jm6b01787_si_002.csv (2.12 kB)
Design, Synthesis, and Pharmacological Characterization of N‑(4-(2 (6,7-Dimethoxy-3,4-dihydroisoquinolin-2(1H)yl)ethyl)phenyl)quinazolin-4-amine Derivatives: Novel Inhibitors Reversing P‑Glycoprotein-Mediated Multidrug Resistance
datasetposted on 2017-03-29, 00:00 authored by Qianqian Qiu, Baomin Liu, Jian Cui, Zheng Li, Xin Deng, Hao Qiang, Jieming Li, Chen Liao, Bo Zhang, Wei Shi, Miaobo Pan, Wenlong Huang, Hai Qian
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.