Journal of Medicinal Chemistry p. 3289 - 3302 (2017)
Update date:2022-08-15
Topics:
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
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 (EC50 = 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.
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