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

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.