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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.
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 to be potent p53-MDM2 inhibitors. 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. The data was that 4,5-dihydropyrrolo [3,4-c] pyrazol- valuable scaffold for further development of p53-MDM2 inhibitors.