Author(s):
Leão, Mariana ; Pereira, Clara ; Bisio, Alessandra ; Ciribilli, Yari ; Paiva, Ana M. ; Machado, Neuza ; Palmeira, Andreia ; Fernandes, Miguel X. ; Sousa, Emília ; Pinto, Madalena ; Inga, Alberto ; Saraiva, Lucília
Date: 2013
Persistent ID: http://hdl.handle.net/10400.13/5027
Origin: DigitUMa - Repositório da Universidade da Madeira
Subject(s): Xanthone derivatives; Inhibitor of p53–MDM2 interaction; Computational docking; Yeast-based assays; Antitumor activity; .; Faculdade de Ciências Exatas e da Engenharia
Description
The virtual screening of a library of xanthone derivatives led us to the identification of potential novel MDM2 ligands. The activity of these compounds as inhibitors of p53–MDM2 interaction was investigated using a yeast phenotypic assay, herein developed for the initial screening. Using this approach, in association with a yeast p53 transactivation assay, the pyranoxanthone (3,4-dihydro-12- hydroxy-2,2-dimethyl-2H,6H-pyrano[3,2-b]xanthen-6-one) (1) was identified as a putative small molecule inhibitor of p53–MDM2 interaction. The activity of the pyranoxanthone 1 as inhibitor of p53–MDM2 interaction was further investigated in human tumor cells with wild-type p53 and overexpressed MDM2. Notably, the pyranoxanthone 1 mimicked the activity of known p53 activators, leading to p53 stabilization and activation of p53- dependent transcriptional activity. Additionally, it led to increased protein levels of p21 and Bax, and to caspase-7 cleavage. By computational docking studies, it was predicted that, like nutlin-3a, a known small-molecule inhibitor of p53–MDM2 interaction, pyranoxanthone 1 binds to the p53-binding site of MDM2. Overall, in this work, a novel small-molecule inhibitor of p53–MDM2 interaction with a xanthone scaffold was identified for the first time. Besides its potential use as molecular probe and possible lead to develop anticancer agents, the pyranoxanthone 1 will pave the way for the structure-based design of a new class of p53–MDM2 inhibitors.
