title: 6,7-Dimethoxy-2-{2-[4-(1H-1,2,3-triazol-1-yl)phenyl]ethyl}-1,2,3,4-tetrahydroisoquinolines as superior reversal agents for P-glycoprotein-mediated multidrug resistance.
abstract: P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a major obstacle for successful cancer chemotherapy. Based on our previous study, 17 novel compounds with the 6,7-dimethoxy-2-{2-[4-(1H-1,2,3-triazol-1-yl)phenyl]ethyl}-1,2,3,4-tetrahydroisoquinoline scaffold were designed and synthesized. Among them, 2-[(1-{4-[2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl]phenyl}-1H-1,2,3-triazol-4-yl)methoxy]-N-(p-tolyl)benzamide (compound 7 h) was identified as a potent modulator of P-gp-mediated MDR, with high potency (EC50 =127.5 ± 9.1 nM), low cytotoxicity (TI>784.3), and long duration (>24 h) in reversing doxorubicin (DOX) resistance in K562/A02 cells. Compound 7 h also enhanced the effects of other MDR-related cytotoxic agents (paclitaxel, vinblastine, and daunorubicin), increased the accumulation of DOX and blocked P-gp-mediated rhodamine 123 efflux function in K562/A02 MDR cells. Moreover, 7 h did not have any effect on cytochrome (CYP3A4) activity. These results indicate that 7 h is a relatively safe modulator of P-gp-mediated MDR that has good potential for further development.
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009 (P.R. China); Nanjing Research and Development Center, CTTQ Pharmaceutical Research Institute, Building 9, No. 699-8, Xuanwu Dadao, Xuanwu District, Nanjing, Jiangsu (P.R. China).
authors.forename: Baomin
authors.initials: B
authors.lastname: Liu
authors.forename: Qianqian
authors.initials: Q
authors.lastname: Qiu
authors.forename: Tianxiao
authors.initials: T
authors.lastname: Zhao
authors.forename: Lei
authors.initials: L
authors.lastname: Jiao
authors.forename: Yunman
authors.initials: Y
authors.lastname: Li
authors.forename: Wenlong
authors.initials: W
authors.lastname: Huang
authors.forename: Hai
authors.initials: H
authors.lastname: Qian
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000737:chemistry / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A / Q000737:chemistry / Q000378:metabolism; D065692:Cytochrome P-450 CYP3A Inhibitors / Q000737:chemistry / Q000378:metabolism; D003630:Daunorubicin / Q000378:metabolism / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D020014:K562 Cells; D017239:Paclitaxel / Q000494:pharmacology; D011485:Protein Binding; D020112:Rhodamine 123 / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000737:chemistry* / Q000494:pharmacology; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014750:Vincristine / Q000494:pharmacology
chemical_list: C000601547:2-((1-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-N-(p-tolyl)benzamide; D018435:ATP Binding Cassette Transporter, Subfamily B; D000970:Antineoplastic Agents; D001549:Benzamides; D065692:Cytochrome P-450 CYP3A Inhibitors; D044005:Tetrahydroisoquinolines; D014230:Triazoles; D020112:Rhodamine 123; D014750:Vincristine; D051544:Cytochrome P-450 CYP3A; D017239:Paclitaxel; D003630:Daunorubicin
keywords: P-glycoprotein; accumulation; antitumor agents; modulators; multidrug resistance