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The dinoflagellate Ostreopsis cf. ovata produces several families of toxic polyketides. Despite only a few field measurements of these phycotoxins in seawater and aerosols, they are believed to be responsible for dermatitis and the toxic inhalations reported during blooms of this species. Therefore, the stability of these compounds in seawater is essential to understanding the causes of these symptoms, however, this has never been assessed. In the current study, the optimization of a solid phase extraction (SPE) procedure was first performed to ensure the most efficient extraction of all phycotoxins known to be produced by this strain, including the recently described liguriatoxins. The SPE cartridge SDBL® under non acidified conditions offered the best option. The stability of the ovatoxins and the liguriatoxins under biotic and abiotic stress was assessed by exposing the spent medium of a culture of Ostreopsis cf. ovata to its bacterial consortium and natural sunlight. A rapid biotic transformation was detected for both families of compounds. When exposed to bacteria, the half-lives of the ovatoxins were reached before 10 h and at 36 h, 97% of these toxins had been transformed. The half-lives of the liguriatoxins were 10 h under these conditions. Photolysis (abiotic degradation) of the ovatoxins (T1/2 < 36 h) was faster than for the liguriatoxins (T1/2 > 62 h). Although none of the catabolites of these phycotoxins were thoroughly identified, an untargeted metabolomics approach combined with molecular networking highlighted the presence of several compounds exhibiting structural similarities with the ovatoxins. Additional work should confirm the preliminary findings on these potential ovatoxins’ catabolites and their biological properties. The rapid transformation of O. cf. ovata’s phycotoxins introduces questions concerning their presence in seawater and their dispersion in the sea spray aerosols. The compounds involved in the toxic inhalations and dermatitis often experienced by beachgoers may stem from the catabolites of these toxins or even unrelated and as yet unidentified compounds.

Sponges are at the forefront of marine natural product research. In the deep sea, extreme conditions have driven secondary metabolite pathway evolution such that we might expect deep-sea sponges to yield a broad range of unique natural products. Here, we investigate the chemodiversity of a deep-sea tetractinellid sponge, Characella pachastrelloides , collected from ~800 m depth in Irish waters. First, we analyzed the MS/MS data obtained from fractions of this sponge on the GNPS public online platform to guide our exploration of its chemodiversity. Novel glycolipopeptides named characellides were previously isolated from the sponge and herein cyanocobalamin, a manufactured form of vitamin B 12 , not previously found in nature, was isolated in a large amount. We also identified several poecillastrins from the molecular network, a class of polyketide known to exhibit cytotoxicity. Light sensitivity prevented the isolation and characterization of these polyketides, but their presence was confirmed by characteristic NMR and MS signals. Finally, we isolated the new betaine 6-methylhercynine, which contains a unique methylation at C-2 of the imidazole ring. This compound showed potent cytotoxicity towards against HeLa (cervical cancer) cells.

Worldwide diffused diseases such as osteoarthritis, atherosclerosis or chronic kidney disease are associated with a tissue calcification process which may involve unexpected local stem cell differentiation. Current pharmacological treatments for such musculoskeletal conditions are weakly effective, sometimes extremely expensive and often absent. The potential to develop new therapies is represented by the discovery of small molecules modulating resident progenitor cell differentiation to prevent aberrant tissue calcification. The marine environment is a rich reserve of compounds with pharmaceutical potential and many novel molecules are isolated from macro and microorganisms annually. The potential of small molecules synthetized by marine filamentous fungi to influence the osteogenic and chondrogenic differentiation of human mesenchymal stem/stromal cells (hMSCs) was investigated using a novel, high-throughput automated screening platform. Metabolites synthetized by the marine-derived fungus Penicillium antarcticum were evaluated on the platform. Itaconic acid derivatives were identified as inhibitors of calcium elaboration into the matrix of osteogenically differentiated hMSCs and also inhibited hMSC chondrogenic differentiation, highlighting their capacity to impair ectopic calcification. Bioactive small molecule discovery is critical to address ectopic tissue calcification and the use of biologically relevant assays to identify naturally occurring metabolites from marine sources represents a strategy that can contribute to this effort.

So far, the Futuna Islands located in the Central Indo-Pacific Ocean have not been inventoried for their diversity in marine sponges and associated chemical diversity. As part of the Tara Pacific expedition, the first chemical investigation of the sponge Narrabeena nigra collected around the Futuna Islands yielded 18 brominated alkaloids: seven new bromotryptamine derivatives 1 - 7 and one new bromotyramine derivative 8 together with 10 known metabolites of both families 9 - 18 . Their structures were deduced from extensive analyses of nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS) data. In silico metabolite anticipation using the online tool MetWork revealed the presence of a key and minor biosynthetic intermediates. These 18 compounds showed almost no cytotoxic effect up to 10 µM on human neuroblastoma SH-SY5Y and microglia BV2 cells, and some of them exhibited an interesting neuroprotective activity by reducing oxidative damage.

