New piperazine derivatives helvamides B-C from the marine-derived fungus Penicillium velutinum ZK-14 uncovered by OSMAC (One Strain Many Compounds) strategy.

Four extracts of the marine-derived fungus Penicillium velutinum J.F.H. Beyma were obtained via metal ions stress conditions based on the OSMAC (One Strain Many Compounds) strategy. Using a combination of modern approaches such as LC/UV, LC/MS and bioactivity data analysis, as well as in silico calculations, influence metal stress factors to change metabolite profiles Penicillium velutinum were analyzed. From the ethyl acetate extract of the P. velutinum were isolated two new piperazine derivatives helvamides B (1) and C (2) together with known saroclazin A (3) (4S,5R,7S)-4,11-dihydroxy-guaia-1(2),9(10)-dien (4). Their structures were established based on spectroscopic methods. The absolute configuration of helvamide B (1) as 2R,5R was determined by a combination of the X-ray analysis and by time-dependent density functional theory (TD-DFT) calculations of electronic circular dichroism (ECD) spectra. The cytotoxic activity of the isolated compounds against human prostate cancer PC-3 and human embryonic kidney HEK-293 cells and growth inhibition activity against yeast-like fungi Candida albicans were assayed.

Phanogracilins A-C, New Bibenzochromenones of Crinoid Phanogenia gracilis (Hartlaub, 1890).

Three new bibenzochromenones named phanogracilins A-C (1-3) were isolated from the crinoid Phanogenia gracilis. The structure of 1 was established using X-ray crystallography as 5,5',6,6',8,8'-hexahydroxy-2,2'-dipropyl-4H,4'H-[7,9'-bibenzo[g]chromene]-4,4'-dione. This allowed us to assign reliably 2D NMR signals for compound 1 and subsequently for its isomer 2 that differed in the connecting position of two benzochromenone moieties (7,10' instead of 7,9'), and compound for 3 that differed in the length of the aliphatic chain of one of the fragments. Compound 4 was derived from 1 in alkaline conditions, and its structure was elucidated as 5,5',6',8,8'-pentahydroxy-2,2'-dipropyl-4H,4'H-[7,9'-bibenzo[g]chromene]-4,4',6,9-tetraone. Even though compounds 1-4 did not contain stereo centers, they possessed notable optical activity due to sterical hindrances, which limited the internal rotation of two benzochromenone fragments around C(7)-C(9'/10') bonds. Isolated bibenzochromenones 1-4 were tested for their antiradical, neuroprotective and antimicrobial activities. Compounds 1, 3 and 4 demonstrated significant antiradical properties towards ABTS radicals higher than the positive control trolox. Compounds 1 and 4 exhibited moderate neuroprotective activity, increasing the viability of rotenone-treated Neuro-2a cells at a concentration of 1 µM by 9.8% and 11.8%, respectively. Compounds 1 and 3 at concentrations from 25 to 100 µM dose-dependently inhibited the growth of Gram-positive bacteria S. aureus and yeast-like fungi C. albicans, and they also prevented the formation of their biofilms. Compounds 2 and 4 exhibited low antimicrobial activity.

Bioactive Polyketides from the Natural Complex of the Sea Urchin-Associated Fungi Penicillium sajarovii KMM 4718 and Aspergillus protuberus KMM 4747.

The marine-derived fungal strains KMM 4718 and KMM 4747 isolated from sea urchin Scaphechinus mirabilis as a natural fungal complex were identified as Penicillium sajarovii and Aspergillus protuberus based on Internal Transcribed Spacer (ITS), partial ß-tubulin (BenA), and calmodulin (CaM) molecular markers as well as an ribosomal polymerase two, subunit two (RPB2) region for KMM 4747. From the ethyl acetate extract of the co-culture, two new polyketides, sajaroketides A (1) and B (2), together with (2'S)-7-hydroxy-2-(2'-hydroxypropyl)-5-methylchromone (3), altechromone A (4), norlichexanthone (5), griseoxanthone C (6), 1,3,5,6-tetrahydroxy-8-methylxanthone (7), griseofulvin (8), 6-O-desmethylgriseofulvin (9), dechlorogriseofulvin (10), and 5,6-dihydro-4-methyl-2H-pyran-2-one (11) were identified. The structures of the compounds were elucidated using spectroscopic analyses. The absolute configurations of the chiral centers of sajaroketides A and B were determined using time-dependent density functional theory (TDDFT)-based calculations of the Electronic Circular Dichroism (ECD) spectra. The inhibitory effects of these compounds on urease activity and the growth of Staphylococcus aureus, Escherichia coli, and Candida albicans were observed. Sajaroketide A, altechromone A, and griseofulvin showed significant cardioprotective effects in an in vitro model of S. aureus-induced infectious myocarditis.

