2. Academic Validation
  3. 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

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

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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