New cytotoxic polyketide from the fungus Talaromyces stipitatus selected by genome mining

Fungal polyketides comprise a very large and structurally diverse group and many display important biological activities [1]. These are produced by large multifunctional iterative enzymes, the polyketide synthases (PKS). Recent advances in genomic analysis revealed a large number of PKS-encoding genes in fungal genomes, most of which are related to unknown metabolites. In this context, we are interested in using a genome mining approach to discover novel chemical entities from fungi, particularly those derived from hybrid PKSs and non-ribosomal peptide synthetases (NRPS). The fungus Talaromyces stipitatus was chosen in this study. Several new polyketides (e.g. 1 and 2) have been isolated and characterized by extensive 2D NMR analysis. Absolute configurations of some new structures were assigned by CD. Comparison between experimental and theoretical electronic CD (ECD) was used to assess the relative and absolute configurations. Additionally, elucidation of the biosynthetic pathway leading to the original spiro-bis(oxaphenalenone) dimer (2) is under study by feeding experiments. Finally, some of these compounds showed potent cytotoxic activities against HeLa cell line compared to cisplatin.

Keywords: Talaromyces stipitatus, polyketide, genome mining, cytotoxic

References:

[1] Cox JR. Polyketides, proteins and genes in fungi: programmed nano-machines begin to reveal their secrets. Org Biomol Chem 2007; 5: 2010 – 2026.