ABSTRACT
The structural complexity and diversity of natural products make them attractive sources for potential drug discovery, with their characteristics being derived from the multi-step combination of enzymatic and non-enzymatic conversions of intermediates in each biosynthetic pathway. Intermediates that exhibit multipotent behaviour have great potential for use as starting points in diversity-oriented synthesis. Inspired by the biosynthetic pathways that form complex metabolites from simple intermediates, we developed a semi-synthetic process that combines heterologous biosynthesis and artificial diversification. The heterologous biosynthesis of fungal polyketide intermediates led to the isolation of novel oligomers and provided evidence for ortho-quinonemethide equivalency in their isochromene form. The intrinsic reactivity of the isochromene polyketide enabled us to access various new chemical entities by modifying and remodelling the polyketide core and through coupling with indole molecules. We thus succeeded in generating exceptionally diverse pseudo-natural polyketides through this process and demonstrated an advanced method of using biosynthetic intermediates.
Subject(s)
Biological Products/chemistry , Fungi/metabolism , Polyketides/chemistry , Aspergillus oryzae/enzymology , Benzopyrans/chemistry , Biological Products/metabolism , Chaetomium/metabolism , Indolequinones/biosynthesis , Indolequinones/chemistry , Indoles/chemistry , Indoles/metabolism , Pigments, Biological/chemistry , Polyketide Synthases/genetics , Polyketide Synthases/metabolism , Polyketides/metabolismABSTRACT
Epigenetic manipulation of gene expression in Chaetomium indicum using a HDAC inhibitor led to the isolation of structurally diverse chaetophenols, and 3, 4 and 5 bear unprecedented polycyclic skeletons. The expression of two silent genes (pksCH-1 and pksCH-2) for nonreducing PKSs involved in chaetophenol biosynthesis was associated with an increase of histone acetylation level. The heterologous gene expression study in Aspergillus oryzae revealed pksCH-2 to be the NR-PKS gene for 8.
Subject(s)
Aspergillus oryzae/chemistry , Benzopyrans/chemical synthesis , Chaetomium/chemistry , Phenols/chemistry , Phenols/chemical synthesis , Polycyclic Compounds/chemistry , Polycyclic Compounds/chemical synthesis , Polyketides/chemical synthesis , Acetylation , Aspergillus oryzae/genetics , Benzopyrans/chemistry , Cyclization , Epigenomics , Gene Expression Regulation, Fungal , Genes, Fungal/genetics , Molecular Structure , Polyketides/chemistryABSTRACT
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.