Antitumor agents. 293. Nontoxic dimethyl-4,4′-dimethoxy-5,6,5′, 6′-dimethylenedioxybiphenyl-2,2′-dicarboxylate (DDB) analogues chemosensitize multidrug-resistant cancer cells to clinical anticancer drugs

Hsin Yi Hung, Emika Ohkoshi, Masuo Goto, Kenneth F. Bastow, Kyoko Nakagawa-Goto, Kuo Hsiung Lee

研究成果: Article同行評審

27 引文 斯高帕斯(Scopus)

摘要

Novel dimethyl-4,4′-dimethoxy-5,6,5′,6′- dimethylenedioxybiphenyl-2,2′-dicarboxylate (DDB) analogues were designed and synthesized to improve their chemosensitizing action on KBvin (vincristine-resistant nasopharyngeal carcinoma) cells, a multidrug resistant cell line overexpressing P-glycoprotein (P-gp). Structure-activity relationship analysis showed that aromatic and bulky aliphatic side chains at the 2,2′-positions effectively and significantly sensitized P-gp overexpressing multidrug resistant (MDR) cells to anticancer drugs, such as paclitaxel (TAX), vincristine (VCR), and doxorubicin (DOX). DDB derivatives 16 and 23 showed 5-10 times more effective reversal ability than verapamil (VRP) for TAX and VCR. Analogue 6 also exhibited five times greater chemosensitizing effect against DOX than VRP. Importantly, no cytotoxicity was observed by the active DDB analogues against both non-MDR and MDR cells, suggesting that DDB analogues serve as novel lead compounds for the development of chemosensitizers to overcome the MDR phenotype. The mechanism of action studies demonstrated that effective inhibition of P-glycoprotein by DDB analogues dramatically elevated the cellular concentration of anticancer drugs.

原文English
頁(從 - 到)5413-5424
頁數12
期刊Journal of Medicinal Chemistry
55
發行號11
DOIs
出版狀態Published - 2012 六月 14

All Science Journal Classification (ASJC) codes

  • 分子醫學
  • 藥物發現

指紋

深入研究「Antitumor agents. 293. Nontoxic dimethyl-4,4′-dimethoxy-5,6,5′, 6′-dimethylenedioxybiphenyl-2,2′-dicarboxylate (DDB) analogues chemosensitize multidrug-resistant cancer cells to clinical anticancer drugs」主題。共同形成了獨特的指紋。

引用此