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This review discusses main directions and results of the studies on antibiotics produced by bacteria living in the marine environment. In recent years many obligate marine species and strains were studied, diverse metabolites were isolated, and their chemical structures were elucidated. Among them here were natural compounds toxic against tumor cells, pathogenic bacteria, viruses, and malaria plasmodial species; these compounds often had no analogues among the natural products of terrestrial origin. Some isolated compounds form a basis of active ingredients in medicinal preparations used in clinic practice, while others are under different stages of preclinical or clinical studies. Much attention has been paid in recent years to producers of marine-derived antibiotics isolated from the deep-sea habitats, from the surface of marine invertebrates and algae, as well as from symbiotic microorganisms.

Oceanalin B (1), an α,ω-bipolar natural product belonging to a rare family of sphingoid tetrahydoisoquinoline β-glycosides, was isolated from the EtOH extract of the lyophilized marine sponge Oceanapia sp. as the second member of the series after oceanalin A (2) from the same animal. The compounds are of particular interest due to their biogenetically unexpected structures as well as their biological activities. The structure and absolute stereochemistry of 1 as a α,ω-bifunctionalized sphingoid tetrahydroisoquinoline β-glycoside was elucidated using NMR, CD and MS spectral analysis and chemical degradation. Oceanalin B exhibited in vitro antifungal activity against Candidaglabrata with a MIC of 25 μg/mL.

This review highlights the application of oxidative and reductive chemical transformations in the structure determination of complex marine natural products, including their absolute configurations. Workability of the Baeyer-Villiger reaction, ozonolysis, periodate oxidation, hydrogenolysis, and reductive amination, as well as other related chemical transformations, are discussed.

Two novel C19 terpenoids (1, 2) with an unprecedented carbon skeleton (A) were isolated from a Stelletta sp. sponge collected from Vietnamese waters. Their structures and absolute configurations were established by extensive NMR, MS, and ECD analyses together with quantum chemical modeling and biogenetic considerations. The probable pathways of biogenesis of 1 and 2 from isomalabaricane triterpenoids are discussed. Compounds 1 and 2 significantly increase the production of reactive oxygen species in murine peritoneal macrophages.

Guitarrins A-E (1-5), the first natural 5-azaindoles, and aluminumguitarrin A (1a), the first aluminum-containing compound from marine invertebrates, were isolated from the sponge Guitarra fimbriata. The structures of these compounds were established using detailed analysis of 1D and 2D NMR data, mass spectra, and X-ray analysis of 1 and 1a. Compound 3 was proved to be a natural inhibitor of alkaline phosphatase.

The mini-review highlights the involvement of some elements of Mendeleev Periodic Table into marine biogenic compounds and these elements participation in the marine organisms’ metabolism. Some metals accumulation by marine invertebrates and the metal complexation by highly structurally diverse secondary metabolites are discussed. In addition, examples of the covalent bonds formation in marine bioorganic molecules with a number of non-metals are considered.

New bicyclic guanidine alkaloid, urupocidin C (Ur-C) along with the previously known urupocidin A (Ur-A) were isolated from the rare deep-sea marine sponge Monanchora pulchra, harvested in Northwestern Pacific waters. The unique structure of Ur-C was elucidated using 1D and 2D NMR spectroscopy as well as mass spectra. We discovered a promising selectivity of both alkaloids for human prostate cancer (PCa) cells, including highly drug-resistant lines, compared to non-malignant cells. In cancer cells, marine derived compounds were able to induce G1- and S-cell cycle arrest as well as caspase-mediated cell death. For the first time we have identified mitochondrial targeting as a central mechanism of anticancer action for these and similar molecules. Thus, treatment with the isolated alkaloids resulted in mitochondrial membrane permeabilization consequently leading to the release of cytotoxic mitochondrial proteins to cellular cytoplasm, ROS upregulation, consequent activation of caspase-9 and -3, followed by PARP cleavage, DNA fragmentation, and apoptosis. Moreover, synergistic effects were observed when Ur-A and Ur-C were combined with clinically approved PARP inhibitor olaparib. Finally, these alkaloids exhibited additive effects in combination with docetaxel and androgen receptor inhibitor enzalutamide, both applied in PCa therapy. In conclusion, urupocidin-like compounds are promising lead molecules for the development of new drugs for the treatment of advanced PCa.

