期刊
DRUG DESIGN DEVELOPMENT AND THERAPY
卷 9, 期 -, 页码 3481-3495出版社
DOVE MEDICAL PRESS LTD
DOI: 10.2147/DDDT.S84982
关键词
multidrug resistance; cancer cells; ABCG2/BCRP; indenoindole inhibitors; structure-activity relationships; ATPase activity
资金
- Brazilian CNPq-CAPES [245762/2012-4]
- CAPES [8792127, 2303/10-8]
- postdoctoral fellowship for the Control of Cancer-CNPq (Science without Borders Program)
- CNRS
- Universite Lyon 1 [UMR 5086]
- Ligue Nationale Contre le Cancer (Equipe labellisee Ligue)
- French ANR
- Hungarian NIH [2010-INT-1101-01]
Ketonic indeno[1,2-b]indole-9,10-dione derivatives, initially designed as human casein kinase II (CK2) inhibitors, were recently shown to be converted into efficient inhibitors of drug efflux by the breast cancer resistance protein ABCG2 upon suited substitutions including a N-5-phenethyl on C-ring and hydrophobic groups on D-ring. A series of ten phenolic and seven p-quinonic derivatives were synthesized and screened for inhibition of both CK2 and ABCG2 activities. The best phenolic inhibitors were about threefold more potent against ABCG2 than the corresponding ketonic derivatives, and showed low cytotoxicity. They were selective for ABCG2 over both P-glycoprotein and MRP1 (multidrug resistance protein 1), whereas the ketonic derivatives also interacted with MRP1, and they additionally displayed a lower interaction with CK2. Quite interestingly, they strongly stimulated ABCG2 ATPase activity, in contrast to ketonic derivatives, suggesting distinct binding sites. In contrast, the p-quinonic indenoindoles were cytotoxic and poor ABCG2 inhibitors, whereas a partial inhibition recovery could be reached upon hydrophobic substitutions on D-ring, similarly to the ketonic derivatives.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据