Title: Design, synthesis and biological evaluation of selective survivin inhibitors


Authors: Min Xiao1, Yi Xue1, Zhongzhi Wu1, Zi-Ning Lei2, Jin Wang1, Zhe-Sheng Chen2, Wei Li1


Institutions: 1Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, TN, 38163, USA; 2Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. Johns University, Queens, NY 11439, USA.


Abstract: The differential distribution between cancer cells and normal adult tissues makes survivin a very attractive cancer drug target. We have previously reported a series of novel selective survivin inhibitors with the most potent compound MX106 reaching nanomolar activity in several cancer cell lines. Further optimization of the MX106 scaffold leads to the discovery of more potent and more selective survivin inhibitors. Various structural modifications were synthesized and their anticancer activities were evaluated to determine the structure activity relationships for this MX106 scaffold. In vitro anti-proliferative assays using two human melanoma cell lines showed that several new analogs have improved potency compared to MX106. Very interestingly, these new analogs generally showed significantly higher potency against P-glycoprotein overexpressed cells compared with the corresponding parental cells, suggesting that these compounds may strongly sensitize tumors that have high expressions of the P-glycoprotein drug efflux pumps. Western blotting analysis confirmed that the new MX106 analogs maintained their mechanism of actions by selectively suppressing survivin expression level among major inhibitors of apoptotic proteins and induced strong apoptosis in melanoma tumor cells.


Keywords: selective survivin inhibitors, structure activity relationships, melanoma, human epidermoid carcinoma, colorectal cancer, P-glycoprotein drug efflux pumps


Full Text: JBR-2016-0173.pdf JBR-2016-0173-supplementary.pdf


J Biomed Res published on 30 May 2017, doi:10.7555/JBR.31.20160173