Chemical Investigation of the Calcareous Marine Sponge Pericharax heteroraphis, Clathridine-A Related Derivatives Isolation, Synthesis and Osteogenic Activity.

As a result of screening a panel of marine organisms to identify lead molecules for the stimulation of endochondral bone formation, the calcareous sponge Pericharax heteroraphis was identified to exhibit significant activity during endochondral differentiation. On further molecular networking analysis, dereplication and chemical fractionation yielded the known clathridine A-related metabolites 3-6 and the homodimeric complex (clathridine A)2 Zn2+ (9), together with the new unstable heterodimeric complex (clathridine A-clathridimine)Zn2+ (10). With the presence of the zinc complexes annotated through the LC-MS analysis of the crude extract changing due to the instability of some metabolites and complexes constituting the mixture, we combined the isolation of the predicted molecules with their synthesis in order to confirm their structure and to understand their reactivity. Interestingly, we also found a large quantity of the contaminant benzotriazoles BTZ (7) and its semi-dimer (BTZ)2CH2 (8), which are known to form complexes with transition metals and are used for preventing corrosion in water. All isolated 2-aminoimidazole derivatives and complexes were synthesized not only for structural confirmation and chemical understanding but to further study their bioactivity during endochondral differentiation, particularly the positively screened imidazolone derivatives. Compounds leucettamine B, clathridine A and clathridimine were found to increase type X collagen transcription and stimulate endochondral ossification in the ATDC5 micromass model.

Isolation, Synthesis and Absolute Configuration of the Pericharaxins A and B, Epimeric Hydroxy-Polyene Glycerol Ethers from the Calcarean Sponge Pericharax heteroraphis.

Naturally occurring epimeric hydroxy-polyene glycerol ether pericharaxins A (1a) and B (1b) were isolated from the calcarean sponge Pericharax heteroraphis. The structural and stereochemical characterization of both diastereoisomers were established on the basis of spectroscopic data analysis and total synthesis in seven steps. The mixture of pericharaxins A (1a) and B (1b) was proven to be epimeric by chiral-phase HPLC analysis of both synthetic and natural samples. Further separation of the epimers and application of Mosher's method to the synthetic compounds allowed unequivocal absolute configuration assignment. While natural products and the synthetic intermediates were shown to be non-cytotoxic on the HCT116 cell line, the endochondral differentiation activity using human type X collagen transcription activity in ATDC5 cells is interesting.

Bioactive Bromotyrosine Derivatives from the Pacific Marine Sponge Suberea clavata (Pulitzer-Finali, 1982).

Chemical investigation of the South-Pacific marine sponge Suberea clavata led to the isolation of eight new bromotyrosine metabolites named subereins 1-8 (2-9) along with twelve known co-isolated congeners. The detailed configuration determination of the first representative major compound of this family 11-epi-fistularin-3 (11R,17S) (1) is described. Their chemical characterization was achieved by HRMS and integrated 1D and 2D NMR (nuclear magnetic resonance) spectroscopic studies and extensive comparison with literature data. For the first time, a complete assignment of the absolute configurations for stereogenic centers C-11/17 of the known members (11R,17S) 11-epi-fistularin-3 (1) and 17-deoxyfistularin-3 (10) was determined by a combination of chemical modifications, Mosher's technology, and ECD spectroscopy. Consequently, the absolute configurations of all our new isolated compounds 2-9 were determined by the combination of NMR, Mosher's method, ECD comparison, and chemical modifications. Interestingly, compounds 2-7 were obtained by chemical transformation of the major compound 11-epi-fistularin-3 (1). Evaluation for acetylcholinesterase inhibition (AChE), DNA methyltransferase 1 (DNMT1) modulating activity and antifouling activities using marine bacterial strains are also presented.

Quorum Sensing Inhibitory and Antifouling Activities of New Bromotyrosine Metabolites from the Polynesian Sponge Pseudoceratina n. sp.

Four new brominated tyrosine metabolites, aplyzanzines C-F (1-4), were isolated from the French Polynesian sponge Pseudoceratina n. sp., along with the two known 2-aminoimidazolic derivatives, purealidin A (5) and 6, previously isolated, respectively, from the sponges Psammaplysilla purpurea and Verongula sp. Their structures were assigned based on the interpretation of their NMR and HRMS data. The compounds exhibited quorum sensing inhibition (QSi) and antifouling activities against several strains of bacteria and microalgae. To our knowledge, the QSi activity of this type of bromotyrosine metabolite is described here for the first time.

New Antimalarial and Antimicrobial Tryptamine Derivatives from the Marine Sponge Fascaplysinopsis reticulata.