Soft corals (Cnidaria, Anthozoa, Octocorallia) are a diverse group of marine invertebrates that inhabit various marine environments in tropical and subtropical areas. Several species are recognized as prolific sources of compounds with a wide array of biological activities. Recent advances in analytical techniques, supported by robust statistical analyses, have allowed the analysis and characterization of the metabolome present in a single living organism. In this study, a liquid chromatography-high resolution mass spectrometry metabolomic approach was applied to analyze the metabolite composition of 28 soft corals present in the Caribbean coast of Colombia. Multivariate data analysis was used to correlate the chemical fingerprints of soft corals with their cytotoxic activity against tumor cell lines for anticancer purpose. Some diterpenoids were identified as specific markers to discriminate between cytotoxic and non-cytotoxic crude extracts of soft corals against tumor cell lines. In the models generated from the comparative analysis of PLS-DA for tumor lines, A549 and SiHa, the diterpene 13-keto-1,11-dolabell-3(E),7(E),12(18)-triene yielded a high score in the variable importance in projection. These results highlight the potential of metabolomic approaches towards the identification of cytotoxic agents against cancer of marine origin. This workflow can be useful in several studies, mainly those that are time consuming, such as traditional bioprospecting of marine natural products.

Two new zoanthamine alkaloids, namely 3-acetoxynorzoanthamine ( 1 ) and 3-acetoxyzoanthamine ( 2 ), have been isolated from the zoantharian Zoanthus cf. pulchellus collected off the coast of the Santa Elena Peninsula, Ecuador, together with three known derivatives: zoanthamine, norzoanthamine, and 3-hydroxynorzoanthamine. The chemical structures of 1 and 2 were determined by interpretation of their 1D and 2D NMR data and comparison with literature data. This is the first report of zoanthamine-type alkaloids from Zoanthus cf. pulchellus collected in the Tropical Eastern Pacific. The neuroinflammatory activity of all the isolated compounds was evaluated in microglia BV-2 cells and high inhibitory effects were observed in reactive oxygen species (ROS) and nitric oxide (NO) generation.

Despite a large occurrence, especially over the Pacific Ocean, the chemical diversity of marine invertebrates belonging to the order Zoantharia is largely underexplored. For the two species of the genus Antipathozoanthus no chemical study has been reported so far. The first chemical investigation of Antipathozoanthus hickmani collected at the Marine Protected Area "El Pelado", Santa Elena, Ecuador, led to the isolation of four new ecdysteroid derivatives named ecdysonelactones. The structures of ecdysonelactones A-D ( 1 - 4 ) were determined based on their spectroscopy data, including 1D and 2D NMR and HRMS. The four compounds of this family of ecdysteroids feature an unprecedented γ-lactone fused at the C-2/C-3 position of ring A. These derivatives exhibited neither antimicrobial nor cytotoxic activities.

The first chemical investigation of the Mediterranean deep-sea sponge Poecillastra compressa (Bowerbank, 1866) led to the identification of seven new steroidal saponins named poecillastrosides A-G ( 1 - 7 ). All saponins feature an oxidized methyl at C-18 into a primary alcohol or a carboxylic acid. While poecillastrosides A-D ( 1 - 4 ) all contain an exo double bond at C-24 of the side-chain and two osidic residues connected at O-2', poecillastrosides E-G ( 5 - 7 ) are characterized by a cyclopropane on the side-chain and a connection at O-3' between both sugar units. The chemical structures were elucidated through extensive spectroscopic analysis (High-Resolution Mass Spectrometry (HRESIMS), 1D and 2D NMR) and the absolute configurations of the sugar residues were assigned after acidic hydrolysis and cysteine derivatization followed by LC-HRMS analyses. Poecillastrosides D and E, bearing a carboxylic acid at C-18, were shown to exhibit antifungal activity against Aspergillus fumigatus ., Competing Interests: The authors declare no conflict of interest.

Most marine sponges are known to produce a large array of low molecular-weight metabolites which have applications in the pharmaceutical industry. The production of so-called specialized metabolites may be closely related to environmental factors. In this context, assessing the contribution of factors like temperature, nutrients or light to the metabolomes of sponges provides relevant insights into their chemical ecology as well as the supply issue of natural sponge products. The sponge Crambe crambe was chosen as a model due to its high content of specialized metabolites belonging to polycyclic guanidine alkaloids (PGA). First results were obtained with field data of both wild and farmed specimens collected in two seasons and geographic areas of the North-Western Mediterranean. Then, further insights into factors responsible for changes in the metabolism were gained with sponges cultivated under controlled conditions in an aquarium. Comparative metabolomics showed a clear influence of the seasons and to a lesser extent of the geography while no effect of depth or farming was observed. Interestingly, sponge farming did not limit the production of PGA, while ex situ experiments did not show significant effects of several abiotic factors on the specialized metabolome at a one-month time scale. Some hypotheses were finally proposed to explain the very limited variations of PGA in C. crambe placed under different environmental conditions., Competing Interests: The authors declare no conflict of interest.