Sulfated Triterpene Glycosides from the Far Eastern Sea Cucumber Cucumaria djakonovi: Djakonoviosides C1, D1, E1, and F1; Cytotoxicity against Human Breast Cancer Cell Lines; Quantitative Structure-Activity Relationships.

Four new mono- and trisulfated triterpene penta- and tetraosides, djakonoviosides C1 (1), D1 (2), E1 (3), and F1 (4) were isolated from the Far Eastern sea cucumber Cucumaria djakonovi (Cucumariidae, Dendrochirotida), along with six known glycosides found earlier in other Cucumaria species. The structures of unreported compounds were established on the basis of extensive analysis of 1D and 2D NMR spectra as well as by HR-ESI-MS data. The set of compounds contains six different types of carbohydrate chains including two new ones. Thus, djakonovioside C1 (1) is characterized by xylose as the second residue, that was a branchpoint in the pentasaccharide chain. Meanwhile, only quinovose and rarely glucose have been found earlier in pentasaccharide chains branched at C-2 of the second sugar unit. Djakonovioside E1 (3) is characterized by a tetrasaccharide trisulfated chain, with glucose as the second residue. So, in the series of isolated glycosides, three types of sugars in the second position were presented: the most common, quinovose-in six compounds; glucose-in three substances; and the rare xylose-in one glycoside. The set of aglycones was composed of holostane- and non-holostane-type polycyclic systems; the latter comprised normal and reduced side chains. Noticeably, isokoreoside A (9), isolated from C. djakonovi, was a single glycoside having a 9(11)-double bond, indicating two oxidosqualenecyclases are operating in the process of the biosynthesis of aglycones. Some of the glycosides from C. djakonovi, which were characterized by pentasaccharide branched chains containing one to three sulfate groups, are chemotaxonomic features of the representatives of the genus Cucumaria. The assortment of sugar parts of Cucumaria's glycosides was broadened with previously undescribed penta- and tetrasaccharide moieties. The metabolic network of sugar parts and aglycones is constructed based on biogenetic relationships. The cytotoxic action of compounds 1-10, isolated from C. djakonovi, against human breast cancer cell lines was investigated along with the hemolytic activity. Erythrocytes were, as usual, more sensitive to the membranolytic action of the glycosides than cancer cells. The triple-negative breast cancer MDA-MB-231 cell line was more vulnerable to the action of glycosides in comparison with the other tested cancer cells, while the MCF-7 cell line was less susceptible to cytotoxic action. Djakonovioside E1 (3) demonstrated selective action against ER-positive MCF-7 and triple-negative MDA-MB-231 cell lines, while the toxic effect in relation to normal mammary epithelial cells (MCF-10A) was absent. Cucumarioside A2-5 (6) inhibited the formation and growth of colonies of cancer cells to 44% and tumor cell migration to 85% of the control. Quantitative structure-activity relationships (QSAR) were calculated on the basis of the correlational analysis of the physicochemical properties and structural features of the glycosidic molecules and their membranolytic activity. QSAR revealed the extremely complex nature of such relationships, but these calculations correlated well with the observed SAR.

The Metabolite Profiling of Aspergillus fumigatus KMM4631 and Its Co-Cultures with Other Marine Fungi.