Chemical study of the CH2Cl2-MeOH (1:1) extract of the sponge Fascaplysinopsis reticulata collected in Mayotte highlighted three new tryptophan derived alkaloids, 6,6'-bis-(debromo)-gelliusine F (1), 6-bromo-8,1'-dihydro-isoplysin A (2) and 5,6-dibromo-8,1'-dihydro-isoplysin A (3), along with the synthetically known 8-oxo-tryptamine (4) and the three known molecules from the same family, tryptamine (5), (E)-6-bromo-2'-demethyl-3'-N-methylaplysinopsin (6) and (Z)-6-bromo-2'-demethyl-3'-N-methylaplysinopsin (7). Their structures were elucidated by 1D and 2D NMR spectra and HRESIMS data. All compounds were evaluated for their antimicrobial and their antiplasmodial activities. Regarding antimicrobial activities, the best compounds are (2) and (3), with minimum inhibitory concentration (MIC) of 0.01 and 1 µg/mL, respectively, towards Vibrio natrigens, and (5), with MIC values of 1 µg/mL towards Vibrio carchariae. In addition the known 8-oxo-tryptamine (4) and the mixture of the (E)-6-bromo-2'-demethyl-3'-N-methylaplysinopsin (6) and (Z)-6-bromo-2'-demethyl-3'-N-methylaplysinopsin (7) showed moderate antiplasmodial activity against Plasmodium falciparum with IC50 values of 8.8 and 8.0 µg/mL, respectively.

Chemical Diversity and Biological Activities of Marine Sponges of the Genus Suberea: A Systematic Review.

Marine natural products (MNPs) continue to be in the spotlight in the global drug discovery endeavor. Currently, more than 30,000 structurally diverse secondary metabolites from marine sources have been isolated, making MNPs a profound, renewable source to investigate novel drug compounds. Marine sponges of the genus Suberea (family: Aplysinellidae) are recognized as producers of bromotyrosine derivatives, which are considered distinct chemotaxonomic markers for the marine sponges belonging to the order Verongida. This class of compounds exhibits structural diversity, ranging from simple monomeric molecules to more complex molecular scaffolds, displaying a myriad of biological and pharmacological potentialities. In this review, a comprehensive literature survey covering the period of 1998⁻2018, focusing on the chemistry and biological/pharmacological activities of marine natural products from marine sponges of the genus Suberea, with special attention to the biogenesis of the different skeletons of halogenated compounds, is presented.

Chemistry and Biological Activities of the Marine Sponges of the Genera Mycale (Arenochalina), Biemna and Clathria.

Over the past seven decades, particularly since the discovery of the first marine-derived nucleosides, spongothymidine and spongouridine, from the Caribbean sponge Cryptotethya crypta in the early 1950s, marine natural products have emerged as unique, renewable and yet under-investigated pools for discovery of new drug leads with distinct structural features, and myriad interesting biological activities. Marine sponges are the most primitive and simplest multicellular animals, with approximately 8900 known described species, although more than 15,000 species are thought to exist worldwide today. These marine organisms potentially represent the richest pipeline for novel drug leads. Mycale (Arenochalina) and Clathria are recognized marine sponge genera belonging to the order Poecilosclerida, whereas Biemna was more recently reclassified, based on molecular genetics, as a new order Biemnida. Together, these sponge genera contribute to the production of physiologically active molecular entities with diverse structural features and a wide range of medicinal and therapeutic potentialities. In this review, we provide a comprehensive insight and up-to-date literature survey over the period of 1976⁻2018, focusing on the chemistry of the isolated compounds from members of these three genera, as well as their biological and pharmacological activities, whenever available.

Synergistic AML Cell Death Induction by Marine Cytotoxin (+)-1(R), 6(S), 1'(R), 6'(S), 11(R), 17(S)-Fistularin-3 and Bcl-2 Inhibitor Venetoclax.

Treatment of acute myeloid leukemia (AML) patients is still hindered by resistance and relapse, resulting in an overall poor survival rate. Recently, combining specific B-cell lymphoma (Bcl)-2 inhibitors with compounds downregulating myeloid cell leukemia (Mcl)-1 has been proposed as a new effective strategy to eradicate resistant AML cells. We show here that 1(R), 6(S), 1'(R), 6'(S), 11(R), 17(S)-fistularin-3, a bromotyrosine compound of the fistularin family, isolated from the marine sponge Suberea clavata, synergizes with Bcl-2 inhibitor ABT-199 to efficiently kill Mcl-1/Bcl-2-positive AML cell lines, associated with Mcl-1 downregulation and endoplasmic reticulum stress induction. The absolute configuration of carbons 11 and 17 of the fistularin-3 stereoisomer was fully resolved in this study for the first time, showing that the fistularin we isolated from the marine sponge Subarea clavata is in fact the (+)-11(R), 17(S)-fistularin-3 stereoisomer keeping the known configuration 1(R), 6(S), 1'(R), and 6'(S) for the verongidoic acid part. Docking studies and in vitro assays confirm the potential of this family of molecules to inhibit DNA methyltransferase 1 activity.