Leptogorgins A–C (1–3), new humulane sesquiterpenoids, and leptogorgoid A (4), a new dihydroxyketosteroid, were isolated from the gorgonian Leptogorgia sp. collected from the South China Sea. The structures were established using MS and NMR data. The absolute configuration of 1 was confirmed by a modification of Mosher’s method. Configurations of double bonds followed from NMR data, including NOE correlations. This is the first report of humulane-type sesquiterpenoids from marine invertebrates. Sesquiterpenoids leptogorgins A (1) and B (2) exhibited a moderate cytotoxicity and some selectivity against human drug-resistant prostate cancer cells 22Rv1.

Monanchoxymycalin C (MomC) is a new marine pentacyclic guanidine alkaloid, recently isolated from marine sponge Monanchora pulchra by us. Here, anticancer activity and mechanism of action was investigated for the first time using a human prostate cancer (PCa) model. MomC was active in all PCa cell lines at low micromolar concentrations and induced an unusual caspase-independent, non-apoptotic cell death. Kinase activity screening identified activation of mitogen-activated protein kinase (MAPK) c-Jun N-terminal protein kinase (JNK1/2) to be one of the primary molecular mechanism of MomC anticancer activity. Functional assays demonstrated a specific and selective JNK1/2 activation prior to the induction of other cell death related processes. Inhibition of JNK1/2 by pretreatment with the JNK-inhibitor SP600125 antagonized cytotoxic activity of the marine compound. MomC caused an upregulation of cytotoxic ROS. However, in contrast to other ROS-inducing agents, co-treatment with PARP-inhibitor olaparib revealed antagonistic effects indicating an active PARP to be necessary for MomC activity. Interestingly, although no direct regulation of p38 and ERK1/2 were detected, active p38 kinase was required for MomC efficacy, while the inhibition of ERK1/2 increased its cytotoxicity. In conclusion, MomC shows promising activity against PCa, which is exerted via JNK1/2 activation and non-apoptotic cell death.

Melonoside B (1) and melonosins B (2) and A (3), new lipids based on polyoxygenated fatty acid amides, and known melonoside A (4) were isolated from two different collections of the marine sponge Melonanchora kobjakovae. The structures of these compounds, including their absolute configurations, were established using detailed analysis of 1D and 2D NMR, ECD, and mass spectra as well as chemical transformations. Melonosins 2 and 3 inhibit AP-1- and NF-kB-dependent transcriptional activities in JB6 Cl41 cells at noncytotoxic concentrations, demonstrating potential cancer preventive activity.

Development of resistance to standard therapies complicates treatment of advanced prostate cancer. Alternative splicing variants of the androgen receptor (AR), e.g. AR-V7 can mediate resistance to AR-targeting substances abiraterone and enzalutamide. Semi-synthetic marine natural compound rhizochalinin decreases the expression of AR-V7 in human castration-resistant prostate cancer cells and thus resensitizes cells to enzalutamide. In the current study, we modified the structure of rhizochalin in order to determine structure-activity relationships (SAR) and optimize anticancer properties. Thus, we synthesized new 18-hydroxy- and 18-aminorhizochalins and its aglycones. All compounds exhibited anticancer properties in human castration-resistant prostate cancer cells, induced apoptosis and G2/M cell cycle arrest, and were capable of autophagy inhibition. SAR analysis showed an increase of pro-apoptotic activity in the row 18-amino < 18-hydroxy < 18-keto derivatives. In general, aglycones were more cytotoxic compared to glycosides. The sugar elimination was critical for the ability to suppress AR-signaling. Rhizochalinin (2) and 18-hydroxyrhizochalinin (4) were identified as the most promising derivatives and are promoted for further development.

