists from the USA (700) and Japan (682)
potential ciguatera poisoning vectors,730 while similar studies of being the next most active contributors. A map of author
Portuguese maritime zone sh species identied high levels in affiliations by city provides an interesting perspective (Fig. 3).
sh from the intermediate position in the food web.731 A review There are several cities hosting more than 100 authors that
of geographical distribution, clinical cases of poisoning and include Guangzhou, Qingdao, Shanghai, Beijing, Haikou,
a summary of recent research on venom properties and Xiamen, Zhoushan, San Diego, Tokyo and Seoul, and authors
components of stonesh Synanceia spp. has been published.732 from 76 countries have contributed to new MNPs research.
The discovery of halogenated NPs e.g. hepta- Interestingly 82% of all authors appear on three or fewer
chloromethylbipyrrole, tetrabrominated methoxylated diphenyl papers while 369 (9.4%) have co-authored more than 10
ethers, PCBs and DDT metabolites, has been extended to large papers. Only 54 corresponding authors (out of 966) have pub-
sh in the Seychelles pelagic ecosystem.733 Two shark bile lished more than 10 papers in the last ve years and 80% have
components, 5b-scymnol and 5b-scymnol sulfate are agonists of published three papers or fewer. This suggests that most of the
the TGR5 “Takeda G-protein receptor 5” bile acid receptor, the research reporting new MNPs is being undertaken by graduate
former being almost four-times more potent, highlighting student/early career researchers. Many of these junior authors
potential roles in preventing the progression of
atherosclerosis.734
13 Conclusion
In the conclusion to last year's MNP review, we analysed
bioactivity trends and highlighted an overall low hit rate
associated with new MNPs. Given that the number of new
MNPs reported annually continues to rise, this year's conclu-
sion investigates who is publishing MNP research, what are the
overarching themes that motivate these studies and what is the
impact of these papers (using citation metrics accessed in
November 2022). Ten years ago, this review reported metrics
relating to the distribution of papers by country, journal, and
Fig. 4 150 × 150 cell SOM of all published MNPs (36 646) colour
citations for the period 2006–2011 and in the following year coded based on the use of MS molecular networking (red) or not (blue
reported on corresponding author productivity.735,736 Through >2017 or green <2017) and a highlighted example of a cluster showing
analysis of publication metrics for papers published between analogues (blue) of network selected MNPs (red).
View Article Online
are likely to be undertaking training in NPs research involving

purication and structure determination and will have
a strong motivation to publish. It is therefore no surprise that
a key-word search of the abstracts for the new MNP papers
overwhelmingly include words such as “structure determina-
tion”, “new compounds” and “NMR” and this at least provides
some insight into the research objectives motivating these
studies.
From the 2261 papers reporting new MNPs published over
the last ve years, 35 report structure revisions through the re-
isolation and interpretation of spectroscopic data, 75 report
total syntheses leading to structure revisions, 365 simply report
structure determinations, 42 use genome mining of microbes to
identify new chemistry, 19 give no real justication for the study
and the remainder combine reporting on new structures with

