TY - JOUR
T1 - Triazole Bridged Flavonoid Dimers as Potent, Nontoxic, and Highly Selective Breast Cancer Resistance Protein (BCRP/ABCG2) Inhibitors
AU - Zhu, Xuezhen
AU - Wong, Iris L.K.
AU - Chan, Kin Fai
AU - Cui, Jiahua
AU - Law, Man Chun
AU - Chong, Tsz Cheung
AU - Hu, Xuesen
AU - Chow, Larry M.C.
AU - Chan, Tak Hang
PY - 2019/9/26
Y1 - 2019/9/26
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85072686388&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.9b00963
DO - 10.1021/acs.jmedchem.9b00963
M3 - Journal article
C2 - 31465686
AN - SCOPUS:85072686388
SN - 0022-2623
VL - 62
SP - 8578
EP - 8608
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 18
ER -
