Identification of the spiro(oxindole-3,3'-thiazolidine)-based derivatives as potential p53 activity modulators

J Med Chem. 2010 Dec 9;53(23):8319-29. doi: 10.1021/jm100838z.

Isabel Gomez-Monterrey ¹, Alessia Bertamino, Amalia Porta, Alfonso Carotenuto, Simona Musella, Claudio Aquino, Ilaria Granata, Marina Sala, Diego Brancaccio, Delia Picone, Carmine Ercole, Paola Stiuso, Pietro Campiglia, Paolo Grieco, Pio Ianelli, Bruno Maresca, Ettore Novellino

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Affiliation

1 Department of Pharmaceutical and Toxicological Chemistry, University of Naples "Federico II", Italy.

PMID: 21058726 DOI: 10.1021/jm100838z

Abstract

Here, we report the design of new analogues of spirooxoindolepyrrolidine nucleus as modulators of p53 activity. Compounds (3R,7aR)-6-(4-chlorobenzyl)-1H-spiro[imidazo[1,5-c]thiazole-3,3'-indoline]-2',5,7(6H,7aH)-trione (9c) and (3R,7aR)-5'-methyl-6-(3,4,5-trimethoxybenzyl)-1H-spiro[imidazo[1,5-c]thiazole-3,3'-indoline]-2',5,7(6H,7aH)-trione (10d) are the most potent compounds of this series, inhibiting cell growth of different human tumor cells at submicromolar and micromolar concentrations, respectively. Compound 9c induces apoptotic cell death in human melanoma cell line M14 at 24 h, while in the same condition, treatment with 10d showes a clear arrest at G2/M phase inducing delay of cell cycle progression. Possibly, these activities may be due to inhibition of p53-MDM2 interaction and subsequent p53 release and activation.

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