6,7-Dimethoxy-2-{2-[4-(1H-1,2,3-triazol-1-yl)phenyl]ethyl}-1,2,3,4-tetrahydroisoquinolines as superior reversal agents for P-glycoprotein-mediated multidrug resistance

Baomin Liu; Qianqian Qiu; Tianxiao Zhao; Lei Jiao; Yunman Li; Wenlong Huang; Hai Qian

doi:10.1002/cmdc.201402463

6,7-Dimethoxy-2-{2-[4-(1H-1,2,3-triazol-1-yl)phenyl]ethyl}-1,2,3,4-tetrahydroisoquinolines as superior reversal agents for P-glycoprotein-mediated multidrug resistance

ChemMedChem. 2015 Feb;10(2):336-44. doi: 10.1002/cmdc.201402463. Epub 2014 Dec 2.

Authors

Baomin Liu¹, Qianqian Qiu, Tianxiao Zhao, Lei Jiao, Yunman Li, Wenlong Huang, Hai Qian

Affiliation

¹ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009 (P.R. China); Nanjing Research and Development Center, CTTQ Pharmaceutical Research Institute, Building 9, No. 699-8, Xuanwu Dadao, Xuanwu District, Nanjing, Jiangsu (P.R. China).

PMID: 25470220
DOI: 10.1002/cmdc.201402463

Abstract

P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) is a major obstacle for successful cancer chemotherapy. Based on our previous study, 17 novel compounds with the 6,7-dimethoxy-2-{2-[4-(1H-1,2,3-triazol-1-yl)phenyl]ethyl}-1,2,3,4-tetrahydroisoquinoline scaffold were designed and synthesized. Among them, 2-[(1-{4-[2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl]phenyl}-1H-1,2,3-triazol-4-yl)methoxy]-N-(p-tolyl)benzamide (compound 7 h) was identified as a potent modulator of P-gp-mediated MDR, with high potency (EC50 =127.5 ± 9.1 nM), low cytotoxicity (TI>784.3), and long duration (>24 h) in reversing doxorubicin (DOX) resistance in K562/A02 cells. Compound 7 h also enhanced the effects of other MDR-related cytotoxic agents (paclitaxel, vinblastine, and daunorubicin), increased the accumulation of DOX and blocked P-gp-mediated rhodamine 123 efflux function in K562/A02 MDR cells. Moreover, 7 h did not have any effect on cytochrome (CYP3A4) activity. These results indicate that 7 h is a relatively safe modulator of P-gp-mediated MDR that has good potential for further development.

Keywords: P-glycoprotein; accumulation; antitumor agents; modulators; multidrug resistance.

Publication types

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

MeSH terms

ATP Binding Cassette Transporter, Subfamily B / chemistry
ATP Binding Cassette Transporter, Subfamily B / metabolism*
Antineoplastic Agents / pharmacology
Benzamides / chemical synthesis
Benzamides / chemistry*
Benzamides / pharmacology
Cell Survival / drug effects
Cytochrome P-450 CYP3A / chemistry
Cytochrome P-450 CYP3A / metabolism
Cytochrome P-450 CYP3A Inhibitors / chemistry
Cytochrome P-450 CYP3A Inhibitors / metabolism
Daunorubicin / metabolism
Daunorubicin / pharmacology
Drug Resistance, Neoplasm / drug effects
Humans
K562 Cells
Paclitaxel / pharmacology
Protein Binding
Rhodamine 123 / chemistry
Rhodamine 123 / metabolism
Structure-Activity Relationship
Tetrahydroisoquinolines / chemistry*
Tetrahydroisoquinolines / pharmacology
Triazoles / chemical synthesis
Triazoles / chemistry*
Triazoles / pharmacology
Vincristine / pharmacology

Substances

2-((1-(4-(2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)ethyl)phenyl)-1H-1,2,3-triazol-4-yl)methoxy)-N-(p-tolyl)benzamide
ATP Binding Cassette Transporter, Subfamily B
Antineoplastic Agents
Benzamides
Cytochrome P-450 CYP3A Inhibitors
Tetrahydroisoquinolines
Triazoles
Rhodamine 123
Vincristine
Cytochrome P-450 CYP3A
Paclitaxel
Daunorubicin