Pestones A and B from a Fungus Pestalotiopsis sp. Bound to Mutant p53 and Changed Its Conformation.

Abstract

Oncogenic mutant p53 is one of the targets for cancer therapy, and the development of anticancer drugs that reactivate mutant p53 is a promising strategy. The extract of fungus Pestalotiopsis sp. changed mutant p53 to wild-type-like p53 in Saos-2 (p53^R175H) cells, as shown by fluorescent immunostaining, and bioassay-guided purification of the extract afforded new dimeric epoxyquinoids, pestones A and B (1 and 2), and a known compound, rosnecatrone (3). The relative and absolute configurations of 1 and 2 were determined based on the spectroscopic data and semisynthesis from 3. Compounds 1 and 2 altered the conformation of mutant p53 in Saos-2 (p53^R175H) cells, as shown by immunofluorescence staining. The cellular thermal shift assay analysis showed that 1 increased the thermostability of mutant p53 in Saos-2 (p53^R175H) cells, suggesting the direct binding of 1 to mutant p53. Compounds 1 and 2 exhibited cytotoxic activities against Saos-2 (p53^R175H) cells with IC₅₀ values of 1.0 and 1.1 μM, respectively. Compound 1 was found to induce apoptosis in Saos-2 (p53^R175H) cells by flow cytometry analysis and decreased tumor growth in vivo using a mouse model with HuCCT1 (p53^R175H) cells.