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Rhizochalinin (Rhiz) is a recently discovered cytotoxic sphingolipid synthesized from the marine natural compound rhizochalin. Previously, Rhiz demonstrated high in vitro and in vivo efficacy in various cancer models. Here, we report Rhiz to be highly active in human glioblastoma cell lines as well as in patient-derived glioma-stem like neurosphere models. Rhiz counteracted glioblastoma cell proliferation by inducing apoptosis, G2/M-phase cell cycle arrest, and inhibition of autophagy. Proteomic profiling followed by bioinformatic analysis suggested suppression of the Akt pathway as one of the major biological effects of Rhiz. Suppression of Akt as well as IGF-1R and MEK1/2 kinase was confirmed in Rhiz-treated GBM cells. In addition, Rhiz pretreatment resulted in a more pronounced inhibitory effect of γ-irradiation on the growth of patient-derived glioma-spheres, an effect to which the Akt inhibition may also contribute decisively. In contrast, EGFR upregulation, observed in all GBM neurospheres under Rhiz treatment, was postulated to be a possible sign of incipient resistance. In line with this, combinational therapy with EGFR-targeted tyrosine kinase inhibitors synergistically increased the efficacy of Rhiz resulting in dramatic inhibition of GBM cell viability as well as a significant reduction of neurosphere size in the case of combination with lapatinib. Preliminary in vitro data generated using a parallel artificial membrane permeability (PAMPA) assay suggested that Rhiz cannot cross the blood brain barrier and therefore alternative drug delivery methods should be used in the further in vivo studies. In conclusion, Rhiz is a promising new candidate for the treatment of human glioblastoma, which should be further developed in combination with EGFR inhibitors.

Assimiloside A (1), an unprecedented marine glycolipid containing a γ-lactone of 4R,16,26R-trihydroxy C28fatty acid as an aglycon and a trisaccharide carbohydrate moiety, was isolated from the marine sponge Hymeniacidon assimilis. Its structure was elucidated by NMR spectroscopy, mass spectrometry, chemical transformations, and ECD spectroscopy combined with time-dependent density functional theory calculations. Assimiloside A at nontoxic concentrations of 0.01–0.1 μM was shown to present lysosomal activity stimulation and intracellular reactive oxygen species level elevation in RAW 264.7 murine macrophages.

The bacterium Streptomycessp. KMM 9044 from a sample of marine sediment collected in the northwestern part of the Sea of Japan produces highly chlorinated depsiheptapeptides streptocinnamides A (1) and B (2), representatives of a new structural group of antibiotics. The structures of 1and 2were determined using nuclear magnetic resonance and mass spectrometry studies and confirmed by a series of chemical transformations. Streptocinnamide A potently inhibits Micrococcussp. KMM 1467, Arthrobactersp. ATCC 21022, and Mycobacterium smegmatisMC2 155.

Toporosides A–D (1–4), new ω-glycosylated fatty acid amides, were isolated from the sponge Stelodoryx toporoki. The structures of these compounds, including absolute configurations of stereogenic centers, were established using analysis of 1D and 2D NMR, ECD, and HR mass spectra as well as chemical transformations. Toporosides A (1) and B (2) are the first lipids containing a cyclopentenyl α,β-unsaturated carbonyl moiety in the polymethylene chain. Toporoside C (3) is likely a precursor, which undergoes intramolecular aldol condensation to produce 1and 2. Toporosides A, C, and D showed protective effects against TNF-α-induced injury in H9c2 cardiomyocytes.

Background: The researchers of PIBOC RAS developed the dermo-protective topical drug called «Kourochitin», active substance of which is known quinazoline alkaloid tryptanthrin. In the present work, therapeutic efficacy of this drug in the treatment of allergic dermatosis was evaluated. Methods: Dermo-protective action of «Kourochitin» was studied in tow murine models: 2, 4- dinitrofluorobenzene- induced allergic contact dermatitis (ACD) and imiquimod-induced psoriasis. Results and Discussion: In a model ACD, it was shown that «Kourochitin» exhibits the curative action on pathophysiological, hematological and immunological parameters in ACD. Namely, «Kourochitin» 1) reduces the level of erythema in the allergen damaged skin area and increases the healing index of the epidermis; 2) normalizes the content of eosinophils, basophils and monocytes in the blood of experimental animals; 3) inhibits the production of main pro-inflammatory cytokines: interleukins - 1 and 2, interferon-gamma, and granulocyte-macrophage colony-stimulating factor. In a murine model of imiquimod-induced psoriasis, it was shown that «Kourochitin» application led to reduction in psoriasis severity on the inflamed epidermis of experimental animals. Additionally, in veterinary research, «Kourochitin»-treatment of canine atopic dermatitis almost completely eliminated signs of allergic manifestations on the epidermis. Conclusion: The obtained data suggest that «Kourochitin» as anti-inflammatory, anti-allergic, and wound healing remedy is a potential drug for therapy of various dermatological diseases, in particular allergic skin lesions.