The effect of pentacyclic guanidine alkaloids monanchomycalin B, monanchocidin A and normonanchocidin A isolated from the Far-Eastern marine sponge Monanchora pulchra was investigated towards the activity of exo-β-1,3-D-glucanase from the filamentous marine fungus Chaetomium indicum and endo-β-1,3-D-glucanase LIV from the marine bivalve mollusk Spisula sachalinensis. All compounds were shown to be slow irreversible inhibitors of exo-β-1,3-D-glucanase and significantly activated endo-β-1,3-Dglucanase. The equilibrium inhibition constants (Ki, μM) and the inactivation rate constants (kinact, min–1) were determined for each compound. The inhibitory capacities of alkaloids were shown to depend on the structure of the “anchor” part of the molecule of the compounds. Normonanchocidin A was the best inhibitor of exo-β-1,3-D-glucanase from fungi. A possible biological role of these compounds in the life of sponges and their microbial symbionts is discussed here.

A new pentacyclic guanidine alkaloid, monanchoxymycalin C (1) was isolated from a new collection of marine sponge Monanchora pulchra along with the known monanchoxymycalin A (2). The structure of 1 was elucidated on the basis of spectroscopic data. Monanchoxymycalin C exhibits cytotoxic activity against human cancer HeLa cells at low micromolar concentrations, induces apoptosis-related death of malignant cells and inhibits cancer cell colony formation. In addition, synergistic and additive effects have been observed in combination with cisplatin.

The absolute configuration of the cytotoxic guanidine alkaloid monanchocidin A with 11 stereogenic centers from the marine sponge Monanchora pulchra was determined as 5 R, 8 S, 10 S, 13 R, 14 S, 15 R, 19 R, 23 R, 37 S, 42 S, 43 R after extensive reductive degradation and conversion of the resulting alcohols to MTPA derivatives.

Two novel C

Twenty-three bacterial strains were isolated from the secreted mucus trapping net of the marine polychaete Chaetopterus variopedatus (phylum Annelida) and twenty strains were identified using 16S rRNA gene analysis. Strain CB1-14 was recognized as a new species of the genus Vibrio using the eight-gene multilocus sequence analysis (MLSA) and genome sequences of nineteen type Vibrio strains. This Vibrio sp. was cultured, and 6-epi-monanchorin (2), previously isolated from the polychaete and two sponge species, was found in the cells and culture broth. The presence of the 6-epi-monanchorin was confirmed by its isolation followed by 1H NMR and HRESIMS analysis. These results showed the microbial origin of the bicyclic guanidine alkaloid 2 in C. variopedatus.

The cytotoxic and cancer preventive activities of synthetic analogs of natural varacins with polysulfide groups were studied. Presence of a sulfoxide group was found to have no significant effect on the cytotoxicity of these compounds. At the same time, this group is important for inhibition of colony formation of tumor cells treated with tumor promoter thus demonstrating cancer preventive activity. The most promising compound appears to be a synthetic varacin C analog, sulfoxide 10a, which exhibits the cancer preventive activity at dose into 100 times lower than its cytotoxic concentrations.

Melonoside A (1), the first representative of a new class of ω-glycosylated fatty acid amides, was isolated from the Far Eastern marine sponge Melonanchora kobjakovae. The structure of 1, including absolute configuration, was established using detailed analysis of 1D and 2D NMR, CD, and mass spectra as well as chemical transformations. Compound 1 induces autophagy of human cisplatin-resistant germinal tumor cells NCCIT-R.

Two new natural products, 6-bromogramine (1) and bis-6-bromogramine (2) were isolated from the marine hydroid A bietinaria abietina and their structures were established using NMR and MS analysis. Compounds 1 and 2 activate NF-cB-dependent transcriptional activity in JB6 Cl 41 NF-KB cells at 1.6 AM concentrations.

As a result of the first study on secondary metabolites from the cosmopolitan bioluminescent marine tube polychaete Chaetopterus variopedatus, a new bicyclic guanidine alkaloid, 6-epi-monanchorin (1), along with the previously known monanchorin (2) were isolated. The structure of 1 was elucidated by spectroscopic and chemical methods, including a cleavage of the C₁-0₇ bond to obtain a secondary alcohol (3), which was used to determine the absolute configurations by Mosher's method. It was found that 1 and 2 were mainly accumulated in a secreted mucus special organ of the worm (food net), where green and blue-green microalgae were detected. A biosynthetic pathway to 6-epi-monanchorin and monanchorin from dietary polyeic fatty acid precursors was proposed.

