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

  • J Med Chem. 2017 Apr 27;60(8):3289-3302. doi: 10.1021/acs.jmedchem.6b01787.
Qianqian Qiu  1 ,  Baomin Liu  1 ,  Jian Cui  1 ,  Zheng Li  1 ,  Xin Deng  1 ,  Hao Qiang  1 ,  Jieming Li  1 ,  Chen Liao  1 ,  Bo Zhang  1 ,  Wei Shi  1 ,  Miaobo Pan  1 ,  Wenlong Huang  1  2 ,  Hai Qian  1  2
Affiliations
  • 1. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University , Nanjing 210009, PR China.
  • 2. Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University , Nanjing 210009, PR China.
PMID: 28355069 DOI: 10.1021/acs.jmedchem.6b01787
Abstract

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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