An Aspergillus fumigatus KMM 4631 strain was previously isolated from a Pacific soft coral Sinularia sp. sample and was found to be a source of a number of bioactive secondary metabolites. The aims of this work are the confirmation of this strain' identification based on ITS, BenA, CaM, and RPB2 regions/gene sequences and the investigation of secondary metabolite profiles of Aspergillus fumigatus KMM 4631 culture and its co-cultures with Penicillium hispanicum KMM 4689, Amphichorda sp. KMM 4639, Penicillium sp. KMM 4672, and Asteromyces cruciatus KMM 4696 from the Collection of Marine Microorganisms (PIBOC FEB RAS, Vladivostok, Russia). Moreover, the DPPH-radical scavenging activity, urease inhibition, and cytotoxicity of joint fungal cultures' extracts on HepG2 cells were tested. The detailed UPLC MS qTOF investigation resulted in the identification and annotation of indolediketopiperazine, quinazoline, and tryptoquivaline-related alkaloids as well as a number of polyketides (totally 20 compounds) in the extract of Aspergillus fumigatus KMM 4631. The metabolite profiles of the co-cultures of A. fumigatus with Penicillium hispanicum, Penicillium sp., and Amphichorda sp. were similar to those of Penicillium hispanicum, Penicillium sp., and Amphichorda sp. monocultures. The metabolite profile of the co-culture of A. fumigatus with Asteromyces cruciatus differed from that of each monoculture and may be more promising for the isolation of new compounds.

New Cyclopiane Diterpenes and Polyketide Derivatives from Marine Sediment-Derived Fungus Penicillium antarcticum KMM 4670 and Their Biological Activities.

Two new cyclopiane diterpenes and a new cladosporin precursor, together with four known related compounds, were isolated from the marine sediment-derived fungus Penicillium antarcticum KMM 4670, which was re-identified based on phylogenetic inference from ITS, BenA, CaM, and RPB2 gene regions. The absolute stereostructures of the isolated cyclopianes were determined using modified Mosher's method and quantum chemical calculations of the ECD spectra. The isolation from the natural source of two biosynthetic precursors of cladosporin from a natural source has been reported for the first time. The antimicrobial activities of the isolated compounds against Staphylococcus aureus, Escherichia coli, and Candida albicans as well as the inhibition of staphylococcal sortase A activity were investigated. Moreover, the cytotoxicity of the compounds to mammalian cardiomyocytes H9c2 was studied. As a result, new cyclopiane diterpene 13-epi-conidiogenone F was found to be a sortase A inhibitor and a promising anti-staphylococcal agent.

Anthraquinone Derivatives and Other Aromatic Compounds from Marine Fungus Asteromyces cruciatus KMM 4696 and Their Effects against Staphylococcus aureus.

New anthraquinone derivatives acruciquinones A-C (1-3), together with ten known metabolites, were isolated from the obligate marine fungus Asteromyces cruciatus KMM 4696. Acruciquinone C is the first member of anthraquinone derivatives with a 6/6/5 backbone. The structures of isolated compounds were established based on NMR and MS data. The absolute stereoconfigurations of new acruciquinones A-C were determined using ECD and quantum chemical calculations (TDDFT approach). A plausible biosynthetic pathway of the novel acruciquinone C was proposed. Compounds 1-4 and 6-13 showed a significant antimicrobial effects against Staphylococcus aureus growth, and acruciquinone A (1), dendryol B (4), coniothyrinone B (7), and ω-hydroxypachybasin (9) reduced the activity of a key staphylococcal enzyme, sortase A. Moreover, the compounds, excluding 4, inhibited urease activity. We studied the effects of anthraquinones 1, 4, 7, and 9 and coniothyrinone D (6) in an in vitro model of skin infection when HaCaT keratinocytes were cocultivated with S. aureus. Anthraquinones significantly reduce the negative impact of S. aureus on the viability, migration, and proliferation of infected HaCaT keratinocytes, and acruciquinone A (1) revealed the most pronounced effect.

Djakonoviosides A, A1, A2, B1-B4 - Triterpene Monosulfated Tetra- and Pentaosides from the Sea Cucumber Cucumaria djakonovi: The First Finding of a Hemiketal Fragment in the Aglycones; Activity against Human Breast Cancer Cell Lines.