The effect of monanchomycalin B, monanhocicidin A, and normonanhocidin A isolated from the Northwest Pacific sample of the sponge Monanchora pulchra was investigated on the activity of &alpha, galactosidase from the marine &gamma, proteobacterium Pseudoalteromonas sp. KMM 701 (&alpha, PsGal), and &alpha, N-acetylgalactosaminidase from the marine bacterium Arenibacter latericius KMM 426T (&alpha, NaGa). All compounds are slow-binding irreversible inhibitors of &alpha, PsGal, but have no effect on &alpha, NaGa. A competitive inhibitor d-galactose protects &alpha, PsGal against the inactivation. The inactivation rate (kinact) and equilibrium inhibition (Ki) constants of monanchomycalin B, monanchocidin A, and normonanchocidin A were 0.166 &plusmn, 0.029 min&minus, 1 and 7.70 &plusmn, 0.62 &mu, M, 0.08 &plusmn, 0.003 min&minus, 1 and 15.08 &plusmn, 1.60 &mu, M, 0.026 &plusmn, 0.000 min&minus, 1, and 4.15 &plusmn, 0.01 &mu, M, respectively. The 2D-diagrams of &alpha, PsGal complexes with the guanidine alkaloids were constructed with &ldquo, vessel&rdquo, and &ldquo, anchor&rdquo, parts of the compounds. Two alkaloid binding sites on the molecule of &alpha, PsGal are shown. Carboxyl groups of the catalytic residues Asp451 and Asp516 of the &alpha, PsGal active site interact with amino groups of &ldquo, parts of the guanidine alkaloid molecules.

The new pentacyclic guanidine alkaloids, monanchoxymycalin A (1) and monanchoxymycalin B (2) were isolated from the Far-Eastern marine sponge Monanchora pulchra. Their structures were assigned on the basis of detailed analysis of lD- and 2D-NMR spectroscopic and mass spectrometric data. Compounds 1 and 2 exhibited potent cytotoxic activities against cervical epithelioid carcinoma HeLa cells and breast adenocarcinoma MDA-MB231 cells.

Nicotinic acetylcholine receptors (nAChRs) fulfill a variety of functions making identification and analysis of nAChR subtypes a challenging task. Traditional instruments for nAChR research are d-tubocurarine, snake venom protein α-bungarotoxin (α-Bgt), and α-conotoxins, neurotoxic peptides from Conus snails. Various new compounds of different structural classes also interacting with nAChRs have been recently identified. Among the low-molecular weight compounds are alkaloids pibocin, varacin and makaluvamines C and G. 6-Bromohypaphorine from the mollusk Hermissenda crassicornis does not bind to Torpedo nAChR but behaves as an agonist on human α7 nAChR. To get more selective α-conotoxins, computer modeling of their complexes with acetylcholine-binding proteins and distinct nAChRs was used. Several novel three-finger neurotoxins targeting nAChRs were described and α-Bgt inhibition of GABA-A receptors was discovered. Information on the mechanisms of nAChR interactions with the three-finger proteins of the Ly6 family was found. Snake venom phospholipases A2 were recently found to inhibit different nAChR subtypes. Blocking of nAChRs in Lymnaea stagnalis neurons was shown for venom C-type lectin-like proteins, appearing to be the largest molecules capable to interact with the receptor. A huge nAChR molecule sensible to conformational rearrangements accommodates diverse binding sites recognizable by structurally very different compounds.

The first representatives of a new group of manzamine-related alkaloids with a previously unknown skeletal systems, namely, lissodendoric acids A (1) and B (2), were isolated from the sponge Lissodendoryx florida collected from the Sea of Okhotsk. The structures and absolute configurations have been elucidated by extensive spectroscopic analysis together with chemical transformations and quantum-chemical modeling. The lissodendoric acids show a potent capability to decrease the production of reactive oxygen species in neuroblastoma Neuro 2a and somewhat increase the survival of these cells upon treatment with 6-hydroxydopamine (an in vitro antiparkinson biotest).

