Distachydrimanes A-F,phenylspirodrimane dimers and hybrids with cytotoxic activity from the coral-derived fungus Stachybotrys chartarum

By integrating one strain-many compounds(OSMAC)and LC-MS-based molecular networking strategies,distachydrimanes A-F(1-6),six novel phenylspirodrimane dimers and hybrids representing two types of unprecedented terpenoid-polyketide hybrid skeletons,were isolated from the modified fermented rice substrate of a coral-derived fungus Stachybotrys chartarum.All the structures incorporating their absolute configurations were elucidated based on comprehensive spectroscopic analyses,mainly including HRESIMS and NMR data,single-crystal X-ray diffraction(Cu Kα),and comparison of the experimental electronic circular dichroism(ECD)data.Architecturally,compounds 1-6 represent an unprecedented class of dimeric phenylspirodrimanes with an unexpected C-18-C-23′linkage,of which compounds 1-3 also feature an unexpected 5-methyl-1,3-benzenediol moiety via a carbon-carbon linkage.The bioactivity assay demonstrated that compounds 1,5 and 6 induced cell proliferation inhibition,G0/G1 cell cycle arrest,senescence and mitochondrial-mediated apoptosis in L1210 cells,highlighting their potentials as a new category of anticancer agents.

Structural diversification of phenylspirodrimane lactams by employing a biosynthetic intermediate

Phenylspirodrimanes are a kind of meroterpenoids with structural diversity and complexity,exhibiting a wide of biological properties,especially for the lactam derivatives consisting a y-lactam moiety and N-linked side chains.These compounds were derived from multi-step combination of enzymatic and non-enzymatic conversions of intermediates in their biosynthetic pathways.Stachbotrydial(2)with an o-phthalaldehyde unit was supposed as the high-reactivity intermediate of phenylspirodrimane lactams via nonenzymatic reaction with amines.In the present work,an effective and non-enzymatic diversification strategy was developed for the structural diversification of phenylspirodrimane lactams including monomers and dimers from 2 by feeding structurally various mono-and diamines in the fungus Stachybotrys chartarum cultures.In total,24 phenylspirodrimane lactams(1,3-25)including 18 new compounds were synthesized.Among them,stachybocin A(1),a bioactive phenylspirodrimane lactam dimer,was produced with the yield of 18.7 mg/g of cell dry weight.The structures of these compounds were elucidated by extensive spectroscopic data,single-crystal X-ray diffraction(Cu Kα),and calculated electronic circular dichroism(ECD)analyses.Bioassay revealed that compounds 1,17,and 24 displayed significant inhibitory effect on the inactivated state of hNav 1.2 channels with IC_(50) values of 0.22,2.08,and 0.53μmol/L,respectively.In addition,1 showed potent protein tyrosine phosphatase 1B(PTP1B)inhibitory N-methyl-b-aspartate(NMDA)receptor antagonistic,and anti-inflammatory activities.