化学
Abcg2型
米托蒽醌
药理学
类黄酮
药品
结构-活动关系
癌症研究
三唑
体外
染料木素
流出
多重耐药
乳腺癌
癌细胞
阿霉素
细胞毒性
细胞培养
立体化学
生物化学
运输机
ATP结合盒运输机
有机化学
外科
化疗
基因
抗氧化剂
医学
作者
Iris L. K. Wong,Xue-Zhen Zhu,Kin-Fai Chan,Zhen Liu,Chin Han Chan,Tsun Chow,Tsz Hong Chong,Man Ching Law,Jiahua Cui,Larry M.C. Chow,Tak Mao Chan
标识
DOI:10.1021/acs.jmedchem.1c00779
摘要
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.
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