Discovery of Novel Tricyclic Thiazepine Derivatives
as Anti-Drug-Resistant Cancer Agents by Combining Diversity-Oriented
Synthesis and Converging Screening Approach
posted on 2016-04-15, 15:26authored byJinbao Xiang, Zhuoqi Zhang, Yan Mu, Xianxiu Xu, Sigen Guo, Yongjin Liu, Daniel
P. Russo, Hao Zhu, Bing Yan, Xu Bai
An efficient discovery strategy by
combining diversity-oriented
synthesis and converging cellular screening is described. By a three-round
screening process, we identified novel tricyclic pyrido[2,3-b][1,4]benzothiazepines showing potent inhibitory activity
against paclitaxel-resistant cell line H460TaxR (EC50 < 1.0 μM), which exhibits much less toxicity toward
normal cells (EC50 > 100 μM against normal human
fibroblasts). The most active hits also exhibited drug-like properties
suitable for further preclinical research. This redeployment of antidepressing
compounds for anticancer applications provides promising future prospects
for treating drug-resistant tumors with fewer side effects.