Seven new monosulfated triterpene glycosides, djakonoviosides A (1), A1 (2), A2 (3), and B1-B4 (4-7), along with three known glycosides found earlier in the other Cucumaria species, namely okhotoside A1-1, cucumarioside A0-1, and frondoside D, have been isolated from the far eastern sea cucumber Cucumaria djakonovi (Cucumariidae, Dendrochirotida). The structures were established on the basis of extensive analysis of 1D and 2D NMR spectra and confirmed by HR-ESI-MS data. The compounds of groups A and B differ from each other in their carbohydrate chains, namely monosulfated tetrasaccharide chains are inherent to group A and pentasaccharide chains with one sulfate group, branched by C-2 Qui2, are characteristic of group B. The aglycones of djakonoviosides A2 (3), B2 (5), and B4 (7) are characterized by a unique structural feature, a 23,16-hemiketal fragment found first in the sea cucumbers' glycosides. The biosynthetic pathway of its formation is discussed. The set of aglycones of C. djakonovi glycosides was species specific because of the presence of new aglycones. At the same time, the finding in C. djakonovi of the known glycosides isolated earlier from the other species of Cucumaria, as well as the set of carbohydrate chains characteristic of the glycosides of all investigated representatives of the genus Cucumaria, demonstrated the significance of these glycosides as chemotaxonomic markers. The membranolytic actions of compounds 1-7 and known glycosides okhotoside A1-1, cucumarioside A0-1, and frondoside D, isolated from C. djakonovi against human cell lines, including erythrocytes and breast cancer cells (MCF-7, T-47D, and triple negative MDA-MB-231), as well as leukemia HL-60 and the embryonic kidney HEK-293 cell line, have been studied. Okhotoside A1-1 was the most active compound from the series because of the presence of a tetrasaccharide linear chain and holostane aglycone with a 7(8)-double bond and 16ß-O-acetoxy group, cucumarioside A0-1, having the same aglycone, was slightly less active because of the presence of branching xylose residue at C-2 Qui2. Generally, the activity of the djakonoviosides of group A was higher than that of the djakonoviosides of group B containing the same aglycones, indicating the significance of a linear chain containing four monosaccharide residues for the demonstration of membranolytic action by the glycosides. All the compounds containing hemiketal fragments, djakonovioside A2 (3), B2 (5), and B4 (7), were almost inactive. The most aggressive triple-negative MDA-MB-231 breast cancer cell line was the most sensitive to the glycosides action when compared with the other cancer cells. Okhotoside A1-1 and cucumarioside A0-1 demonstrated promising effects against MDA-MB-231 cells, significantly inhibiting the migration, as well as the formation and growth, of colonies.

Phytoceramides from the Marine Sponge Monanchora clathrata: Structural Analysis and Cytoprotective Effects.

In our research on sphingolipids from marine invertebrates, a mixture of phytoceramides was isolated from the sponge Monanchora clathrata (Western Australia). Total ceramide, ceramide molecular species (obtained by RP-HPLC, high-performance liquid chromatography on reversed-phase column) and their sphingoid/fatty acid components were analyzed by NMR (nuclear magnetic resonance) spectroscopy and mass spectrometry. Sixteen new (1b, 3a, 3c, 3d, 3f, 3g, 5c, 5d, 5f, 5g, 6b-g) and twelve known (2b, 2e, 2f, 3b, 3e, 4a-c, 4e, 4f, 5b, 5e) compounds were shown to contain phytosphingosine-type backbones i-t17:0 (1), n-t17:0 (2), i-t18:0 (3), n-t18:0 (4), i-t19:0 (5), or ai-t19:0 (6), N-acylated with saturated (2R)-2-hydroxy C21 (a), C22 (b), C23 (c), i-C23 (d), C24 (e), C25 (f), or C26 (g) acids. The used combination of the instrumental and chemical methods permitted the more detailed investigation of the sponge ceramides than previously reported. It was found that the cytotoxic effect of crambescidin 359 (alkaloid from M. clathrata) and cisplatin decreased after pre-incubation of MDA-MB-231 and HL-60 cells with the investigated phytoceramides. In an in vitro paraquat model of Parkinson's disease, the phytoceramides decreased the neurodegenerative effect and ROS (reactive oxygen species) formation induced by paraquat in neuroblastoma cells. In general, the preliminary treatment (for 24 or 48 h) of the cells with the phytoceramides of M. clathrata was necessary for their cytoprotective functions, otherwise the additive damaging effect of these sphingolipids and cytotoxic compounds (crambescidin 359, cisplatin or paraquat) was observed.

