No abstract

Four new tetracyclic meroterpnes, dysiherbols A-C (1-3) and dysideanone E (4), were isolated from a Dysidea sp. marine sponge collected from the South China Sea. Their complete structures and absolute configurations were unambiguously determined by a combination of NMR spectroscopic data, ECD calculations, and single-crystal X-ray diffraction analysis. Within the sesquiterpene quinol structures, dysiherbols A-C possess an intriguing 6/6/5/6-fused tetracyclic carbon skeleton. The NF-κB inhibitory and cytotoxic activity evaluation disclosed that dysiherbol A (1) showed potent activity with respective IC50 values of 0.49 and 0.58 μM, which were about 10-fold and 20-fold more potent than those of dysiherbols B (2) and C (3), which feature hydroxy and ketone carbonyl groups at the C-3 position.

Ten new polyhydroxysteroidal glycosides, anthenosides B-K (2-11), were isolated from the ethanol extract of the starfish Anthenea chinensis. Their structures were elucidated by extensive spectroscopic studies and chemical evidence. The unprecedented carbohydrate chain 6-O-methyl-beta-d-galactofuranosyl-(1-->3)-(6-O-methyl-beta-d-galactofuranose) was present in all the compounds except compounds 10 and 11. Compounds 5, 7, a mixture of 8 and 9, and a mixture of 10 and 11 showed inhibitory activity against human tumor K-562 and BEL-7402 cells. Furthermore, the mixture of 10 and 11 also exhibited cytotoxicity against human tumor U87MG cells and promoted tubulin polymerization.

Chemical analysis of a fermentation of the Australian termite nest-derived fungus Trichoderma virens CMB-TN16 yielded five new acyclic nonapeptides, trichodermides A-E (1-5). Amino acid residues, configurations, and sequences were determined by a combination of spectroscopic (NMR and MS-MS) and chemical (C Marfey's) methods. The trichodermides adhere to the sequence homology pattern common to Trichoderma 11 amino acid residue peptaibols; however, unlike other peptaibols the trichodermides do not exhibit antibacterial or antifungal activity and exhibit low to no cytotoxicity against mammalian cells. This variability in biological activity highlights the importance of knowing both planar structures and absolute configurations when interpreting structure-activity relationships.

Aberrant activation of Ras GTPase is closely associated with human cancers. Mechanistic and structural insights into conformational transitions underlying the Ras deactivation pathway provide opportunities for the development of targeted therapies for the treatment of Ras-driven cancers. It remains challenging, however, to completely capture a large-scale conformational transition by atomistic molecular dynamics (MD) simulations. Here, we carry out a computational scheme that combines a transition pathway generation algorithm, extensive MD simulations, and Markov state model analysis for disclosing the conformational landscape of the Ras deactivation pathway. Our findings suggest a stepwise deactivation pathway for Ras hydrolysis and identify several key conformational substates along the deactivation pathway. Furthermore, we discover an unexplored and potentially allosteric binding site on the effector-binding region of Ras in the conformational substates, which is further supported by site-directed mutagenesis experiments. This site could be exploited to the design of Ras inhibitors to block Ras–effector interactions.

By activity-guided fractionation, two new sterols, 3beta,28xi-dihydroxy-24-ethylcholesta-5,23Z-dien (1) and 2a-oxa-2-oxo-5alpha-hydroxy-3,4-dinor-24-ethylcholesta-24(28)-ene (2), together with five known steroids, fucosterol (3), 24-ethylcholesta-4,24(28)-dien-3,6-dione (4), 24xi-hydroperoxy-24-vinylcholesterol (5), 24-ketocholesterol (6), 24R,28R- and 24S, 28S-epoxy-24-ethylcholesterol (7), were isolated from the brown alga Sargassum carpophyllum as active compounds causing morphological abnormality of Pyricularia oryzae mycelia. Compounds 1, 3, 4, 5 and 7 also exhibited cytotoxic activity against various cancer cell lines. The IC50 values for 1 and 5 against HL-60 were 7.8 and 8.5 microg/ml, 3 and 4 against P-388 were 0.7 and 0.8 microg/ml, whereas 7 against MCF-7, HCT-8, 1A9, HOS and PC-3 were 4.0, 8.8, 10.0, 10.0 and 7.2 microg/ml, respectively.

Three new cyclic peptides including a cyclic tetrapeptide (1), an aspochracin-type cyclic tripeptide sclerotiotide L (2) and a diketopiperazine dimer (3), have been isolated from the ethyl acetate extract of a marine sponge-derived fungus Aspergillus violaceofuscus. The structures of all compounds were unambiguously elucidated on the basis of HRESIMS, 1D and 2D NMR spectroscopic data, MS/MS experiments and chemical methods. Compounds 1 and 3 showed anti-inflammatory activity against IL-10 expression of the LPS-induced THP-1 cells with inhibitory rates of 84.3 and 78.1% respectively at concentration of 10 μM.

Five new cyclic peptides (including four heptapeptides and one octapeptide), reniochalistatins A-E (1-5), were isolated and characterized from the marine sponge Reniochalina stalagmitis collected off Yongxing Island in the South China Sea. Their structures were assigned on the basis of HRESIMS, 1D and 2D NMR spectroscopic data, and MALDI-TOF/TOF data for sequence analysis. The absolute configurations of all of the amino acid residues were determined using chiral-phase HPLC and Marfey's analysis. The cyclic octapeptide reniochalistatin E showed biological activity in various cytotoxicity assays employing different tumor cell lines (RPMI-8226, MGC-803, HL-60, HepG2, and HeLa).