期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 51, 期 20, 页码 6421-6431出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm800648y
关键词
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资金
- EEC [FP6-2002]
- TEMPO [LSHG-CT-2006-037543]
- PENED
- Canceropole Grand-Ouest
- Association France-Alzheimer
- ACCAMBA project [CT500485]
- Ministere de la Recherche
- National Institutes of Health [R21 NS054991]
- Vanderbilt Institute for Chemical Biology
Glycogen synthase kinase -3 (GSK-3) is a key enzyme involved in numerous physiological events and in major diseases, such as Alzheimer's disease, diabetes, and cardiac hypertrophy. Indirubins are bis-indoles that can be generated from various natural sources or chemically synthesized. While rather potent and selective as GSK-3 inhibitors, most indirubins exhibit low water solubility. To address the issue of solubility, we have designed novel analogues of 6-bromo-indirubin-3'-oxime with increased hydrophilicity based on the GSK-3/indirubins cocrystal structures. The new derivatives with an extended amino side chain attached at position 3' showed potent GSK-3 inhibitory activity, enhanced selectivity, and dramatically increased water solubility. Furthermore, some of them displayed little or no cytotoxicity. The new indirubins inhibit GSK-3 in a cellular reporter model. They alter the circadian period measured in rhythmically expressing cell cultures, suggesting that they might constitute tools to investigate circadian rhythm regulation.
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