Absolute Stereochemistry and Cytotoxic Effects of Vismione E from Marine Sponge-Derived Fungus Aspergillus sp. 1901NT-1.2.2.

The metabolic profile of the Aspergillus sp. 1901NT-1.2.2 sponge-associated fungal strain was investigated using the HPLC MS technique, and more than 23 peaks in the HPLC MS chromatogram were detected. Only two minor peaks were identified as endocrocin and terpene derivative MS data from the GNPS database. The main compound was isolated and identified as known anthraquinone derivative vismione E. The absolute stereochemistry of vismione E was established for the first time using ECD and quantum chemical methods. Vismione E showed high cytotoxic activity against human breast cancer MCF-7 cells, with an IC50 of 9.0 µM, in comparison with low toxicity for normal human breast MCF-10A cells, with an IC50 of 65.3 µM. It was found that vismione E inhibits MCF-7 cell proliferation and arrests the cell cycle in the G1 phase. Moreover, the negative influence of vismione E on MCF-7 cell migration was detected. Molecular docking of vismione E suggested the IMPDH2 enzyme as one of the molecular targets for this anthraquinone derivative.

Chilensosides E, F, and G-New Tetrasulfated Triterpene Glycosides from the Sea Cucumber Paracaudina chilensis (Caudinidae, Molpadida): Structures, Activity, and Biogenesis.

Three new tetrasulfated triterpene glycosides, chilensosides E (1), F (2), and G (3), have been isolated from the Far-Eastern sea cucumber Paracaudina chilensis (Caudinidae, Molpadida). The structures were established based on extensive analysis of 1D and 2D NMR spectra and confirmed by HR-ESI-MS data. The compounds differ in their carbohydrate chains, namely in the number of monosaccharide residues (five or six) and in the positions of sulfate groups. Chilensosides E (1) and F (2) are tetrasulfated pentaosides with the position of one of the sulfate groups at C-3 Glc3, and chilensoside G (3) is a tetrasulfated hexaoside. The biogenetic analysis of the glycosides of P. chilensis has revealed that the structures form a network due to the attachment of sulfate groups to almost all possible positions. The upper semi-chain is sulfated earlier in the biosynthetic process than the lower one. Noticeably, the presence of a sulfate group at C-3 Glc3-a terminal monosaccharide residue in the bottom semi-chain of compounds 1 and 2-excludes the possibility of this sugar chain's further elongation. Presumably, the processes of glycosylation and sulfation are concurrent biosynthetic stages. They can be shifted in time in relation to each other, which is a characteristic feature of the mosaic type of biosynthesis. The hemolytic action of compounds 1-3 against human erythrocytes and cytotoxic activities against five human cancer cell lines were tested. The compounds showed moderate hemolytic activity but were inactive against cancer cells, probably because of their structural peculiarities, such as the combination of positions of four sulfate groups.

Anti-Inflammatory Activity of 1,4-Naphthoquinones Blocking P2X7 Purinergic Receptors in RAW 264.7 Macrophage Cells.

