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: mariasantos@ff.ul.pt.

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.

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