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 C19terpenoids (1, 2) with an unprecedented carbon skeleton (A) were isolated from a Stellettasp. 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 1and 2from isomalabaricane triterpenoids are discussed. Compounds 1and 2significantly 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 1and 1a. Compound 3was proved to be a natural inhibitor of alkaline phosphatase.

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 2and 3inhibit AP-1- and NF-kB-dependent transcriptional activities in JB6 Cl41 cells at noncytotoxic concentrations, demonstrating potential cancer preventive activity.

This review addresses in-depth recent structure-activity relationship (SAR) studies published in 2015 on new marine compounds and their synthetic analogues with potential or established anticancer activity. Priority was given to papers on in vitro screening methods of marine-derived bioactive compounds, usually performed using panels of human cancer cell lines, as a first step of the anticancer drugs discovery process. Our review describes compounds belonging to different classes of substances, namely terpenoids, glycosides, alkaloids, steroids, as well as other small molecular compounds. We believe that our review will not only help chemists in the design and synthesis of novel anticancer compounds possessing specific cytotoxic or cytostatic activity in human cancer cells, but will also extend the existing databases comprising data on bioactivity of marine natural compounds.

Seven new asterosaponins, pentaregulosides A–G (1–7), including two furostane-type steroid oligoglycosides (2, 3), along with four previously known compounds (8–11) were isolated from the ethanolic extract of the starfish Pentaceraster regulus, collected off the coast of Vietnam. The structures of 1–7were elucidated by extensive NMR and ESIMS techniques as well as chemical transformations. The aglycons of compounds 1and 3have not previously been observed in starfish steroid oligoglycosides, while the aglycons of compounds 2and 4–6are very rare for this structural group. Compound 1exhibited cytotoxic activity with an IC50value of 6.4 ± 0.3 μM against RAW 264.7 murine macrophages. In contrast, nontoxic asterosaponins 3, 4, and 5showed a potential immunomodulatory action at a concentration of 5 μM, reducing by 40%, 28%, and 55%, respectively, reactive oxygen species formation in the RAW 264.7 cells, co-stimulated with the pro-inflammatory endotoxic lipopolysaccharide from E. coli.

Ten new polyhydroxysteroidal glycosides, anthenosides L–U (1–10), with rare positions of carbohydrate fragment attachments, were isolated from the starfish Anthenea aspera. The structures of 1–10were established by NMR and ESIMS techniques as well as by chemical transformations. The unoxidized Δ22-24-nor-cholestane (1), (24S)-Δ22-24-methylcholestane (2–5), and Δ22-cholestane (7) side chains of the steroidal aglycons, 3-O-methyl-β-d-galactofuranosyl residue (2, 8), and 5α-cholest-8(14)-ene-3α,7β,16α-trihydroxysteroidal nucleus (9, 10) have not been found previously in starfish polar steroidal compounds. The mixture of glycosides 9and 10showed hemolytic activity with an EC50= 8 μM. Compound 4at a dose of 10 μM exhibited a potential immunomodulatory action, decreasing by 24% the intracellular ROS content in RAW 264.7 murine macrophages, induced by pro-inflammatory endotoxic lipopolysaccharide from E. coli.

The free sterol fraction from the deep-sea holothurian Orphnurguscf glaberWalsh, 1891, has been isolated and studied by GC–MS. Sterols containing Δ7, Δ0, Δ5, polyunsaturated and 5,8-epidioxy modified cores were found. A high percentage of compounds with polyunsaturated cores distinguish this composition from those of previously studied holothurians. Almost all identified compounds had saturated side chains, which is also a specific feature of this fraction. Peculiarities of biosynthesis and metabolism of the found sterols are discussed.