P2X7 receptors are ligand-gated ion channels activated by ATP and play a significant role in cellular immunity. These receptors are considered as a potential therapeutic target for the treatment of multiple inflammatory diseases. In the present work, using spectrofluorimetry, spectrophotometry, Western blotting and ELISA approaches, the ability of 1,4-naphthoquinone thioglucoside derivatives, compounds U-286 and U-548, to inhibit inflammation induced by ATP/LPS in RAW 264.7 cells via P2X7 receptors was demonstrated. It has been established that the selected compounds were able to inhibit ATP-induced calcium influx and the production of reactive oxygen species, and they also exhibited pronounced antioxidant activity in mouse brain homogenate. In addition, compounds U-286 and U-548 decreased the LPS-induced activity of the COX-2 enzyme, the release of pro-inflammatory cytokines TNF-α and IL-1ß in RAW 264.7 cells, and significantly protected macrophage cells against the toxic effects of ATP and LPS. This study highlights the use of 1,4-naphthoquinones as promising purinergic P2X7 receptor antagonists with anti-inflammatory activity. Based on the data obtained, studied synthetic 1,4-NQs can be considered as potential scaffolds for the development of new anti-inflammatory and analgesic drugs.

Cytoprotective Polyketides from Sponge-Derived Fungus Lopadostoma pouzarii.

The new polyketides lopouzanones A and B, as well as the new 1-O-acetyl and 2-O-acetyl derivatives of dendrodochol B, were isolated from the sponge-derived marine fungus Lopadostoma pouzarii strain 168CLC-57.3. Moreover, six known polyketides, gliorosein, balticolid, dendrodolide G, dihydroisocoumarine, (-)-5-methylmellein, and dendrodochol B, were identified. The structures of the isolated compounds were determined by a combination of NMR and ESIMS techniques. The absolute configurations of the lopouzanones A and B were determined using the Mosher's method. The cytotoxicity of the isolated compounds against human prostate cancer cells PC-3 and normal rat cardiomyocytes H9c2 was investigated. Gliorosein showed weak DPPH radical-scavenging activity and in vitro cardioprotective effects toward rotenone toxicity and CoCl2-mimic hypoxia.

The Isolation, Structure Elucidation and Bioactivity Study of Chilensosides A, A1, B, C, and D, Holostane Triterpene Di-, Tri- and Tetrasulfated Pentaosides from the Sea Cucumber Paracaudina chilensis (Caudinidae, Molpadida).

Five new triterpene (4,4,14-trimethylsterol) di-, tri- and tetrasulfated pentaosides, chilensosides A (1), A1 (2), B (3), C (4), and D (5) were isolated from the Far-Eastern sea cucumber Paracaudina chilensis. The structures were established on the basis of extensive analysis of 1D and 2D NMR spectra and confirmed by HR-ESI-MS data. The structural variability of the glycosides concerned the pentasaccharide chains. Their architecture was characterized by the upper semi-chain consisting of three sugar units and the bottom semi-chain of two sugars. Carbohydrate chains of compounds 2-5 differed in the quantity and positions of sulfate groups. The interesting structural features of the glycosides were: the presence of two sulfate groups at C-4 and C-6 of the same glucose residue in the upper semi-chain of 1, 2, 4, and 5 and the sulfation at C-3 of terminal glucose residue in the bottom semi-chain of 4 that makes its further elongation impossible. Chilensoside D (5) was the sixth tetrasulfated glycoside found in sea cucumbers. The architecture of the sugar chains of chilensosides A-D (1-5), the positions of sulfation, the quantity of sulfate groups, as well as the aglycone structures, demonstrate their similarity to the glycosides of the representatives of the order Dendrochirotida, confirming the phylogenetic closeness of the orders Molpadida and Dendrochirotida. The cytotoxic activities of the compounds 1-5 against human erythrocytes and some cancer cell lines are presented. Disulfated chilensosides A1 (2) and B (3) and trisulfated chilensoside C (4) showed significant cytotoxic activity against human cancer cells.

Structures and Biologic Activity of Chitonoidosides I, J, K, K1 and L-Triterpene Di-, Tri- and Tetrasulfated Hexaosides from the Sea Cucumber Psolus chitonoides.

