Amine linked flavonoid dimers as modulators for P-glycoprotein-based multidrug resistance: Structure-activity relationship and mechanism of modulation

Kin Fai Chan, Iris L K Wong, Jason W Y Kan, Clare S W Yan, Ming Cheung Chow, Tak Hang Chan

Research output: Journal article publicationJournal articleAcademic researchpeer-review

59 Citations (Scopus)


Here we report a great improvement in reversal potency of cancer drug resistance when flavonoid dimers possess a functionally substituted aminopolyethylene glycol linker. The most potent compound, 18, contains a N-benzyl group at the linker. It has many advantages including (1) high potencies in reversing P-glycoprotein (P-gp) mediated resistance in LCC6MDR cells to various anticancer drugs with EC 50 in the nanomolar range, (2) low toxicity and high therapeutic index, and (3) preferential inhibition of P-gp over multidrug resistance protein 1 and breast cancer resistance protein. Compound 18 stimulates P-gp-ATPase activity by 2.7-fold and mediates a dose-dependent inhibition of doxorubicin (DOX) transport activity. Lineweaver-Burk and Dixon plots suggest that 18 is a competitive inhibitor to DOX in binding to P-gp with a K i of 0.28-0.34 μM and a Hill coefficient of 1.17. Moreover, the LCC6MDR cell displays about 2.1-fold lower intracellular accumulation of 18 compared to the wild type, suggesting that 18 is a P-gp substrate as well.
Original languageEnglish
Pages (from-to)1999-2014
Number of pages16
JournalJournal of Medicinal Chemistry
Issue number5
Publication statusPublished - 8 Mar 2012

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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