Qiu Qianqian, Shi Wei, Li Zheng, Zhang Bo, Pan Miaobo, Cui Jian, Dai Yuxuan, Huang Wenlong, Qian Hai
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.
J Med Chem. 2017 Apr 13;60(7):2930-2943. doi: 10.1021/acs.jmedchem.6b01879. Epub 2017 Mar 24.
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 (EC = 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.
ATP结合盒（ABC）转运蛋白（如通常称为P-糖蛋白（P-gp）的ABCB1）的过表达会引发多种结构和功能上不相关的化疗药物的主动外排，导致化疗失败。设计并合成了一系列作为P-糖蛋白介导的多药耐药（MDR）有效逆转剂的2-((吡啶-4-基甲基)氨基)烟酰胺衍生物。大多数目标化合物表现出很强的逆转效力，尤其是9n。深入研究表明，9n在逆转K562/A02细胞对阿霉素（ADM）的耐药性方面具有高效力（EC = 119.6 ± 6.9 nM）、低细胞毒性和长效性（>24小时）。9n还改善了与MDR相关的其他细胞毒性药物的效果，增加了ADM的积累，中断了P-gp介导的Rh123外排功能，并抑制了K562/A02 MDR细胞中的P-gp ATP酶活性。蛋白质印迹分析表明，9n的MDR逆转作用不是由于蛋白质表达的降低。此外，9n不影响CYP3A4的作用，避免了药物相互作用引起的毒性。与经典抑制剂维拉帕米（VRP）和先导化合物阿帕替尼相比，该研究得到的9n具有更优异的性能。
