Citation: . Design, synthesis and structure-activity relationship of 4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-ones as potent p53-MDM2 inhibitors[J]. Chinese Chemical Letters, ;2017, 28(2): 422-425. doi: 10.1016/j.cclet.2016.09.001 shu

Design, synthesis and structure-activity relationship of 4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-ones as potent p53-MDM2 inhibitors

Received Date: 23 June 2016
Revised Date: 26 July 2016
Accepted Date: 10 August 2016
Available Online: 12 February 2016

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In the past decade, the p53-MDM2 protein-protein interaction by small molecules has been confirmed as a successful strategy for cancer therapy. In our previous work, pyrrolo[3,4-c]pyrazol-6(1H)-ones were found to be potent p53-MDM2 inhibitors. Further optimization and structure-activity relationship studies were described in the present work. The result revealed that benzyl group on position N1 of imidazole and bromine on C4-phenyl of pyrrolidone showed higher inhibitory activities. In vitro antiproliferative assay demonstrated the potent p53-MDM2 inhibitor 5c with 4-fold selectivity for U2 OS and Saos-2 cells. These data indicated that 4,5-dihydropyrrolo[3,4-c]pyrazol-6(1H)-one moiety is a valuable scaffold for further development of p53-MDM2 inhibitors.
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