title: Discovery of Novel Tricyclic Thiazepine Derivatives as Anti-Drug-Resistant Cancer Agents by Combining Diversity-Oriented Synthesis and Converging Screening Approach.
abstract: 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.
authors.affiliation: 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.
authors.forename: Jinbao
authors.initials: J
authors.lastname: Xiang
authors.affiliation: 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.
authors.forename: Zhuoqi
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University , Jinan, Shandong 250100, P. R. China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Mu
authors.affiliation: 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.
authors.forename: Xianxiu
authors.initials: X
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Sigen
authors.initials: S
authors.lastname: Guo
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University , Jinan, Shandong 250100, P. R. China.
authors.forename: Yongjin
authors.initials: Y
authors.lastname: Liu
authors.affiliation: The Rutgers Center for Computational and Integrative Biology , Camden, New Jersey 08102, United States.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Russo
authors.affiliation: The Rutgers Center for Computational and Integrative Biology , Camden, New Jersey 08102, United States.|Department of Chemistry, Rutgers University , Camden, New Jersey 08102, United States.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhu
authors.affiliation: School of Chemistry and Chemical Engineering, Shandong University , Jinan, Shandong 250100, P. R. China.
authors.forename: Bing
authors.initials: B
authors.lastname: Yan
authors.affiliation: 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.
authors.forename: Xu
authors.initials: X
authors.lastname: Bai
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D013841:Thiazepines / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D013841:Thiazepines
keywords: H460TaxR; antidepressing; redeployment; selective cytotoxicity; tricyclic thiazepine