Five new triterpene di-, tri- and tetrasulfated hexaosides (chitonoidosides I (1), J (2), K (3), K1 (4) and L (5)) were isolated from the Far-Eastern sea cucumber Psolus chitonoides, collected near Bering Island (Commander Islands) from a depth of 100-150 m. The structural variability of the glycosides concerned both the aglycones (with 7(8)- or 9(11)-double bonds) and carbohydrate chains differing from each other by the third sugar residue (Xyl or sulfated by C-6 Glc) and/or by the fourth-terminal in the bottom semi-chain-residue (Glc or sulfated by C-6 MeGlc) as well as by the positions of a sulfate group at C-4 or C-6 in the sixth-terminal in the upper semi-chain-residue (MeGlc). Hemolytic activities of these compounds 1-5 against human erythrocytes as well as cytotoxicity against human cancer cell lines, HeLa, DLD-1 and HL-60, were studied. The hexaosides, chitonoidosides K (3) and L (5) with four sulfate groups, were the most active against tumor cells in all the tests. Noticeably, the sulfate group at C-4 of MeGlc6 did not decrease the membranolytic effect of 5 as compared with 3, having the sulfate group at C-6 of MeGlc6. Erythrocytes were, as usual, more sensitive to the action of the studied glycosides than cancer cells, although the sensitivity of leukemia promyeloblast HL-60 cells was higher than that of other tumor cells. The glycosides 1 and 2 demonstrated some weaker action in relation to DLD-1 cells than against other tumor cell lines. Chitonoidoside K1 (4) with a hydroxyl at C 25 of the aglycone was not active in all the tests. The metabolic network formed by the carbohydrate chains of all the glycosides isolated from P. chitonoides as well as the aglycones biosynthetic transformations during their biosynthesis are discussed and illustrated with schemes.

New Antibacterial Chloro-Containing Polyketides from the Alga-Derived Fungus Asteromyces cruciatus KMM 4696.

Six new polyketides acrucipentyns A-F (1-6) were isolated from the alga-derived fungus Asteromyces cruciatus KMM 4696. Their structures were established based on spectroscopic methods. The absolute configurations of acrucipentyn A was assigned by the modified Mosher's method and ROESY data analysis. Acrucipentyns A-E were identified to be the very first examples of chlorine-containing asperpentyn-like compounds. The cytotoxic and antimicrobial activities of the isolated compounds were examined. Acrucipentyns A-F were found as antimicrobial agents, which inhibited sortase A enzyme activity, bacterial growth and biofilm formation of Staphylococcus aureus and decreased LDH release from human keratinocytes HaCaT in S. aureus skin infection in an in vitro model.

New Tripeptide Derivatives Asperripeptides A-C from Vietnamese Mangrove-Derived Fungus Aspergillus terreus LM.5.2.

Three new tripeptide derivatives asterripeptides A-C (1-3) were isolated from Vietnamese mangrove-derived fungus Aspergillus terreus LM.5.2. Structures of isolated compounds were determined by a combination of NMR and ESIMS techniques. The absolute configurations of all stereocenters were determined using the Murfey's method. The isolated compounds 1-3 contain a rare fungi cinnamic acid residue. The cytotoxicity of isolated compounds against several cancer cell lines and inhibition ability of sortase A from Staphylococcus aureus of asterripeptides A-C were investigated.

Triterpene Glycosides from the Far Eastern Sea Cucumber Psolus chitonoides: Chemical Structures and Cytotoxicities of Chitonoidosides E1, F, G, and H.

Four new triterpene disulfated glycosides, chitonoidosides E1 (1), F (2), G (3), and H (4), were isolated from the Far-Eastern sea cucumber Psolus chitonoides and collected near Bering Island (Commander Islands) at depths of 100-150 m. Among them there are two hexaosides (1 and 3), differing from each other by the terminal (sixth) sugar residue, one pentaoside (4) and one tetraoside (2), characterized by a glycoside architecture of oligosaccharide chains with shortened bottom semi-chains, which is uncommon for sea cucumbers. Some additional distinctive structural features inherent in 1-4 were also found: the aglycone of a recently discovered new type, with 18(20)-ether bond and lacking a lactone in chitonoidoside G (3), glycoside 3-O-methylxylose residue in chitonoidoside E1 (1), which is rarely detected in sea cucumbers, and sulfated by uncommon position 4 terminal 3-O-methylglucose in chitonoidosides F (2) and H (4). The hemolytic activities of compounds 1-4 and chitonoidoside E against human erythrocytes and their cytotoxic action against the human cancer cell lines, adenocarcinoma HeLa, colorectal adenocarcinoma DLD-1, and monocytes THP-1, were studied. The glycoside with hexasaccharide chains (1, 3 and chitonoidoside E) were the most active against erythrocytes. A similar tendency was observed for the cytotoxicity against adenocarcinoma HeLa cells, but the demonstrated effects were moderate. The monocyte THP-1 cell line and erythrocytes were comparably sensitive to the action of the glycosides, but the activity of chitonoidosides E and E1 (1) significantly differed from that of 3 in relation to THP-1 cells. A tetraoside with a shortened bottom semi-chain, chitonoidoside F (2), displayed the weakest membranolytic effect in the series.