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

Neopetrosides A (1) and B (2), new naturally occurring ribosides of nicotinic acid with extremely rare α-N-glycoside linkages and residues of p-hydroxybenzoic and pyrrole-2-carboxylic acids attached to C-5′, were isolated from a marine Neopetrosiasp. sponge. Structures 1and 2were determined by NMR and MS methods and confirmed by the synthesis of 1and its β-riboside analogue (3). Neopetroside A (1) upregulates mitochondrial functions in cardiomyocytes.

Five new steroid glycosides, luzonicosides B–E (2–5), belonging to a rare structure group of marine glycosides, containing carbohydrate moieties incorporated into a macrocycle, and a related open carbohydrate chain steroid glycoside, luzonicoside F (6), were isolated from the starfish Echinaster luzonicusalong with the previously known cyclic steroid glycoside luzonicoside A (1). The structures of compounds 2–6were established by extensive NMR and ESIMS techniques as well as chemical transformations. Luzonicoside A (1) at concentrations of 0.01–0.1 μM was shown to be potent in lysosomal activity stimulation, intracellular ROS level elevation, and NO synthesis up-regulation in RAW 264.7 murine macrophages. Luzonicoside D (4) was less active in these biotests.

Six new triterpenoids (1–6) and the previously known penasterone, acetylpenasterol, and ergosta-4,24(28)-dien-3-one were isolated from a Penaressp. sponge collected from Vietnamese waters. Structures of the obtained compounds were established by extensive 1D and 2D NMR spectroscopy and mass spectrometry. Configurations of the triterpene epoxy lactones (1–4) were determined on the basis of NOESY and CD data and calculation of spin coupling constants and confirmed by X-ray crystallographic analysis of compound 2. The isolated triterpenoid 6was cytotoxic against human leukemia HL-60 cells (IC50= 9.7 μM).

New unusual polycyclic guanidine alkaloids monanchocidins B–E (2–5) along with monanchocidin A (1), which we recently described, were isolated from the Far-Eastern marine sponge Monanchora pulchra. Their structures were established using spectroscopic data and chemical transformations. Compounds 1–5show potent cytotoxic activities against HL-60 human leukemia cells with IC50values of 540, 200, 110, 830, and 650 nM, respectively.

The structures and mechanisms of biological action of the best known representatives of the main groups of marine toxins are presented. It is shown that many compounds have complex chemical structures and possess extremely high toxicities. Characteristic features of isolation, structure determination and syntheses of these compounds using the achievement of modern organic chemistry are discussed. The methods of identification and quantitative analysis of marine toxins are briefly reviewed.

Dendritic cells (DCs) are the most potent antigen-presenting cells for naive T cells. In this study, scavenger receptor class A type I and type II (SR-A) were shown to be expressed by peripheral blood DCs (PBDCs) and monocyte-derived DCs (MDDCs). In addition, the binding of anti–SR-A antibody to these cells was lower in the presence of fucoidan, an SR-A agonist. Treatment of these DCs with fucoidan or anti–SR-A antibody markedly increased the surface expression of costimulatory molecules CD83 and major histocompatibility complex class II on the CD11chighCD123lowmyeloid subset of PBDCs. Furthermore, fucoidan-treated PBDCs produced tumor necrosis factor-α (TNF-α) but not IL-12p70. In addition, fucoidan-induced maturation was eliminated by pretreatment with TNF-α–neutralizing antibody. Finally, interferon-γ secretion and T-cell proliferation were enhanced by coculture of T cells with fucoidan-matured PBDCs. Specific inhibitors of p38 MAPK and glycogen synthase kinase 3 suppressed TNF-α production and maturation of fucoidan-treated PBDCs. Moreover, MDDCs lacking SR-A failed to up-regulate CD83 expression, TNF-α production, and phosphorylation of p38 MAPK and glycogen synthase kinase 3-β in the presence of fucoidan. Taken together, these results suggest that ligation of SR-A leads to induction of TNF-α, which subsequently induces PBDC maturation, thereby leading to enhanced T-cell stimulatory capacity.

