Flavonoid dimers as bivalent modulators for P-glycoprotein-based multidrug resistance: Synthetic apigenin homodimers linked with defined-length poly(ethylene glycol) spacers increase drug retention and enhance chemosensitivity in resistant cancer cells

Kin Fai Chan, Yunzhe Zhao, Brendan A. Burkett, Iris L.K. Wong, Ming Cheung Chow, Tak Hang Chan

Research output: Journal article publicationJournal articleAcademic researchpeer-review

85 Citations (Scopus)


Much effort has been spent on searching for better P-glycoprotein- (P-gp-) based multidrug resistance (MDR) modulators. Our approach was to target the binding sites of P-gp using dimers of dietary flavonoids. A series of apigenin-based flavonoid dimers, linked by poly(ethylene glycol) chains of various lengths, have been synthesized. These flavonoid dimers modulate drug chemosensitivity and retention in breast and leukemic MDR cells with the optimal number of ethylene glycol units equal to 2-4. Compound 9d bearing four ethylene glycol units increased drug accumulation in drug-resistant cells and enhanced cytotoxicity of paclitaxel, doxorubicin, daunomycin, vincristine, and vinblastine in drug-resistant breast cancer and leukemia cells in vitro, resulting in reduction of IC50by 5-50 times. This compound also stimulated P-gp's ATPase activity by 3.3-fold. Its modulating activity was presumably by binding to the substrate binding sites of P-gp and disrupting drug efflux.
Original languageEnglish
Pages (from-to)6742-6759
Number of pages18
JournalJournal of Medicinal Chemistry
Issue number23
Publication statusPublished - 16 Nov 2006

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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