Unexpected Biotransformation of the HDAC Inhibitor Vorinostat Yields Aniline-Containing Fungal Metabolites

• Published in: ACS chemical biology Vol. 12; no. 7; pp. 1842 - 1847
• Main Authors: Adpressa, Donovon A, Stalheim, Kayla J, Proteau, Philip J, Loesgen, Sandra
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 21.07.2017
• Subjects: Aniline Compounds - chemistry; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; Bacteria - drug effects; Biotransformation - drug effects; Biotransformation - genetics; Cell Survival - drug effects; Epigenesis, Genetic - drug effects; Fungi - chemistry; Fungi - drug effects; Fungi - genetics; Fungi - metabolism; Heterocyclic Compounds, 3-Ring - chemistry; Histone Deacetylase Inhibitors - chemistry; Histone Deacetylase Inhibitors - pharmacology; Hydroxamic Acids - chemistry; Hydroxamic Acids - pharmacology; Magnetic Resonance Spectroscopy; Molecular Docking Simulation; Molecular Structure; Xanthones - chemistry; Xanthones - metabolism; Xanthones - pharmacology
• ISSN: 1554-8929; 1554-8937
• DOI: 10.1021/acschembio.7b00268

The diversity of genetically encoded small molecules produced by filamentous fungi remains largely unexplored, which makes these fungi an attractive source for the discovery of new compounds. However, accessing their full chemical repertoire under common laboratory culture conditions is a challenge. Epigenetic manipulation of gene expression has become a well-established tool for overcoming this obstacle. Here, we report that perturbation of the endophytic ascomycete Chalara sp. 6661, producer of the isofusidienol class of antibiotics, with the HDAC inhibitor vorinostat resulted in the production of four new modified xanthones. The structures of chalanilines A (1) and B (2) and adenosine-coupled xanthones A (3) and B (4) were determined by extensive NMR spectroscopic analyses, and the bioactivities of 1–4 were tested in antibiotic and cytotoxicity assays. Incorporation studies with deuterium-labeled vorinostat indicate that the aniline moiety in chalalanine A is derived from vorinostat itself. Our study shows that Chalara sp. is able to metabolize the HDAC inhibitor vorinostat to release aniline. This is a rare report of fungal biotransformation of the popular epigenetic modifier vorinostat into aniline-containing polyketides.