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 po...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.展开更多
基金supported in part by the National Natural Science Foundation of China (Nos. 81373331 and 81502978)the Bio-Pharmaceutical Project of Science and Technology of Shanghai (No. 14431902300)Youth grant of Second Military Medical University (No. 2014QN08)
文摘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.