Marine sponges contain a variety of low-molecular-weight compounds including guanidine alkaloids possessing different biological activities. Monanchomycalin B and urupocidin A were isolated from the marine sponge Monanchora pulchra. We found that they act as inhibitors of the TRPV1, TRPV2, and TRPV3 channels, but are inactive against the TRPA1 receptor. Monanchomycalin B is the most active among all published marine alkaloids (EC50 6.02, 2.84, and 3.25 μM for TRPV1, TRPV2, and TRPV3, correspondingly). Moreover, monanchomycalin B and urupocidin A are the first samples of marine alkaloids affecting the TRPV2 receptor. Two semi-synthetic urupocidin A derivatives were also obtained and tested against TRP (Transient Receptor Potential) receptors that allowed us to collect some data concerning the structure-activity relationship in this series of compounds. We showed that the removal of one of three side chains or double bonds in the other side chains in urupocidin A led to a decrease of the inhibitory activities. New ligands specific to the TRPV subfamily may be useful for the design of medicines as in the study of TRP channels biology.

Urupocidins A and B (1 and 2), bisguanidine alkaloids with an unprecedented skeleton system, derived from polyketide precursors and containing an unusual N-alkyl-N-hydroxyguanidine moiety, have been isolated from the sponge Monanhora pulchra. The structures of 1 and 2, including absolute configuration, were established using the detailed analysis of 1D and 2D NMR, CD, and mass spectra as well as chemical transformations. Compound 1 increases nitric oxide production in murine macrophages via inducing iNOS expression.

For a small library of natural products from marine sponges and ascidians, in silico docking to the Lymnaea stagnalis acetylcholine-binding protein (AChBP), a model for the ligand-binding domains of nicotinic acetylcholine receptors (nAChRs), was carried out and the possibility of complex formation was revealed. It was further experimentally confirmed via competition with radioiodinated α-bungarotoxin ([¹²⁵I]-αBgt) for binding to AChBP of the majority of analyzed compounds. Alkaloids pibocin, varacin and makaluvamines С and G had relatively high affinities (K(i) 0.5-1.3 μM). With the muscle-type nAChR from Torpedo californica ray and human neuronal α7 nAChR, heterologously expressed in the GH4C1 cell line, no competition with [¹²⁵I]-αBgt was detected in four compounds, while the rest showed an inhibition. Makaluvamines (K(i) ~ 1.5 μM) were the most active compounds, but only makaluvamine G and crambescidine 359 revealed a weak selectivity towards muscle-type nAChR. Rhizochalin, aglycone of rhizochalin, pibocin, makaluvamine G, monanchocidin, crambescidine 359 and aaptamine showed inhibitory activities in electrophysiology experiments on the mouse muscle and human α7 nAChRs, expressed in Xenopus laevis oocytes. Thus, our results confirm the utility of the modeling studies on AChBPs in a search for natural compounds with cholinergic activity and demonstrate the presence of the latter in the analyzed marine biological sources.

A new marine guanidine-containing compound, pulchranin A ( 1 ) was isolated from the marine sponge Monanchora pulchra . Its structure was elucidated by detailed NMR and MS analyses. The Mosher’s method did not allow determination of the absolute configuration of the carbinol center in 1 , but after conversion of 1 into the bis-MTPA esters of 1,3-diol 2 , the same method was successfully used to solve the problem. Compound 1 was active as an inhibitor of the TRPV1 receptor with an EC 50 value of 41.2 μM.

New pentacyclic guanidine alkaloids, monanchomycalins A (1) and B (2) were isolated from the marine sponge, Monanchora pulchra and their structures elucidated using NMR, HRMALDI-TOF-MS, and HRESI MS, as well as by chemical transformations of 1. Compounds 1 and 2 exhibited potent cytotoxic activities against HL-60 human leukemia cells with IC50 values of 120 and 140 nM, respectively.

