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

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• 作者：Wei-Huang Zhou^a ; ^b ; Xi-Guo Xu^a ; ^b ; Jin Li^b ; Xiao Min^b ; Jian-Zhong Yao^b ; Guo-Qiang Dong^b ; Chun-Lin Zhuang^b ; ^{zclnathan@163.com} ; Zhen-Yuan Miao^b ; ^{miaozhenyuan@hotmail.com} ; Wan-Nian Zhang^a ; ^b ; ^{zhangwnk@hotmail.com}
• 关键词：p53-MDM2 ; Protein&ndash ; protein interaction ; Inhibitors ; Drug design ; Structure&ndash ; activity relationships ; Antiproliferative
• 刊名：Chinese Chemical Letters
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：28
• 期：2
• 页码：422-425
• 全文大小：477 K
• 卷排序：28

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.