The Mediterranean marine sponge Crambe crambe is the source of two families of guanidine alkaloids known as crambescins and crambescidins. Some of the biological effects of crambescidins have been previously reported while crambescins have undergone little study. Taking this into account, we performed comparative transcriptome analysis to examine the effect of crambescin-C1 (CC1) on human tumor hepatocarcinoma cells HepG2 followed by validation experiments to confirm its predicted biological activities. We report herein that, while crambescin-A1 has a minor effect on these cells, CC1 protects them against oxidative injury by means of metallothionein induction even at low concentrations. Additionally, at high doses, CC1 arrests the HepG2 cell cycle in G0/G1 and thus inhibits tumor cell proliferation. The findings presented here provide the first detailed approach regarding the different effects of crambescins on tumor cells and provide a basis for future studies on other possible cellular mechanisms related to these bioactivities.

Cancer and infectious diseases continue to be a major public health problem, and new drugs are necessary. As marine organisms are well known to provide a wide range of original compounds, the aim of this study was to investigate the bioactivity of the main constituents of the cosmopolitan red alga, Sphaerococcus coronopifolius. The structure of several bromoditerpenes was determined by extensive spectroscopic analysis and comparison with literature data. Five molecules were isolated and characterized which include a new brominated diterpene belonging to the rare dactylomelane family and named sphaerodactylomelol (1), along with four already known sphaerane bromoditerpenes (2-5). Antitumor activity was assessed by cytotoxicity and anti-proliferative assays on an in vitro model of human hepatocellular carcinoma (HepG-2 cells). Antimicrobial activity was evaluated against four pathogenic microorganisms: Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus and Candida albicans. Compound 4 exhibited the highest antimicrobial activity against S. aureus (IC50 6.35 µM) and compound 5 the highest anti-proliferative activity on HepG-2 cells (IC50 42.9 µM). The new diterpene, sphaerodactylomelol (1), induced inhibition of cell proliferation (IC50 280 µM) and cytotoxicity (IC50 720 µM) on HepG-2 cells and showed antimicrobial activity against S. aureus (IC50 96.3 µM).

In this paper, we show the effect of crambescidin-816, -800, and -830 on Saccharomyces cerevisiae viability. We determined that, of the three molecules tested, crambescidin-816 was the most potent. Based on this result, we continued by determining the effect of crambescidin-816 on the cell cycle of this yeast. The compound induced cell cycle arrest in G2/M followed by an increase in cell DNA content and size. When the type of cell death was analyzed, we observed that crambescidin-816 induced apoptosis. The antifungal effect indicates that crambescidins, and mostly crambescidin-816, could serve as a lead compound to fight fungal infections.

The chemical investigation of the recently described Mediterranean Homoscleromorpha sponge Oscarella balibaloi revealed an original family of five closely related glucosylated sesterterpenes 1-4, named balibalosides. Their structure elucidation was mainly inferred from NMR and HRMS data analyses. Balibalosides differ by the pattern of acetyl substitutions on the three sugar residues linked to the same aglycone sesterterpenoid core. From a biosynthetic perspective, these compounds may represent intermediates in the pathways leading to more complex sesterterpenes frequently found in Dictyoceratida, a sponge Order belonging to Demospongiae, a clade which is phylogenetically distinct from the Homoscleromorpha. While steroid and triterpenoid saponins were already well known from marine sponges, balibalosides are the first examples of glycosilated sesterterpenes.

Nine bromotyrosine-derived compounds were isolated from the Caribbean marine sponge Verongula rigida. Two of them, aeroplysinin-1 (1) and dihydroxyaerothionin (2), are known compounds for this species, and the other seven are unknown compounds for this species, namely: 3,5-dibromo-N,N,N-trimethyltyraminium (3), 3,5-dibromo-N,N,N, O-tetramethyltyraminium (4), purealidin R (5), 19-deoxyfistularin 3 (6), purealidin B (7), 11-hydroxyaerothionin (8) and fistularin-3 (9). Structural determination of the isolated compounds was performed using one- and two-dimensional NMR, MS and other spectroscopy data. All isolated compounds were screened for their in vitro activity against three parasitic protozoa: Leishmania panamensis, Plasmodium falciparum and Trypanosoma cruzi. Compounds 7 and 8 showed selective antiparasitic activity at 10 and 5 μM against Leishmania and Plasmodium parasites, respectively. Cytotoxicity of these compounds on a human promonocytic cell line was also assessed.