Previously, we have purified three distinct DNases from spermatozoa of sea urchin Strongylocentrotus intermedius and we suppose the role of Ca(2+), Mg(2+)-dependent DNase (Ca, Mg-DNase) in apoptosis of spermatozoa. Two-headed sphingolipid rhizochalin (Rhz) induced characteristic apoptotic nuclear chromatin changes, internucleosomal DNA cleavage, and activation of caspase-9, caspase-8, and caspase-3 in spermatozoa as was shown by fluorescence Hoechst 33342/PI/FDA analysis, DNA fragmentation assay, and fluorescence caspase inhibitors FAM-LEHD-fmk, FAM-IETD-fmk, and FAM-DEVD-fmk, respectively. Inhibitor of caspase-3 z-DEVD-fmk subdued Rhz-induced internucleosomal ladder formation, which confirmed the major role of caspase-3 in apoptotic DNA cleavage probably through Ca, Mg-DNase activation. Participation of sea urchin Ca, Mg-DNase in apoptosis of spermatozoa was demonstrated by ions Zn(2+) blocking of Rhz-induced DNA fragmentation due to direct inhibition of the Ca, Mg-DNase and internucleosomal cleavage of HeLa S and Vero E6 cell nuclei chromatin by highly purified Ca, Mg-DNase.

Rhizochalin [(2R,3R,26R,27R)-2,27-diamino-3-hydroxy-26-[(2R,3R,4S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy]octacosan-11-one], an antimicrobial and cytotoxic marine two-headed sphingolipid-like natural product, isolated from the sponge Rhizochalina incrustata, and some related compounds were studied as anticarcinogenic and proapoptotic agents. The corresponding effects were tested on the mouse skin epidermal JB6 P(+) Cl 41 cell line, its stable transfectants, THP-1, HeLa, and SNU-C4 human tumor cells using a variety of assessments, including cell viability (MTS), flow cytometry, anchorage-independent soft agar, and luciferase assays. At 5-10 muM concentrations, rhizochalin was effective as an inhibitor of the malignant transformation of JB6 P(+) Cl 41 cells or colony formation of human tumor cells, which exerted its action, at least in part, through the induction of p53-dependent apoptosis. Structure-activity relationship study showed aglycon of rhizochalin to be the most active while peracetylated aglycon was the least active among the compounds studied.

The chemical composition of water-ethanol extracts of the brown algae Laminaria cichorioides, Costaria costata, and Fucus evanescens were studied. The extracts contained mannitol, iodine, micro elements, free amino acids, glycolipids, polyunsaturated fatty acids, fucosterine, and polyphenols. The extracts were distinguished by high contents of mannitol and iodine (L. cichorioides), lipophilic matter (C. costata), and polyphenol compounds (F. evanescens). All the extracts under study inhibited the growth of DLD-1 and HT-29 human intestine tumor cells. The strongest inhibitory effect was exerted by the extract of F. evanescens at a concentration of 50 μg/ml. The extracts can be recommended for the production of fucosterol, phlorotannins, chlorophyll derivatives, mannitol, and compositions for medical and veterinary application.

Rhizochalins C and D ( 1, 2), new representatives of two-headed glycosphingolipids, were isolated from the sponge Rhizochalina incrustata. Rhizochalin D is an unexpected C 29 homologue of the canonical C 28 dimeric sphingolipid structures. Their structures including absolute configurations were established using spectroscopic data, micromolar-scale Baeyer-Villiger oxidation, and LCMS interpretation of the products. Application of the latter method leads to a revision of the structure of oceanapiside and placement of the keto group at C-18 rather than C-11.

The guanidine alkaloids, dihydropulchranin A (2), prepared from pulchranin A from the sponge Monanchora pulchra, and hexadecylguanidine (3), a synthetic analog of pulchranins, were studied for their TRPV channel-regulating activities. Compound 2 was active as an inhibitor of rTRPV1 and hTRPV3 receptors with EC50 values of 24.3 and 59.1 μM, respectively. Hexadecylguanidine (3) was not active against these receptors.