Qiu Qianqian, Liu Baomin, Cui Jian, Li Zheng, Deng Xin, Qiang Hao, Li Jieming, Liao Chen, Zhang Bo, Shi Wei, Pan Miaobo, Huang Wenlong, Qian Hai
Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, PR China.
Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University , Nanjing 210009, PR China.
J Med Chem. 2017 Apr 27;60(8):3289-3302. doi: 10.1021/acs.jmedchem.6b01787. Epub 2017 Apr 5.
P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a principal obstacle for successful cancer chemotherapy. A novel P-gp inhibitor with a quinazoline scaffold, 12k, was considered to be the most promising for in-depth study. 12k possessed high potency (EC = 57.9 ± 3.5 nM), low cytotoxicity, and long duration of activity in reversing doxorubicin (DOX) resistance in K562/A02 cells. 12k also boosted the potency of other MDR-related cytotoxic agents with different structures, increased accumulation of DOX, blocked P-gp-mediated Rh123 efflux, and suppressed P-gp ATPase activity in K562/A02 MDR cells. However, 12k did not have any effects on CYP3A4 activity or P-gp expression. In particular, 12k had a good half-life and oral bioavailability and displayed no influence on DOX metabolism to obviate the side effects closely related to increased plasma concentrations of cytotoxic agents in vivo.
P-糖蛋白（P-gp）介导的多药耐药性（MDR）是癌症化疗成功的主要障碍。一种具有喹唑啉骨架的新型P-gp抑制剂12k被认为最有深入研究的前景。12k在逆转K562/A02细胞对多柔比星（DOX）的耐药性方面具有高效能（EC = 57.9 ± 3.5 nM）、低细胞毒性和长效活性。12k还增强了其他具有不同结构的MDR相关细胞毒性药物的效能，增加了DOX的蓄积，阻断了P-gp介导的罗丹明123外排，并抑制了K562/A02 MDR细胞中的P-gp ATP酶活性。然而，12k对CYP3A4活性或P-gp表达没有任何影响。特别是，12k具有良好的半衰期和口服生物利用度，并且对DOX代谢没有影响，从而避免了与体内细胞毒性药物血浆浓度升高密切相关的副作用。