Dendritic cells (DCs) are the most potent antigen-presenting cells for naive T cells. In this study, scavenger receptor class A type I and type II (SR-A) were shown to be expressed by peripheral blood DCs (PBDCs) and monocyte-derived DCs (MDDCs). In addition, the binding of anti–SR-A antibody to these cells was lower in the presence of fucoidan, an SR-A agonist. Treatment of these DCs with fucoidan or anti–SR-A antibody markedly increased the surface expression of costimulatory molecules CD83 and major histocompatibility complex class II on the CD11chighCD123low myeloid subset of PBDCs. Furthermore, fucoidan-treated PBDCs produced tumor necrosis factor-α (TNF-α) but not IL-12p70. In addition, fucoidan-induced maturation was eliminated by pretreatment with TNF-α–neutralizing antibody. Finally, interferon-γ secretion and T-cell proliferation were enhanced by coculture of T cells with fucoidan-matured PBDCs. Specific inhibitors of p38 MAPK and glycogen synthase kinase 3 suppressed TNF-α production and maturation of fucoidan-treated PBDCs. Moreover, MDDCs lacking SR-A failed to up-regulate CD83 expression, TNF-α production, and phosphorylation of p38 MAPK and glycogen synthase kinase 3-β in the presence of fucoidan. Taken together, these results suggest that ligation of SR-A leads to induction of TNF-α, which subsequently induces PBDC maturation, thereby leading to enhanced T-cell stimulatory capacity.

Three new triterpene glycosides, achlioniceosides A1(1), A2(2), and A3(3), have been isolated from the Antarctic sea cucumber Achlionice violaecuspidata. The glycoside structures were elucidated using extensive NMR spectroscopic analysis including one-dimensional 1H and 13C spectra, 1H−1H-COSY, HMBC, HMQC, and NOESY and mass spectrometry. Gycosides 1−3are disulfated pentaosides that are branched at the first xylose residue. The sulfates are attached to C-6 of the glucose residues. Glycosides 1−3are the first triterpene glycosides isolated from a sea cucumber belonging to the order Elasipodida.

Five new triterpene glycosides, liouvillosides A 1( 1), A 2( 2), A 3( 3), B 1( 4), and B 2( 5), have been isolated from the Antarctic sea cucumber Staurocucumis liouvielleialong with the known liouvilloside A ( 6), isolated earlier from the same species, and hemoiedemosides A ( 7) and B ( 8), isolated earlier from the Patagonian sea cucumber Hemioedema spectabilis. The isolation was carried out using a new chromatographic procedure including application of ion-pair reversed-phase chromatography followed by chiral chromatography on a cyclodextrin ChiraDex column. The structures of the new glycosides were elucidated using extensive NMR spectroscopy ( 1H and 13C NMR spectrometry, DEPT, 1H− 1H COSY, HMBC, HMQC, and NOESY), ESI-FTMS, and CID MS/MS, and chemical transformations. Glycosides 1− 3are disulfated tetraosides and glycosides 4and 5are trisulfated tetraosides. Glycosides 2and 3contain 3- O-methylquinovose, found for the first time as a natural monosaccharide in sea cucumber glycosides. On the basis of analyses of glycoside structures a taxonomic revision is proposed.

Three novel steroidal triglycosides, designated as kurilensosides A, B, and C ( 1– 3), were isolated along with a new steroidal diglycoside, kurilensoside D ( 4), and two new ( 6, 7) and one known ( 5) polyhydroxysteroid from the alcoholic extract of the Far Eastern starfish Hippasteria kurilensis. Compounds 1– 3are the first triglycosides containing two carbohydrate chains found from starfish. The structures of 1– 7were elucidated by spectroscopic methods (mainly 2D NMR) and chemical derivatization. Glycosides 1– 4and steroids 6and 7inhibited sea urchin egg fertilization by sperm preincubated with these compounds.

Three new triterpene oligoglycosides, okhotosides B 1( 1), B 2( 2), and B 3( 3), have been isolated from the sea cucumber Cucumaria okhotensisalong with the known compounds frondoside A ( 4), frondoside A 1, cucumarioside A 2-5, and koreoside A. The structures of 1– 3were elucidated on the basis of their spectroscopic data (2D NMR and MS). Compounds 1– 3were moderately toxic against HeLa tumor cells. Frondoside A ( 4) showed more potent cytotoxicity against THP-1 and HeLa tumor cell lines (with IC 50values of 4.5 and 2.1 µg/mL, respectively) and decreased both the AP-1-dependent trascriptional activities induced by UVB, EGF, or TPA in JB6-LucAP-1 cells and the EGF-induced NF-κB-dependent transcriptional activity in JB6-LucNF-kB cells at doses of about 1 µg/mL. At the same doses, it increased the p53-dependent transcriptional activity in nonactivated JB6-Lucp53 cells and inhibited the colony formation of JB6 P +Cl 41 cells activated with EGF (INCC 50= 0.8 µg/mL).

