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6,7‐Dimethoxy‐2‐{2‐[4‐(1 H ‐1,2,3‐triazol‐1‐yl)phenyl]ethyl}‐1,2,3,4‐tetrahydroisoquinolines as Superior Reversal Agents for P‐Glycoprotein‐Mediated Multidrug Resistance
Author(s) -
Liu Baomin,
Qiu Qianqian,
Zhao Tianxiao,
Jiao Lei,
Li Yunman,
Huang Wenlong,
Qian Hai
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402463
Subject(s) - p glycoprotein , daunorubicin , multiple drug resistance , chemistry , cytotoxicity , rhodamine 123 , doxorubicin , pharmacology , efflux , paclitaxel , stereochemistry , tetrahydroisoquinoline , chalcone , in vitro , biology , leukemia , chemotherapy , biochemistry , medicine , antibiotics
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‐(1 H ‐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(1 H )‐yl)ethyl]phenyl}‐1 H ‐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 (EC 50 =127.5±9.1 n M ), 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.