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Discovery to solve multidrug resistance: Design, synthesis, and biological evaluation of novel agents
Author(s) -
Qiu Qianqian,
Shi Wei,
Zhao Shiyuan,
Zhu Yan,
Ding Zhengquan,
Zhou Shaoyang,
Kairuki Mutta,
Huang Wenlong,
Qian Hai
Publication year - 2019
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.201900127
Subject(s) - efflux , p glycoprotein , multiple drug resistance , verapamil , rhodamine 123 , pharmacology , doxorubicin , chemistry , cytotoxicity , chemotherapy , drug resistance , in vitro , medicine , biology , biochemistry , antibiotics , organic chemistry , microbiology and biotechnology , calcium
Chemotherapy remains a pillar in the treatment and management of various cancers. However, multidrug resistance (MDR) becomes a severe problem after long‐term administration of chemotherapy drugs. Overexpression of P‐glycoprotein (P‐gp) is a significant cause for tumor MDR. Therefore, P‐gp inhibition is considered as an effective strategy to reverse MDR. A third‐generation P‐gp inhibitor tariquidar was selected as a lead compound, and a new series of triazol‐ N ‐ethyl tetrahydroisoquinoline based compounds were designed as novel P‐gp inhibitors and synthesized through click chemistry. These compounds presented higher reversal activities than the positive‐control verapamil (VRP). Among 18 compounds, compound 11 without cytotoxicity reversed MDR in a dose‐dependent manner, with a persistent longer chemosensitizing effect and reversibility compared to others. Mechanism studies discovered that compound 11 could escalate the intracellular accumulation of rhodamine‐123 and doxorubicin in K562/A02 cells as well as inhibit their efflux from cells. The results obtained suggest that compound 11 is more potent than VRP administered under the same conditions; it may be a potent and safe candidate for P‐gp modulation for further development.