some bioactivity results, even through most of the new
compounds reported are inactive. Of the papers exclusively
describing new structures, 22 used dereplication/molecular
Fig. 6 Country focus on other MNP related research (2017–2021).
networking tools for extract selection and a further 60 had
some discussion of the plausible biosynthesis of the new MNPs.
The use of MS/MS based molecular networking (GNPS) to guide
>80% of their papers reporting new MNPs), while a further 39
extract selection is growing rapidly (3 in 2017, 10 in 2018, 11 in
authors focus mainly on other marine related studies.
2019, 16 in 2020 and 22 in 2021) and 62 papers have specically
Papers reporting other aspects of MNP research mainly focus
used the technique to select extracts for investigation. Analysis
on the synthesis of MNPs (32%), bioactivity of known MNPs
of the new MNPs reported in these papers using a 150 × 150 cell
(28%), structure and function of peptides and proteins (10%;
SOM (generated in Datawarrior332) reveals that all new MNPs are
including mainly cone snail and anemone peptides), supple-
analogues of previously reported MNPs highlighting the tech-
ments (9%; carotenoids, polyphenols, fatty acids), genomics
niques utility for exploring potential SAR within a structure
and biosynthesis (7%), toxins that threaten food safety (5%;
class, but not as a tool to nd novel chemistry (Fig. 4).
including domoic acid, ciguatoxins and dinoagellate and
For other aspects of MNP studies (predominantly synthesis,
diatom toxins), and metabolomics including known MNPs from
biosynthesis, bioactivities, ecological studies, genomic studies)
new sources (5%) (Fig. 5). The highest mean citations reported
a similar authorship trend is observed. The 3568 papers pub-
are for papers on food supplements, genomics and biosynthesis
lished between 2017 and 2021 have 14 913 authors from 90
and food safety studies (Fig. 5). This is unsurprising given that
countries with 3572 authors having Chinese, 1727 US and 1294
the food supplements and seafood industries have multibillion
Japanese affiliations. There are 19 891 authors contributing to
dollar sales per year and genomic and biosynthetic studies
all MNP research over the last ve years and the vast majority
overwhelmingly study microorganisms that are of broad
(91%, 18 130) have published three papers or fewer. Surpris-
interest to researchers irrespective of the habitat the microbes
ingly only a small number (<10%) of researchers contribute to
originate from.
both the new compounds studies and other MNP research
Authors from different countries have varied focus across
studies and of the authors with 10 or more papers (399), most
these broad research elds with, for example, South Korean
primarily focus on new MNP studies (273 of these authors have
Fig. 5 Proportion of other MNP studies (3568 papers in total) classified Fig. 7 Number of papers published in journals with 50 or more total
by focus area (blue bars) and their mean citations per paper (orange MNP papers (2017–2021, blue bars) and the mean citation per paper in
line) (2017–2021). each journal (orange line).
View Article Online
being J. Nat. Prod. with 6.6% of all papers. Mean citations per
paper are little different between new MNP studies (10.7 mean
cites per paper) and other marine focused studies (10.1 mean
cites per paper) but some of the 20 journals with 50 or more
papers (J. Nat. Prod.; Org. Lett.; Agnew. Chem. Int. Ed.; J. Am.
Chem. Soc, Sci. Rep.; Front. Microbiol.; Phytochemistry) have
citations above this mean (Fig. 7).
Since Chinese studies represent half of all research outputs
this could potentially mask worldwide trends. All papers
reporting new MNPs were split into Chinese and those under-
taken by researchers outside of China. Trends were then plotted
based on yearly tallies of studies vs. phyla. There are increasing
numbers of Chinese studies on cyanobacteria, cnidarians and
sponges and a decrease in actinomycetes studies while asco-
Fig. 8 Share of studies undertaken on each of the major MNP mycetes are clearly the main Chinese focus. Studies across the
producing phyla. (a) Chinese studies, (b) non-Chinese studies (2017– rest of the world are more evenly spread across phyla (Fig. 8).
2021). A survey of the collection sites for new MNPs by corre-
sponding author from the 15 countries with the most papers
reporting new MNPs, shows that many authors collect locally,
researchers more focused on food supplements and the bioac- others collect from past colonies or their territories (France –
tivity of known MNPs than on MNP synthesis, while US French Polynesia, Madagascar, Guadeloupe) others from state-
researchers undertake a higher proportion of genomic studies gically aligned countries (Russia – Vietnam) while lead authors
and Australian researchers have a higher focus on peptides and from China and the US have more globally diverse collections.
proteins (Fig. 6). The Chinese collections outside of their territorial waters
MNP research has been published in 551 journals over the predominately focus on microorganisms from oceanic trenches
last ve years and, with its broad coverage of almost anything in international waters. The US international collections are
marine related including metabolomics, extract screening, predominately associated with the National Cancer Institutes
supplements, bioactivity, synthesis, peptides and proteins and partnerships in the Pacic for macro-organism collections and
new NPs it is little surprise that Mar. Drugs have published 20% widespread cyanobacteria collections (Fig. 9).
of all outputs, with the next highest percentage of total output
Fig. 9 Collection location of organism colour coded by corresponding authors host country (2017–2021).
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Society of Chemistry.2 We thank Raphael Ritson-Williams from

the Luesch Group at the University of Florida for the image of
the cyanobacterium that was used to create the TOC graphic.
This review will be the last one contributed to by Associate
Professor Rohan Davis. Rohan joined the authorship team in
2017 and has written the bacteria and cyanobacteria sections
over the last six years. His diligence in critically assessing the
quality of published results, to highlight exemplary research
and call out questionable studies has been excellent. He has
also provided valuable advice on the overall style and emphasis
for the review. The other authors are particularly grateful to
Rohan for his contributions to these reviews.
Fig. 10 Number of papers per country with or without international

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Carroll Et Al 2022 - Marine Natural Products

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Natural Product

Marine natural products‡

Covering: January to December 2021

Natural Product Reports Review

associated with restrictions in domestic and international travel

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values ranging from 2–10 mg mL−1.3 New antibacterial tetronate-

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strategy using this marine bacterium and comparative metab-

Svalbamides A 61 and B 62, lipodipeptides possessing a pyr-

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multiple resistant Staphylococcus aureus (MRSA) and Entero-

Four new chlorinated meroterpenoids, merochlorins G–J

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a Streptomyces species. Pyranpolyenolides C–F were identied as

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produced in large quantities by phytoplankton and a key

nobacteria during 2021 including the linear lipopeptides

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The rst total syntheses of 14 cyanobacterial metabolites

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the enantiomers isolated as a racemate but separated by chiral

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a Curvularia strain,183 and a sponge-derived Cymostachys species

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sequencing resulted in the identication of the genomic locus

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genome has some clusters, transporters and genes that appear to

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Other compounds were claimed but were only established by

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Four new 3-alkylpyridinium dimer alkaloids, neo-

Methyl lipid glyceroether 971 and alkylated phenol ether 972

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sterol commonly found from genus Theonella.470 An unusual

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for discovery of proline-rich cyclic peptides has been described.

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lobocrasol 1293.556,557 XRD played a role in securing the absolute

Specimens of Sinularia siaesensis (Ximao Island, South China

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methoxybenzyl protection at the 7-hydroxyl group has been

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The complete genome assembly of C. betulinus has been re-

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11 Echinoderms The biological activities of the sea urchin pigment echino-

saponin biosynthesis.719 Frondoside A is active in in vitro

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the anatomical distribution of tetrodotoxin in ribbon worm

Fig. 3 Location of researchers who are authors of new MNP papers

2017–2021. Circle size proportional to number of authors in each

2017–2021 (using Scopus), the most striking change that has

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