Discovery of spirooxindole-ferrocene hybrids as novel MDM2 inhibitors  

作　　者：Jun Mu Xin Xie Shanshan Xiong Yuehua Zhang Yuting Wang Qian Zhao Hongping Zhu Wei Huang Gu He 

机构地区：[1]State Key Laboratory of Biotherapy and Cancer Center,West China Hospital,Sichuan University,Chengdu 610041,China [2]State Key Laboratory of Southwestern Chinese Medicine Resources,Hospital of Chengdu University of Traditional Chinese Medicine,School of Pharmacy,Chengdu University of Traditional Chinese Medicine,Chengdu 611137,China

出　　处：《Chinese Chemical Letters》2021年第6期1897-1901,共5页中国化学快报（英文版）

基　　金：supported by grants from the National Natural Science Foundation(Nos.21772131,81672552,81773890,82073997);the Fundamental Research Funds of Science&Technology Department of Sichuan Province(Nos.2019YFSY0004,2017JY0226,2019YFS0298);Project First-Class Disciplines Development supported by CDUTCM。

摘　　要：A series of spirooxindole-ferrocene hybrids bearing five or four contiguous chiral centers were designed and synthesized via organocatalysis.In vitro protein binding and cellular proliferation assays suggested that compound 5 d was the most potent mouse double minute 2 homolog(MDM2)inhibitor.In addition,mechanistic studies indicated that compound 5 d suppressed MDM2-mediated p53 degradation,induced apoptosis and promoted oxidative damage.Molecular docking studies have suggested that 5 d binds to MDM2 by mimicking the Trp23 and Leu26 residues of p53.This work can provide a basis for the development of novel multifunctional MDM2 inhibitors.The further exploration of more derivatives from this library and additional investigation of organocatalysis application in the development of new molecules may generate new potential lead compounds for cancer-targeted therapy.

关 键 词：SPIROOXINDOLE FERROCENE MDM2 Apoptosis Breast cancer 

分 类 号：TQ460.1[化学工程—制药化工]