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

doi:10.1021/acs.jmedchem.9b00963

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. Epub 2019 Sep 12.

Authors

Xuezhen Zhu¹, Iris L K Wong¹, Kin-Fai Chan¹, Jiahua Cui², Man Chun Law¹, Tsz Cheung Chong¹, Xuesen Hu¹, Larry M C Chow¹, Tak Hang Chan^{1

3}

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.

MeSH terms

3T3 Cells
ATP Binding Cassette Transporter, Subfamily B, Member 1 / chemistry
ATP Binding Cassette Transporter, Subfamily G, Member 2 / antagonists & inhibitors*
Animals
Antineoplastic Agents / chemistry
Antineoplastic Agents / pharmacology*
Computer Simulation
Copper / chemistry
Dimerization
Drug Design
Drug Resistance, Multiple / drug effects
Drug Resistance, Neoplasm / drug effects
Flavones / chemistry
Flavonoids / chemistry
Flavonoids / pharmacology*
HEK293 Cells
Humans
Mice
Multidrug Resistance-Associated Proteins / antagonists & inhibitors
Multidrug Resistance-Associated Proteins / chemistry
Neoplasm Proteins / antagonists & inhibitors*
Triazoles / chemistry*

Substances

ABCG2 protein, human
ATP Binding Cassette Transporter, Subfamily B, Member 1
ATP Binding Cassette Transporter, Subfamily G, Member 2
Abcg2 protein, mouse
Antineoplastic Agents
Flavones
Flavonoids
Multidrug Resistance-Associated Proteins
Neoplasm Proteins
Triazoles
Copper
multidrug resistance-associated protein 1