title: Discovery of novel P-glycoprotein-mediated multidrug resistance inhibitors bearing triazole core via click chemistry.
abstract: A novel series of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) inhibitors bearing a triazol-phenethyl-tetrahydroisoquinoline scaffold were designed and synthesized via click chemistry. Most of the synthesized compounds showed higher reversal activity than verapamil (VRP). Among them, the most potent compound 5 showed a comparable activity with the known potent P-gp inhibitor WK-X-34 with lower cytotoxicity (IC50s > 100 μm). Compared with VRP, compound 5 exhibited more potency in increasing drug accumulation in K562/A02 MDR cells. Moreover, compound 5 persisted longer chemo-sensitizing effect (>24 h) than VRP (<6 h) with reversibility. Given the low intrinsic cytotoxicity and the potent reversal activity, compound 5 may represent a promising candidate for developing P-gp-mediated MDR inhibitor.
authors.affiliation: State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, 210009, 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: Jianyu
authors.initials: J
authors.lastname: Hou
authors.forename: Yunman
authors.initials: Y
authors.lastname: Li
authors.forename: Hai
authors.initials: H
authors.lastname: Qian
authors.forename: Wenlong
authors.initials: W
authors.lastname: Huang
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D001549:Benzamides / Q000737:chemistry / Q000493:pharmacokinetics; D057930:Click Chemistry; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D006801:Humans; D020014:K562 Cells; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism; D014230:Triazoles / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D001549:Benzamides; D014230:Triazoles; C511688:WK-X-34; D004317:Doxorubicin
keywords: P-glycoprotein; click chemistry; multidrug resistance inhibitors; reversal activity