Bioactive Bromotyrosine-Derived Alkaloids from the Polynesian Sponge Suberea ianthelliformis.

Herein, we describe the isolation and spectroscopic identification of eight new tetrabrominated tyrosine alkaloids 2⁻9 from the Polynesian sponge Suberea ianthelliformis, along with known major compound psammaplysene D (1), N,N-dimethyldibromotyramine, 5-hydroxy xanthenuric acid, and xanthenuric acid. Cytotoxicity and acetylcholinesterase inhibition activities were evaluated for some of the isolated metabolites. They exhibited moderate antiproliferative activity against KB cancer cell lines, but psammaplysene D (1) displayed substantial cytotoxicity as well as acetylcholinesterase inhibition with IC50 values of 0.7 μM and 1.3 μM, respectively.

Orbicularisine: A Spiro-Indolothiazine Isolated from Gills of the Tropical Bivalve Codakia orbicularis.

A novel spiro-indolofuranone fused to a thiazine skeleton, orbicularisine (1), was isolated from gills of the mollusk Codakia orbicularis. The isolation and structure elucidation using spectroscopic evidence including mass and NMR spectroscopy are described. The final structure of 1 was supported by key HMBC correlation.

Unguiculin A and Ptilomycalins E-H, Antimalarial Guanidine Alkaloids from the Marine Sponge Monanchora unguiculata.

Chemical study of the CH2Cl2-MeOH (1:1) extract from the sponge Monanchora unguiculata collected in Madagascar highlighted five new compounds, one acyclic guanidine alkaloid, unguiculin A (1) and four pentacyclic alkaloids, ptilomycalins E-H (2-5), along with four known compounds: crambescidin 800 (6) and crambescidin 359 (7), crambescidic acid (8), and fromiamycalin (9). Their structures were elucidated by 1D and 2D NMR spectra and HRESIMS data. All compounds were evaluated for their cytotoxicity against KB cells and their antiplasmodial activity. The new ptilomycalin E (2) and the mixture of the new ptilomycalins G (4) and H (5) showed promising cytotoxicity against KB cells with IC50 values of 0.85 and 0.92 µM, respectively. Ptilomycalin F (3) and fromiamycalin (9) exhibited promising activity against Plasmodium falciparum with IC50 values of 0.23 and 0.24 µM, respectively.

Remarkably high homoselectivity in [2 + 2] photodimerization of trans-cinnamic acids in multicomponent systems.

[2 + 2] homoadducts were exclusively obtained with total regio- and stereo-selectivities when a suspension of several solid photoactive trans-cinnamic acids in cyclohexane was stirred and irradiated.

Cytotoxic Guanidine Alkaloids from a French Polynesian Monanchora n. sp. Sponge.

Four bicyclic and three pentacyclic guanidine alkaloids (1-7) were isolated from a French Polynesian Monanchora n. sp. sponge, along with the known alkaloids monalidine A (8), enantiomers 9-11 of known natural product crambescins, and the known crambescidins 12-15. Structures were assigned by spectroscopic data interpretation. The relative and absolute configurations of the alkaloids were established by analysis of (1)H NMR and NOESY spectra and by circular dichroism analysis. The new norcrambescidic acid (7) corresponds to interesting biosynthetic variation within the pentacyclic core. All compounds exhibited antiproliferative and cytotoxic efficacy against KB, HCT116, HL60, MRC5, and B16F10 cancer cells, with IC50 values ranging from 4 nM to 10 µM.

Netamines O-S, Five New Tricyclic Guanidine Alkaloids from the Madagascar Sponge Biemna laboutei, and Their Antimalarial Activities.

In our continuing program to isolate new compounds from the Madagascar sponge Biemna laboutei, five new tricyclic guanidine alkaloids, netamines O - S (1-5, resp.), have been identified together with the known compounds netamine E (6) and mirabilin J (7). The structures of all new netamines were assigned on the basis of spectroscopic analyses. Their relative configurations were established by analysis of ROESY data and comparison with literature data. Netamines O, P, and Q, which were isolated in sufficient quantities, were tested for their cytotoxic activities against KB cells and their activities against the malaria parasite Plasmodium falciparum. Netamines O and Q were found to be moderately cytotoxic. Netamines O, P, and Q exhibited antiplasmodial activities with IC50 values of 16.99 ± 4.12, 32.62 ± 3.44, and 8.37 ± 1.35 µM, respectively.

Netamines H-N, tricyclic alkaloids from the marine sponge Biemna laboutei and their antimalarial activity.

