ABSTRACT
Exposure of the fungus Chaetomium cancroideum to an NAD(+)-dependent HDAC inhibitor, nicotinamide, enhanced the production of aromatic and branched aliphatic polyketides, which allowed us to isolate new secondary metabolites, chaetophenol G and cancrolides A and B. Their structures were determined using spectroscopic analyses, and their absolute configuration was elucidated by electronic circular dichroism (ECD), vibrational circular dichroism (VCD), and chemical transformations. Biosynthesis of the branched aliphatic polyketide skeletons in cancrolides A and B was evidenced by conducting a feeding experiment using compounds labeled with a (13)C stable isotope.
Subject(s)
Chaetomium/drug effects , Chaetomium/metabolism , Histone Deacetylase Inhibitors/pharmacology , Histone Deacetylases/metabolism , NAD/metabolism , Polyketides/metabolism , HCT116 Cells , Histone Deacetylase Inhibitors/chemical synthesis , Histone Deacetylase Inhibitors/chemistry , Humans , Molecular Conformation , NAD/pharmacology , Polyketides/chemistry , Structure-Activity RelationshipABSTRACT
Cultivation of Chaetomium mollipilium with nicotinamide, a NAD(+)-dependent HDAC inhibitor, stimulated its secondary metabolism, leading to the isolation of structurally diverse new C(13)-polyketides, mollipilin A-E (1-5) as well as two known compounds (6 and 7). Spectroscopic methods, X-ray single crystal diffraction analysis, and VCD elucidated the absolute configurations of structures 1-6, and plausible biosynthetic pathways for 1-7 were proposed based on structural relationships. Mollipilins A (1) and B (2) exhibited moderate growth inhibitory effects on HCT-116 cells.
