Discovery of Novel Tricyclic Thiazepine Derivatives as Anti-Drug-Resistant Cancer Agents by Combining Diversity-Oriented Synthesis and Converging Screening Approach

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• 作者：Jinbao Xiang ; Zhuoqi Zhang ; Yan Mu ; Xianxiu Xu ; Sigen Guo ; Yongjin Liu ; Daniel P. Russo ; Hao Zhu ; Bing Yan ; Xu Bai
• 刊名：ACS Combinatorial Science
• 出版年：2016
• 出版时间：May 9, 2016
• 年：2016
• 卷：18
• 期：5
• 页码：230-235
• 全文大小：392K
• 年卷期：0
• ISSN：2156-8944

文摘

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 H460_TaxR (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.