Two novel triterpene holostane glycosides, synaptosides A ( 1) and A 1( 2), have been isolated from the Vietnamese sea cucumber Synapta maculata(Synaptida, Apodida). Their structures were elucidated by spectroscopic methods (NMR and MS) and chemical transformations. Glycosides 1and 2have rare branched pentasaccharide carbohydrate chains featuring a 3- O-methylglucuronic acid residue not previously reported in glycosides from sea cucumbers and a 6- O-sulfated glucose. Glycoside 2has an oxo group at C-7 and a 8(9)-double bond. All these structural features are unknown in glycosides from sea cucumbers. Glycoside 1has moderate cytotoxic activity (IC 508.6 µg/mL) and glycoside 2is inactive against HeLa tumor cells.

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 29homologue of the canonical C 28dimeric 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.

Five new (1, 2, 4−6) and one known (3) diterpenoid were isolated from the keratose sponge Spongia (Heterofibria) sp. Structures of these compounds and their absolute configurations were proposed on the basis of X-ray analysis of 1, its CD spectrum, and NMR and MS spectroscopic studies of 1−6. One of the new diterpenoids was shown to be 2(R),3(S),4(S)-3,18-methylene-2-acetoxyspongia-13(16),14-diene (6), possessing a novel carbon skeleton system.

Nine new triterpene glycosides, erylosides F1−F4(1−4), M (5), N (6), O (7), P (8), and Q (9), along with previously known erylosides F (10) and H (11) were isolated from the sponge Erylus formosuscollected from the Mexican Gulf (Puerto Morelos, Mexico). Structures of 1−4were determined as the corresponding biosides having aglycons related to penasterol with additional oxidation patterns in their side chains. Erylosides 5−9contain new variants of carbohydrate chains with three (5, 6), four (7), and six (8, 9) sugar units, respectively. Erylosides 5, 7, 8, and 6, 9contain 14-carboxy-24-methylenelanost-8(9)-en-3-ol and penasterol as aglycons, respectively. In contrast with its epimer 2, the compound 3induced the early apoptosis of Ehrlich carcinoma cells at a concentration of 100 g/mL, while 1and 10activated the Ca2influx into mouse spleenocytes (130% of the control) at the same doses.

Five new polar steroids, polyhydroxysterols 2−5 and the glycoside leviusculoside J (7), were isolated, along with the previously known compounds 1, 6, 8, and 9, from the alcoholic extract of the Far Eastern starfish Henricia leviuscula. The structures of novel compounds were elucidated by interpretation of spectral data (mainly 2D-NMR), and the stereochemistry of chiral centers in the side chain of sterols 2 and 3 was determined by using J-based configuration analysis and the modified Mosher's method. Steroids 1, 3, 6, 7, and 9 showed moderate hemolytic activity in the mouse erythrocytes assay.

3-Demethylubiquinone Q2(1) was isolated from the ascidian Aplidium glabrum. The cancer-preventive properties and the structure–activity relationship for 3-demethylubiquinone Q2(1) and 12 of its synthetic analogs (3–14) are reported.Compounds 3–14, having one or several di- or triprenyl substitutions and quinone moieties with methoxyls in different positions, were synthesized. The cancer-preventive properties of compounds 1and 3–14were tested in JB6 Cl41 mouse skin cells, using a variety of assessments, including the methanethiosulfonate (MTS) assay, flow cytometry, and soft agar assay. Statistical nonparametric methods were used to confirm statistical significance.All quinones tested were shown to inhibit JB6 Cl41 cell transformation, to induce apoptosis, AP-1, and NF-κB activity, and to inhibit p53 activity. The most promising effects were indicated for compounds containing two isoprene units in a side chain and a methoxyl group at the para-position to a polyprenyl substitution.Quinones 1and 3–14demonstrated cancer-preventive activity in JB6 Cl41 cells, which may be attributed to the induction of p53-independent apoptosis. These activities depended on the length of side chains and on the positions of the methoxyl groups in the quinone part of the molecule.

