title: Exploration of 2-((Pyridin-4-ylmethyl)amino)nicotinamide Derivatives as Potent Reversal Agents against P-Glycoprotein-Mediated Multidrug Resistance.
abstract: Overexpression of the ATP-binding cassette (ABC) transport proteins, like ABCB1, commonly referred to as P-glycoprotein (P-gp), initiates active efflux of a broad spectrum of unrelated chemotherapeutic drugs in structure and function, leading to chemotherapy failure. A series of 2-((pyridin-4-ylmethyl)amino)nicotinamide derivatives as potent reversal agents against P-glycoprotein-mediated multidrug resistance (MDR) were designed and synthesized. The majority of target compounds displayed great reversal potency, especially 9n. In-depth studies demonstrated 9n has high potency (EC50= 119.6 ± 6.9 nM), low cytotoxicity, and long duration (>24 h) in reversing adriamycin (ADM) resistance in K562/A02 cells. 9n also improved the effects of other cytotoxic agents related to MDR, increased accumulation of ADM, interrupted P-gp-mediated Rh123 efflux function, and suppressed P-gp ATPase activity in K562/A02 MDR cells. The Western blot analysis indicated that the MDR reversal by 9n was not due to a decrease in protein expression. Besides, the effect of CYP3A4 was not influenced by 9n, avoiding the toxicity caused by drug interactions. The study yielded 9n with superior properties compared to the classical inhibitor verapamil (VRP) and leading compound apatinib.
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, P. R. 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 , Nanjing 210009, P. R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Shi
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, P. R. China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, P. R. China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, P. R. China.
authors.forename: Miaobo
authors.initials: M
authors.lastname: Pan
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, P. R. China.
authors.forename: Jian
authors.initials: J
authors.lastname: Cui
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, P. R. China.
authors.forename: Yuxuan
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, P. R. China.|Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University , Nanjing 210009, P. R. China.
authors.forename: Wenlong
authors.initials: W
authors.lastname: Huang
authors.affiliation: Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, P. R. China.|Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University , Nanjing 210009, P. R. China.
authors.forename: Hai
authors.identifier: 0000-0002-3827-0992
authors.initials: H
authors.lastname: Qian
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology*; D055808:Drug Discovery; D018432:Drug Resistance, Multiple / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D006801:Humans; D020014:K562 Cells; D009369:Neoplasms / Q000188:drug therapy; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D009536:Niacinamide; D004317:Doxorubicin; D051544:Cytochrome P-450 CYP3A