Diastereomeric Spirooxindoles as Highly Potent and Efficacious MDM2 Inhibitors

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• 作者：Yujun Zhao ; Liu Liu ; Wei Sun ; Jianfeng Lu ; Donna McEachern ; Xiaoqin ; Li ; Shanghai Yu ; Denzil Bernard ; Philippe Ochsenbein ; Vincent Ferey ; Jean-Christophe Carry ; Jeffrey R. Deschamps ; Duxin Sun ; Shaomeng Wang
• 刊名：The Journal of the American Chemical Society
• 出版年：2013
• 出版时间：May 15, 2013
• 年：2013
• 卷：135
• 期：19
• 页码：7223-7234
• 全文大小：672K
• 年卷期：v.135,no.19(May 15, 2013)
• ISSN：1520-5126

文摘

Small-molecule inhibitors that block the MDM2-p53 protein鈥損rotein interaction (MDM2 inhibitors) are being intensely pursued as a new therapeutic strategy for cancer treatment. We previously published a series of spirooxindole-containing compounds as a new class of MDM2 small-molecule inhibitors. We report herein a reversible ring-opening-cyclization reaction for some of these spirooxindoles, which affords four diastereomers from a single compound. Our biochemical binding data showed that the stereochemistry in this class of compounds has a major effect on their binding affinities to MDM2, with >100-fold difference between the most potent and the least potent stereoisomers. Our study has led to the identification of a set of highly potent MDM2 inhibitors with a stereochemistry that is different from that of our previously reported compounds. The most potent compound (MI-888) binds to MDM2 with a K_i value of 0.44 nM and achieves complete and long-lasting tumor regression in an animal model of human cancer.