Triterpene glycosides are characteristic metabolites of sea cucumbers (Holothurioidea, Echinodermata). Majority of the glycosides belong to holostane type (lanostane derivatives with 18(20)-lactone). Carbohydrate chains of these glycosides contain xylose, glucose, quinovose, 3-O-methylglucose and 3-O-methyl sylose. During the last 5 years, main investigations were focused on holothurians belonging to the order Dendrochirotida collected in the North Pacific, North Atlantic, Antarctic and in subtropical waters. The glycosides of holothurians belonging to the order Aspidochirotida have also been studied. The most uncommon structural features of carbohydrate chains of new glycosides were: (1) the presence of quinovose as fifth terminal monosaccharide unit and the presence of two quinovose residues; (2) the presence of glucose instead of common xylose as fifth terminal monosaccharide unit; (3) trisaccharide carbohydrate chain; (4) the presence of two 3-O-methylxylose terminal monosaccharide units; (5) the presence of sulfate group at C-3 of quinovose residue. New glycosides without lactone or with 18(16)-lactone and having shortened side chains have also been isolated. The presence of 17α and 12α-hydroxyls, which are characteristic for glycosides from holothurians belonging to the family Holothuriidae (Aspidochirotida) in glycosides of dendrochirotids confirms parallel and relatively independent character of evolution of glycosides. All three families belonging to the order Aspidochirotida: Holothuriidae, Stichopodidae and Synallactidae have similar and parallel trends in evolution of the glycosides carbohydrate chains, namely from non-sulfated hexaosides to sulfated tetraosides. Sets of aglycones in glycosides from holothurians belonging to the genus Cucumaria (Cucumariidae, Dendrochirotida) are specific for each species. The carbohydrate chains are similar in all representatives of the genus Cucumaria.

Abstract: Triterpene glycosides are characteristic metabolites of sea cucumbers (Holothurioidea, Echinodermata). Majority of the glycosides belong to holostane type (lanostane derivatives with 18(20)-lactone). Carbohydrate chains of these glycosides contain xylose, glucose, quinovose, 3-O-methylglucose and 3-O-methyl sylose. During the last 5 years, main investigations were focused on holothurians belonging to the order Dendrochirotida collected in the North Pacific, North Atlantic, Antarctic and in subtropical waters. The glycosides of holothurians belonging to the order Aspidochirotida have also been studied. The most uncommon structural features of carbohydrate chains of new glycosides were: (1) the presence of quinovose as fifth terminal monosaccharide unit and the presence of two quinovose residues; (2) the presence of glucose instead of common xylose as fifth terminal monosaccharide unit; (3) trisaccharide carbohydrate chain; (4) the presence of two 3-O-methylxylose terminal monosaccharide units; (5) the presence of sulfate group at C-3 of quinovose residue. New glycosides without lactone or with 18(16)-lactone and having shortened side chains have also been isolated. The presence of 17α and 12α-hydroxyls, which are characteristic for glycosides from holothurians belonging to the family Holothuriidae (Aspidochirotida) in glycosides of dendrochirotids confirms parallel and relatively independent character of evolution of glycosides. All three families belonging to the order Aspidochirotida: Holothuriidae, Stichopodidae and Synallactidae have similar and parallel trends in evolution of the glycosides carbohydrate chains, namely from non-sulfated hexaosides to sulfated tetraosides. Sets of aglycones in glycosides from holothurians belonging to the genus Cucumaria (Cucumariidae, Dendrochirotida) are specific for each species. The carbohydrate chains are similar in all representatives of the genus Cucumaria.

Polycarpine from ascidian Polycarpa auratawas previously found to be active against different human tumor cells. In this study, we investigated the antitumor mechanisms of polycarpine and its synthetic derivative, desmethoxyethoxy-polycarpine (dimethylpolycarpine), through the induction of apoptosis. This new knowledge regarding the proapoptotic action of polycarpine and dimethylpolycarpine should lead to a better understanding of their effects and development of a new class of anticancer drugs. Apoptosis was clearly observed by flow cytometry and Western blotting using an antibody against cleaved caspase-3 as an apoptotic marker. Polycarpines differentially activated p38 kinase, JNKs, and ERKs in JB6 Cl 41 cells. The polycarpines-induced apoptosis was decreased in cells expressing a dominant-negative mutant of JNK. Both compounds stimulated p53-dependent transcriptional activity and phosphorylation. Induction of p53-phosphorylation at serine 15 was suppressed in JNK1 and JNK2 knockout cells. Furthermore, polycarpines were unable to induce apoptosis in p53-deficient MEFs in contrast to a strong induction of apoptosis in wild type MEFs, suggesting that p53 is involved in apoptosis induced by polycarpines. The p53 phosphorylation in turn was mediated by activated JNKs. These results indicate that all three MAPK signaling pathways are involved in the response of JB6 cells to treatment with polycarpines. Evidence also supports a proapoptotic role of the JNKs signaling pathway in vivoand clearly indicates that JNKs are required for phosphorylation of c-Jun, activation of p53, and subsequent apoptosis induced by polycarpines.

