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

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)5413-5424
Number of pages12
JournalJournal of Medicinal Chemistry
Volume55
Issue number11
DOIs
Publication statusPublished - 2012 Jun 14

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

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