Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 56, Issue 13, Pages 5407-5421Publisher
AMER CHEMICAL SOC
DOI: 10.1021/jm400311n
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- Italian Ministero dell'Istruzione, Universita e Ricerca, Italy [PRIN 20098SJX4F-002]
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Analogues of the previously described spiro[imidazo[1,5-c]thiazole-3,3'-indoline]-2',5,7(6H,7aH)-trione p53 modulators were prepared to explore new structural requirements at the thiazolidine domain for the antiproliferative activity and p53 modulation. In cell, antiproliferative activity was evaluated against two human tumor cell lines Derivative 5-bromo-3'-(cyclohexane carbonyl)-1-methyl-2-oxospiro[indoline-3,2'-thiazolidine] (4n) emerged as the most potent compound of this series inhibiting in vitro 30% of p53-MDM2 interaction at 5 mu M and the cell growth of different human tumor cells at nanomolar concentrations. Docking studies confirmed the interactions of 4n with the well-known Trp23 and Phe19 clefts, explaining the reasons for its binding affinity, for MDM2. 4n at 50 nM is capable of inducing the accumulation of p53 protein, inducing significant apoptotic,cell death without affecting the cell cycle progression. Comparative studies using nutlin in the same cellular system confirm the potential of 4n as a tool for increasing understanding of the process involved in the nontranscriptional proapoptotic activities of p53.
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