Antitumor Agents. 293. Nontoxic Dimethyl-4,4鈥?dimethoxy-5,6,5鈥?6鈥?dimethylenedioxybiphenyl-2,2鈥?dicarboxylate (DDB) Analogues Chemosensitize Multidrug-Resistant Cancer Cells to Clinical Anticancer Dru

详细信息    查看全文

• 作者：Hsin-Yi Hung ; Emika Ohkoshi ; Masuo Goto ; Kenneth F. Bastow ; Kyoko Nakagawa-Goto ; Kuo-Hsiung Lee
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：June 14, 2012
• 年：2012
• 卷：55
• 期：11
• 页码：5413-5424
• 全文大小：553K
• 年卷期：v.55,no.11(June 14, 2012)
• ISSN：1520-4804

文摘

Novel dimethyl-4,4鈥?dimethoxy-5,6,5鈥?6鈥?dimethylenedioxybiphenyl-2,2鈥?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鈥揳ctivity relationship analysis showed that aromatic and bulky aliphatic side chains at the 2,2鈥?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鈥?0 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.