Synthesis and biological evaluation of JL-A7 derivatives as potent ABCB1 inhibitors

  • Bioorg Med Chem. 2017 Aug 1;25(15):4194-4202. doi: 10.1016/j.bmc.2017.06.015.
Miaobo Pan  1 ,  Jian Cui  1 ,  Lei Jiao  2 ,  Hesham Ghaleb  1 ,  Chen Liao  1 ,  Jiaqi Zhou  1 ,  Mutta Kairuki  1 ,  Haiyan Lin  3 ,  Wenlong Huang  4 ,  Hai Qian  5
Affiliations
  • 1. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
  • 2. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Department of Pharmacology, State-Province Key Laboratories of Biomedicine-Pharmaceutics, Key Laboratory of Cardiovascular Research, Ministry of Education, College of Pharmacy, Harbin Medical University, Harbin 150000, PR China.
  • 3. Department of Biochemistry and Molecular Biology, Nanjing Medical University, 140 Hanzhong Road, Nanjing 210029, PR China.
  • 4. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: [email protected].
  • 5. Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: [email protected].
PMID: 28645831 DOI: 10.1016/j.bmc.2017.06.015
Abstract

Cancer chemotherapy failure is often due to the overexpression of ATP-binding cassette (ABC) transporters (particularly ABCB1), resulting in a variety of structurally and pharmacologically unrelated drugs efflux. The multidrug resistance (MDR) phenomenon could be reversed by ABCB1 inhibitors. Now, JL-A7 as the lead compound based on a triazol-N-ethyl-tetrahydroisoquinoline scaffold, 18 compounds were designed and synthesized. Substitution in para positions yielded high activities toward ABCB1. Moreover, compound 5 could effectively block the drug efflux function of ABCB1 and increase the accumulation of anti-cancer drugs to achieve effective treatment concentration in MDR cells.

Keywords
ABCB1 inhibitors; Cancer resistance; MDR; P-glycoprotein.