Journal
BIOCHEMICAL PHARMACOLOGY
Volume 85, Issue 9, Pages 1234-1245Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2013.01.032
Keywords
Xanthone derivatives; Inhibitor of p53-MDM2 interaction; Computational docking; Yeast-based assays; Antitumor activity
Categories
Funding
- FCT (Fundacao para a Ciencia e a Tecnologia) through REQUIMTE [PEst-C/EQB/LA0006/2011]
- CEQUIMED-UP [Pest-OE/SAU/U14040/2011]
- FEDER through the COMPETE program
- U. Porto/Santander Totta
- Italian Association for Cancer Research, AIRC (IG) [9086]
- FCT
- [FCOMP-01-0124-FEDER-015752]
- [FCOMP-01-0124-FEDER-011057]
- [SFRH/BD/64184/2009]
- [PTDC/SAU-FCT/100930/2008]
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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 I will pave the way for the structure-based design of a new class of p53-MDM2 inhibitors. (C) 2013 Elsevier Inc. All rights reserved.
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