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

Miaobo Pan; Jian Cui; Lei Jiao; Hesham Ghaleb; Chen Liao; Jiaqi Zhou; Mutta Kairuki; Haiyan Lin; Wenlong Huang; Hai Qian

doi:10.1016/j.bmc.2017.06.015

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. Epub 2017 Jun 13.

Authors

Miaobo Pan¹, Jian Cui¹, Lei Jiao², Hesham Ghaleb¹, Chen Liao¹, Jiaqi Zhou¹, Mutta Kairuki¹, Haiyan Lin³, Wenlong Huang⁴, Hai Qian⁵

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: ydhuangwenlong@126.com.
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: qianhai24@163.com.

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.

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / antagonists & inhibitors
Antibiotics, Antineoplastic / pharmacology
Carbon-13 Magnetic Resonance Spectroscopy
Cell Line, Tumor
Doxorubicin / pharmacology
Drug Resistance, Multiple / drug effects
Humans
Isoquinolines / chemical synthesis*
Isoquinolines / pharmacology*
Proton Magnetic Resonance Spectroscopy
Spectrometry, Mass, Electrospray Ionization
Structure-Activity Relationship
Triazoles / chemical synthesis*
Triazoles / pharmacology*

Substances

ABCB1 protein, human
ATP Binding Cassette Transporter, Subfamily B
Antibiotics, Antineoplastic
Isoquinolines
JL-A7 compound
N-(4-(tert-butyl)phenyl)-2-((1-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)-1H-1,2,3-triazol-4-yl)methoxy)benzamide
Triazoles
Doxorubicin