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

作者：Zhou, Wei-Huang; Xu, Xi-Guo; Li, Jin; Min, Xiao; Yao, Jian-Zhong; Dong, Guo-Qiang; Zhuang, Chun-Lin^*; Miao, Zhen-Yuan^*; Zhang, Wan-Nian^*

来源：Chinese Chemical Letters, 2017, 28(2): 422-425.

DOI：10.1016/j.cclet.2016.09.001

• p53-MDM2
• Protein-protein interaction
• Inhibitors
• Drug design
• Structure-activity relationships
• Antiproliferatiye

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-clpyrazol-6(1H)-one moiety is a valuable scaffold for further development of p53-MDM2 inhibitors.

• 出版日期2017-2
• 单位中国人民解放军第二军医大学; 宁夏医科大学