Synthesis and evaluation of spiroisoxazoline oxindoles as anticancer agents

  • Bioorg Med Chem. 2014 Jan 1;22(1):577-84. doi: 10.1016/j.bmc.2013.10.048.
Carlos J A Ribeiro  1 ,  Joana D Amaral  1 ,  Cecília M P Rodrigues  1 ,  Rui Moreira  1 ,  Maria M M Santos  2
Affiliations
  • 1. Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal.
  • 2. Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal. Electronic address: [email protected].
PMID: 24268795 DOI: 10.1016/j.bmc.2013.10.048
Abstract

Restoring p53 levels through disruption of p53-MDM2 interaction has been proved to be a valuable approach in fighting Cancer. We herein report the synthesis and evaluation of eighteen spiroisoxazoline oxindoles derivatives as p53-MDM2 interaction inhibitors. Seven compounds showed an antiproliferative profile superior to the p53-MDM2 interaction inhibitor nutlin-3, and induced cell death by Apoptosis. Moreover, proof-of-concept was demonstrated by inhibition of the interaction between p53 and MDM2 in a live-cell bimolecular fluorescence complementation assay.

Keywords
Cancer; MDM2; Protein–protein interactions; Spiro compounds; p53.