title: Design, synthesis and evaluation of novel triazole core based P-glycoprotein-mediated multidrug resistance reversal agents.
abstract: A novel series of triazol-N-ethyl-tetrahydroisoquinoline based compounds were designed and synthesized via click chemistry. Most of the synthesized compounds showed P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) reversal activities. Among them, compound 7 with little cytotoxicity towards GES-1 cells (IC50 >80μM) and K562/A02 cells (IC50 >80μM) exhibited more potency than verapamil (VRP) on increasing anticancer drug accumulation in K562/A02 cells. Moreover, compound 7 could significantly reverse MDR in a dose-dependent manner and also persist longer chemo-sensitizing effect than VRP with reversibility. Further mechanism studies revealed that compound 7 in reversing MDR revealed that it could remarkably increase the intracellular accumulation of both rhodamine-123 (Rh123) and adriamycin (ADM) in K562/A02 cells as well as inhibit their efflux from the cells. These results suggested that compound 7 showed more potency than the classical P-gp inhibitor VRP under the same conditions, which may be a promising P-gp-mediated MDR modulator for further development.
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
authors.forename: Lei
authors.initials: L
authors.lastname: Jiao
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Qiu
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Nan Jing Research and Development Center, CTTQ Pharmaceutical Research Institute, Building 9, NO. 699-8, Xuanwu Dadao, Xuanwu District, Nanjing, Jiangsu, PR China.
authors.forename: Baomin
authors.initials: B
authors.lastname: Liu
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
authors.forename: Tianxiao
authors.initials: T
authors.lastname: Zhao
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: ydhuangwenlong@126.com.
authors.forename: Wenlong
authors.initials: W
authors.lastname: Huang
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: qianhai24@163.com.
authors.forename: Hai
authors.initials: H
authors.lastname: Qian
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D057930:Click Chemistry; D004317:Doxorubicin / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020014:K562 Cells; D020112:Rhodamine 123 / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: C000599917:4-(tert-butyl)-N-(2-((1-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)phenyl)benzamide; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D001549:Benzamides; D007546:Isoquinolines; D014230:Triazoles; D020112:Rhodamine 123; D004317:Doxorubicin; C039109:isoquinoline
keywords: Click chemistry; Multidrug resistance; P-glycoprotein; Reversal activity