Design, synthesis and biological evaluation of novel tetrahydroisoquinoline derivatives as P-glycoprotein-mediated multidrug resistance inhibitors

Yang Gao; Wei Shi; Jian Cui; Chunxia Liu; Xinzhou Bi; Zhuo Li; Wenlong Huang; Guangji Wang; Hai Qian

doi:10.1016/j.bmc.2018.03.045

Design, synthesis and biological evaluation of novel tetrahydroisoquinoline derivatives as P-glycoprotein-mediated multidrug resistance inhibitors

Bioorg Med Chem. 2018 May 15;26(9):2420-2427. doi: 10.1016/j.bmc.2018.03.045. Epub 2018 Apr 3.

Authors

Yang Gao¹, Wei Shi², Jian Cui², Chunxia Liu², Xinzhou Bi², Zhuo Li², Wenlong Huang³, Guangji Wang⁴, Hai Qian⁵

Affiliations

¹ Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009, PR China.
² Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
³ 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.
⁴ Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, 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: 29631786
DOI: 10.1016/j.bmc.2018.03.045

Abstract

Multidrug resistance (MDR) is one of the main obstacles of clinical chemotherapy. A great deal of research shows that the occurrence of drug resistance in various malignant tumors is closely related to the expression of P-glycoprotein (P-gp) on the surface of the cell membrane. In this paper, based on the structure-activity relationship of phenylethyl tetrahydroisoquinoline, we choose tariquidar as the lead compound for the design and synthesis of 17 novel tetrahydroisoquinoline P-gp inhibitors. Additionally, in vitro and in vivo cytotoxicity assays and reversed MDR activity assays were evaluated. Among them, compound 3 had a good reversal of MDR activity and the reversal mechanism study of it was carried out. All of these results demonstrated that compound 3 was considered to be a promising P-gp-mediated MDR reversal candidate.

Keywords: Cancer; Multidrug resistance; P-glycoprotein; Reversal agents.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Binding Cassette Transporter, Subfamily B, Member 1 / antagonists & inhibitors*
ATP Binding Cassette Transporter, Subfamily B, Member 1 / chemistry
Binding Sites
Cell Survival / drug effects
Doxorubicin / pharmacology
Drug Resistance, Neoplasm / drug effects*
Fluorescent Dyes / metabolism
Fluorescent Dyes / pharmacology
Humans
Isoquinolines / chemical synthesis
Isoquinolines / chemistry
Isoquinolines / pharmacology*
Isoquinolines / toxicity
K562 Cells
Molecular Docking Simulation
Quinolines / chemistry
Quinolines / pharmacology
Rhodamine 123 / metabolism
Rhodamine 123 / pharmacology
Structure-Activity Relationship

Substances

ATP Binding Cassette Transporter, Subfamily B, Member 1
Fluorescent Dyes
Isoquinolines
Quinolines
Rhodamine 123
Doxorubicin
tariquidar