Flavonoid Monomers as Potent, Nontoxic, and Selective Modulators of the Breast Cancer Resistance Protein (ABCG2)

We synthesize various substituted
triazole-containing flavonoids
and identify potent, nontoxic, and highly selective BCRP inhibitors. Ac18Az8, Ac32Az19, and Ac36Az9 possess m-methoxycarbonylbenzyloxy substitution at C-3 of the flavone
moiety and substituted triazole at C-4′ of the B-ring. They
show low toxicity (IC50 toward L929 > 100 μM),
potent
BCRP-inhibitory activity (EC50 = 1–15 nM), and high
BCRP selectivity (BCRP selectivity over MRP1 and P-gp > 67–714).
They inhibit the efflux activity of BCRP, elevate the intracellular
drug accumulation, and restore the drug sensitivity of BCRP-overexpressing
cells. Like Ko143, Ac32Az19 remarkably exhibits a 100%
5D3 shift, indicating that it can bind and cause a conformational
change of BCRP. Moreover, it significantly reduces the abundance of
functional BCRP dimers/oligomers by half to retain more mitoxantrone
in the BCRP-overexpressing cell line and that may account for its
inhibitory activity. They are promising candidates to be developed
into combination therapy to overcome MDR cancers with BCRP overexpression.