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

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

  • J Med Chem. 2019 Sep 26;62(18):8578-8608. doi: 10.1021/acs.jmedchem.9b00963.
Xuezhen Zhu 1,  Iris L K Wong 1,  Kin-Fai Chan 1,  Jiahua Cui 2,  Man Chun Law 1,  Tsz Cheung Chong 1,  Xuesen Hu 1,  Larry M C Chow 1,  Tak Hang Chan 1 3
Affiliations

Affiliations

  • 1 Department of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery , Hong Kong Polytechnic University , Hong Kong SAR, China.
  • 2 School of Environmental Science and Engineering , Shanghai Jiao Tong University , Shanghai 200240 , China.
  • 3 Department of Chemistry , McGill University , Montreal , Quebec H3A 2K6 , Canada.
PMID: 31465686 DOI: 10.1021/acs.jmedchem.9b00963
Abstract

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.

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