Structures, taxonomic distribution and biological activities of polar steroids isolated from various marine organisms over the last 8—10 years are considered. The peculiarities of steroid biogenesis in the marine biota and their possible biological functions are discussed. Syntheses of some highly active marine polar steroids are described. The bibliography includes 254 references.

No Abstract Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2002/2000/z15254_s.pdf or from the author.

No Abstract Supporting information for this article is available on the WWW under http://www.wiley-vch.de/contents/jc_2001/2000/z15254_s.pdf or from the author.

Structural diversity of triterpene glycosides produced by sea cucumbers or holothurians (Holothuroidea, Echinodermata) is extremely high, although all of them are either lanostane derivatives or, rarely, products of their molecular rearrangements. The majority of them are holostane derivatives possessing an 18(20)-lanostane lactone as aglycone. They contain carbohydrate chains consisting of one to six monosaccharide units including sulfated ones. The glycosides demonstrate interesting biological activities, mainly caused by membranolytic action, namely cytotoxic, ichthyotoxic, antifungal, and hemolytic properties, as well as a series of additional effects at sub-toxic doses, including immunomodulatory, and cancer preventive. This review summarizes the literature data concerning structures and biological activities of all the new triterpene glycosides isolated from sea cucumbers during 2017 to 2021.

Pibocin 11The name is coined from PIBOC (Pacific Institute of Bioorganic Chemistry).( 1), the first representative of marine ergoline alkaloids, was isolated from the Far-Eastern ascidian Eudistoma sp. Its structure and absolute stereochemistry have been established as (8β)-2-bromo-6,8-dimethylergoline on the basis of spectroscopic and X-Ray analysis data. Pibocin showed moderate cytotoxic activity against mouse Ehrlich carcinoma cells.

Frondoside C (1) is a new sulfated nonholostane triterpene glycoside obtained (with the glycosides closed by aglycone structure as impurities) from the sea cucumber Cucumaria frondosa. Its structure has been elucidated on the basis of spectral data (NMR and MS) of compound 1and of its desulfated derivative (2) obtained by solvolysis. Frondoside C (1) is just the seventh glycoside reported from sea cucumbers, having a lanostane-type aglycone devoid of the typical 18(20)- lactone ring.Key words: Cucumaria frondosa, sea cucumbers, frondosides, triterepene glycosides, antitumor activity.

Data on the membranotropic action of triterpene glycosides from sea cucumbers (Holothurioidea,Echindermata) are used as a model for studying the evolution of biochemical adaptations. Conceptions such as the theory of modes of organogenesis, and the theory of phylembryogeneses developed by the Russian school of evolutionary morphology, and other morphological trends of evolutionary transformations of anatomical structures are applicable to the phylogenetic interpretation of chemotaxonomic data. The processes of ontogenesis and biosynthesis of secondary metabolites are compared within the framework of the theory of phylembryogeneses. The deep inner similarity of these processes are shown. Concurrence of the modes of phyembryogenesis noted by Severtsov and the principles of micromolecular evolution noted by Gottlieb and Harborne are also shown. The biological significance of presence or absence of substances, (or some features of these substances) for the whole organism that produced them is the main criterion we propose as an approach for polarization of a biochemical phylogenetic series. The application of methods of comparative anatomy to the molecular level for purposes of investigation on evolution of biomolecules and their functions could be called “chemical morphology”.

The occurrence, special aspects of structural determination, biological activities, and potential taxonomic application of eremophilane-type glycosides, a rare group of metabolites from higher plants, are reviewed. This mini review covers the literature published for period 2006 to 2018.

