通过结合多样化导向合成和汇聚筛选方法发现新型三环噻氮平衍生物作为抗耐药性癌症药物
Discovery of Novel Tricyclic Thiazepine Derivatives as Anti-Drug-Resistant Cancer Agents by Combining Diversity-Oriented Synthesis and Converging Screening Approach.
作者信息
Xiang Jinbao, Zhang Zhuoqi, Mu Yan, Xu Xianxiu, Guo Sigen, Liu Yongjin, Russo Daniel P, Zhu Hao, Yan Bing, Bai Xu
机构信息
The Center for Combinatorial Chemistry and Drug Discovery, The School of Pharmaceutical Sciences, and The College of Chemistry, Jilin University , Changchun, Jilin 130021, P. R. China.
School of Chemistry and Chemical Engineering, Shandong University , Jinan, Shandong 250100, P. R. China.
出版信息
ACS Comb Sci. 2016 May 9;18(5):230-5. doi: 10.1021/acscombsci.6b00010. Epub 2016 Apr 15.
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.
描述了一种通过结合多样化导向合成和汇聚细胞筛选的高效发现策略。通过三轮筛选过程，我们鉴定出了新型三环吡啶并[2,3 - b][1,4]苯并硫氮杂䓬，其对紫杉醇耐药细胞系H460TaxR显示出强效抑制活性（EC50 < 1.0 μM），而对正常细胞的毒性则小得多（对正常人成纤维细胞的EC50 > 100 μM）。活性最强的命中化合物还表现出适合进一步临床前研究的类药性质。这种将抗抑郁化合物重新用于抗癌应用为治疗耐药肿瘤且副作用较少提供了有前景的未来前景。
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