Chemical examination of the CH2Cl2-MeOH (1:1) extract of the Madagascar sponge Biemna laboutei resulted in the isolation of seven new tricyclic alkaloids, netamines H-N (1-7), along with the known netamine G and mirabilins A, C, and F. Their structures were elucidated by interpretation of 1D and 2D NMR spectra and HRESIMS data. All compounds were evaluated for their cytotoxicity against KB cells and their antiplasmodial activity. Netamine M (6) was found to be cytotoxic, with an IC50 value in the micromolar range, and netamine K (4) exhibited activity against Plasmodium falciparum with an IC50 value of 2.4 µM.

Elemental sulfur disproportionation in the redox condensation reaction between o-halonitrobenzenes and benzylamines.

The disproportionation of elemental sulfur at moderate temperatures is investigated in the redox condensation involving o-halonitrobenzenes 1 and benzylamines 2. As a redox moderator, elemental sulfur plays the dual role of both electron donor and acceptor, generating its lowest and highest oxidation states: S(-2) (sulfide equivalent) in benzothiazole 3 and S(+6) (sulfate equivalent) in sulfamate 4, and filling the electron gap of the global redox condensation process. Along with this process, a cascade of reactions of reduction of the nitro group of 1, oxidation of the aminomethyl group of 2, metal-free aromatic halogen substitution, and condensation finally led to 2-arylbenzothiazoles 3.

Iron sulfide catalyzed redox/condensation cascade reaction between 2-amino/hydroxy nitrobenzenes and activated methyl groups: a straightforward atom economical approach to 2-hetaryl-benzimidazoles and -benzoxazoles.

Iron sulfide generated in situ from elemental sulfur and iron was found to be highly efficient in catalyzing a redox/condensation cascade reaction between 2-amino/hydroxy nitrobenzenes and activated methyl groups. This method represents a straightforward and highly atom economical approach to 2-hetaryl-benzimidazoles and -benzoxazoles.

Unprecedented biomimetic homodimerization of oroidin and clathrodin marine metabolites in the presence of HMPA or phosphonate salt tweezers.

The first biomimetic homodimerization of oroidin and clathrodin was effected in the presence HMPA and diphosphonate salts, strong guanidinium and amide chelating agents. The intermolecular associations probably interfere with the entropically and kinetically favored intramolecular cyclizations. Use of oroidin·(1)/2HCl salt or clathrodin·(1)/2HCl was indicative in the presence of the ambident nucleophilic and electrophilic tautomers of the 2-aminoimidazolic oroidin and clathrodin precursors. Surprisingly, the homodimerization of oroidin led to the nagelamide D skeleton, while the homodimerization of clathrodin gave the benzene para-symmetrical structure 19. The common process was rationalized from tautomeric precursors I and III.

Pipestelides A-C: cyclodepsipeptides from the Pacific marine sponge Pipestela candelabra.

Pipestelides A-C (2-4) are three new NRPS-PKS hybrid macrolides containing uncommon moieties, isolated from the Pacific marine sponge Pipestela candelabra. Their structures were elucidated on the basis of spectroscopic data. These cyclodepsipeptides appear to be biosynthetically related to jaspamide (aka jasplakinolide) (1) by chemical modification of the building blocks of the polyketide or peptide chains. Pipestelides A-C (2-4) contain a bromotyrosine [3-amino-3-(bromo-4-hydroxyphenyl)propanoic acid] unit, a polypropionate with a Z double bond, and a 2-hydroxyquinolinone, respectively. Revised chemical shift assignments are provided for the co-isolated known jasplakinolide C(a) (5). In addition, compounds 2 and 3 exhibited cytotoxic activities in the micromolar range.

Organic Matrix and Secondary Metabolites in Nacre.

Nacre, also called mother-of-pearl, is a naturally occurring biomineral, largely studied by chemists, structural biologists, and physicists to understand its outstanding and diverse properties. Nacre is constituted of aragonite nanograins surrounded by organic matrix, and it has been established that the organic matrix is responsible for initiating and guiding the biomineralization process. The first challenge to study the organic matrix of nacre lays in its separation from the biomineral. Several extraction methods have been developed so far. They are categorized as either strong (e.g., decalcification) or soft (e.g., water, ethanol) and they allow specific extractions of targeted compounds. The structure of the nacreous organic matrix is complex, and it provides interesting clues to describe the mineralization process. Proteins, sugars, lipids, peptides, and other molecules have been identified and their role in mineralization investigated. Moreover, the organic matrix of nacre has shown interesting properties for human health. Several studies are investigating its activity on bone mineralization and its properties for skin care. In this review, we focus on the organic constituents, as lipids, sugars, and small metabolites which are less studied since present in small quantities.