Marine Fungal Cerebroside Flavuside B Protects HaCaT Keratinocytes against Staphylococcus aureus Induced Damage.

Cerebrosides are glycosylated sphingolipids, and in mammals they contribute to the pro-/anti-inflammatory properties and innate antimicrobial activity of the skin and mucosal surfaces. Staphylococcus aureus infection can develop, not only from minor scratches of the skin, but this pathogen can also actively promote epithelial breach. The effect of cerebroside flavuside B from marine sediment-derived fungus Penicillium islandicum (Aniva Bay, the Sea of Okhotsk) on viability, apoptosis, total caspase activity, and cell cycle in human epidermal keratinocytes HaCaT line co-cultivated with S. aureus, as well as influence of flavuside B on LPS-treated HaCaT cells were studied. Influence of flavuside B on bacterial growth and biofilm formation of S. aureus and its effect on the enzymatic activity of sortase A was also investigated. It was found S. aureus co-cultivated with keratinocytes induces caspase-depended apoptosis and cell death, arrest cell cycle in the G0/G1 phase, and increases in cellular immune inflammation. Cerebroside flavuside B has demonstrated its antimicrobial and anti-inflammatory properties, substantially eliminating all the negative consequences caused by co-cultivation of keratinocytes with S. aureus or bacterial LPS. The dual action of flavuside B may be highly effective in the treatment of bacterial skin lesions and will be studied in the future in in vivo experiments.

Unusual Structures and Cytotoxicities of Chitonoidosides A, A1, B, C, D, and E, Six Triterpene Glycosides from the Far Eastern Sea Cucumber Psolus chitonoides.

Six new triterpene tetra-, penta- and hexaosides, chitonoidosides A (1), A1 (2), B (3), C (4), D (5), and E (6), containing one or two sulfate groups, have been isolated from the Far-Eastern sea cucumber Psolus chitonoides, collected near Bering Island (Commander Islands) from the depth of 100-150 m. Three of the isolated compounds (1, 3 and 6) are characterized by the unusual aglycone of new type having 18(20)-ether bond and lacking a lactone in contrast with wide spread holostane derivatives. Another unexpected finding is 3-O-methylxylose residue as a terminal unit in the carbohydrate chains of chitonoidosides B (3), C (4), and E (6), which has never been found before in the glycosides from holothurians belonging to the Psolidae family. Moreover, this monosaccharide is sulfated in the compound 4 into unprecedented 3-O-methylxylose 4-O-sulfate residue. Chitonoidoside C (4) is characterized by tetrasaccharide moiety lacking a part of the bottom semi-chain, but having disaccharide fragment attached to C-4 of Xyl1. Such architecture is not common in sea cucumber glycosides. Cytotoxic activities of the compounds 1-5 against mouse and human erythrocytes and human cancer cell lines: adenocarcinoma HeLa, colorectal adenocarcinoma DLD-1, and leukemia promyeloblast HL-60 cells were studied. The cytotoxic effect of chitonoidoside d (5) was the most significant in this series due to the presence of pentasaccharide disulfated sugar chain in combination with holostane aglycone. Surprisingly, the glycosides 1 and 3, comprising the new aglycone without γ-lactone, demonstrated similar activity to the known compounds with holostane aglycones. Chitonoidoside C (4) was less cytotoxic due to the different architecture of the carbohydrate chain compared to the other glycosides and probably due to the presence of a sulfate group at C-4 in 3-O-MeXyl4.