Discovery, Synthesis, and Biological Evaluation of Orally Active Pyrrolidone Derivatives as Novel Inhibitors of p53鈥揗DM2 Protein鈥揚rotein Interaction

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• 作者：Chunlin Zhuang ; Zhenyuan Miao ; Lingjian Zhu ; Guoqiang Dong ; Zizhao Guo ; Shengzheng Wang ; Yongqiang Zhang ; Yuelin Wu ; Jianzhong Yao ; Chunquan Sheng ; Wannian Zhang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：55
• 期：22
• 页码：9630-9642
• 全文大小：615K
• 年卷期：v.55,no.22(November 26, 2012)
• ISSN：1520-4804

文摘

The p53鈥揗DM2 interaction has been proved to be a valuable target to develop effective antitumor agents. Novel p53鈥揗DM2 inhibitors bearing pyrrolidone scaffolds were successfully identified by structure-based design. The nanomolar inhibitor 5 possessed good p53鈥揗DM2 inhibitory activity (K_i = 780 nM) due to its hydrophobic and hydrogen bonding interactions with MDM2. Further hit optimization led to the discovery of a number of highly potent pyrrolidone derivatives with improved p53鈥揗DM2 inhibitory activity and in vitro antiproliferative potency. Compounds 41 (K_i = 260.0 nM) and 60a (K_i = 150.0 nM) showed good and selective activity against tumor cells with deleted p53. In addition, these two compounds also effectively inhibited the tumor growth in the A549 xenograft model. Interestingly, compound 41 was proved to be a potent MDM2/MDMX dual inhibitor. The novel pyrrolidone p53鈥揗DM2 inhibitors represent promising lead structures for the development of novel antitumor agents.