A new unique steroidal glycoside, granulatoside C (1), was isolated from the ethanol extract of the starfish Choriaster granulatus.The structure of 1 was elucidated by extensive NMR and ESI-MS techniques as (20R)-16,21-O-di-(P-D-fucopyranosyl)-24-methyl-cholesta-5,24(28)-diene-3p,7a,16a,21-tetraol (1). This glycoside is unusual one, because combines some characteristic structural peculiarities of steroids from several different phyla of marine invertebrates, it has a range of structural features that not previously found in starfish polyhydroxysteroidal glycosides, such as Δ5-3β,7α,16α-trihydroxysteroidal nucleus, Δ24(28)-21-hydroxy-24-methyl-cholestane side chain and 16,21-diglycosylation by D-fucopyranosyl residues, but also characteristic of sponges, ophiuroids and soft corals, respectively.

A facile synthesis of a set of deuterium-labeled steroid 3,6-diols with different steroid A/B ring fusion, unsaturations, and configurations of hydroxyl groups at C-3 and C-6 is described. Reduction and deuteration, based on deuterium-exchange of the obtained the cholest-4-ene-3,6-dione from cholesterol using sodium borodeuteride and deuterium water, were used. The obtained steroid diols are intended to be used as precursors in the studies on biosynthesis of some marine polar steroids.

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 1D- and 2D-NMR spectroscopic and mass spectrometric data. Compounds 1and 2exhibited potent cytotoxic activities against cervical epithelioid carcinoma HeLa cells and breast adenocarcinoma MDA-MB231 cells.

Two polar steroid compounds, taurochenodeoxycholic acid sodium salt (1) and a rare cyclic steroid glycoside luzonicoside A (2), were isolated from the tropical starfish Leiastersp. and identified by extensive NMR and ESIMS techniques. The isolation of primary bile acid 1 is the first report from a representative of the class Asteroidea and on the whole in invertebrates. Its presence confirms the hypothesis about the digestive role of some polar steroids in starfish and possibly demonstrates the parallel evolution of fat emulsifying agents in vertebrates and some starfish. Compound 2 was also obtained from starfish belonging to this genus for the first time. This finding indicates that cyclic steroid glycosides are more widely distributed in starfish than the two species of the genus Echinasterfrom which they were isolated earlier.

Triterpene glycosides isolated from holothurians are natural products known to possess cytotoxic properties against cancer cells. However, their anticancer prophylactic activity has not been studied sufficiently. The anticancer prophylactic, cytotoxic, and pro-apoptotic properties of 18 triterpene glycosides, as well as their effects on the transcriptional activities of activator protein-1 (AP-1) and nuclear factor-κB (NF-κB), were examined using methods that included EGF-induced JB6 Cl41 P+cell transforation in soft agar, flow cytometry, MTS assessment of cell viability, and a luciferase activity assay. The compounds inhibited EGF-induced neoplastic JB6 Cl41 P+cell transforation in soft agar and caused apoptosis and necrosis of human HL-60 and THP-1 leukemia cells. AP-1 and NF-κB were involved in the cellular response to the treatment by the compounds. Conclusion: glycosides isolated from holothurians of Cucumariidae, Stichopodidae, Psolidae, Holothuriidae and Synaptidae families have potential for development as new antitumor agents and as instruments to study AP-1 and NF-κB.

Two new natural products, 6-bromogramine (1) and bis-6-bromogramine (2) were isolated from the marine hydroid Abietinaria abietinaand their structures were established using NMR and MS analysis. Compounds 1and 2activate NF-κB-dependent transcriptional activity in JB6 Cl 41 NF-κB cells at 1.6 μM 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 1was elucidated by spectroscopic and chemical methods, including a cleavage of the C1–O7bond to obtain a secondary alcohol (3), which was used to determine the absolute configurations by Mosher's method. It was found that 1and 2were 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 polyenic fatty acid precursors was proposed.

Two new guaiane derivatives (1and 2) along with six known sesquiterpenoids (3-8) were isolated from the gorgonian Menella woodin.Their structures were elucidated by ID and 2D NMR and HRESIMS data as well as by comparison of their spectra with those in the literature. Relative configurations of asymmetric centers in 1and 2were suggested on the basis of NOESY and ID NOE correlations, absolute stereochemistry of these compounds was proposed in result of comparison of calculated (for both enatiomers) and experimental ECD. Some suggestions were made regarding a biosynthesis of guaiane sesquiterpenoids in this species. All the compounds were firstly isolated from M woodin.