Triazole Bridged Flavonoid Dimers as Potent, Nontoxic, and Highly Selective Breast Cancer Resistance Protein
Xuezhen Zhu1, Iris L K Wong1, Kin-Fai Chan1
1Department of Applied Biology and Chemical Technology and State Key Laboratory of Chemical Biology and Drug Discovery , Hong Kong Polytechnic University , Hong Kong SAR, China.
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), 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) 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) and similar flavonoid dimers appear to be promising candidates for further development into combination therapy to overcome MDR cancers with BCRP overexpression.
Related Concept Videos
10:17Creating Highly Specific Chemically Induced Protein Dimerization Systems by Stepwise Phage Selection of a Combinatorial Single-Domain Antibody Library
06:02Live Imaging to Study Microtubule Dynamic Instability in Taxane-resistant Breast Cancers
09:29Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
05:02Modeling Brain Metastasis Via Tail-Vein Injection of Inflammatory Breast Cancer Cells
07:45Orthotopic Transplantation of Breast Tumors as Preclinical Models for Breast Cancer
07:41Performing Data Mining And Integrative Analysis Of Biomarker in Breast Cancer Using Multiple Publicly Accessible Databases