Triazole Bridged Flavonoid Dimers as Potent, Nontoxic, and Highly Selective Breast Cancer Resistance Protein (BCRP/ABCG2) Inhibitors

Xuezhen Zhu, Iris L.K. Wong, Kin Fai Chan, Jiahua Cui, Man Chun Law, Tsz Cheung Chong, Xuesen Hu, Larry M.C. Chow, Tak Hang Chan

Research output: Journal article publicationJournal articleAcademic researchpeer-review

19 Citations (Scopus)


The present work describes the syntheses of diverse triazole bridged flavonoid dimers and identifies potent, nontoxic, and highly selective BCRP inhibitors. A homodimer, Ac22(Az8)2, with m-methoxycarbonylbenzyloxy substitution at C-3 of the flavone moieties and a bis-triazole-containing linker (21 atoms between the two flavones) showed low toxicity (IC50 toward L929, 3T3, and HFF-1 > 100 μM), potent BCRP-inhibitory activity (EC50 = 1-2 nM), and high BCRP selectivity (BCRP selectivity over MRP1 and P-gp > 455-909). Ac22(Az8)2 inhibits BCRP-ATPase activity, blocks the drug efflux activity of BCRP, elevates the intracellular drug accumulation, and finally restores the drug sensitivity of BCRP-overexpressing cells. It does not down-regulate the surface BCRP protein expression to enhance the drug retention. Therefore, Ac22(Az8)2 and similar flavonoid dimers appear to be promising candidates for further development into combination therapy to overcome MDR cancers with BCRP overexpression.

Original languageEnglish
Pages (from-to)8578-8608
Number of pages31
JournalJournal of Medicinal Chemistry
Issue number18
Publication statusPublished - 26 Sep 2019

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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