Soluble 3′,6-Substituted Indirubins with Enhanced Selectivity toward Glycogen Synthase Kinase -3 Alter Circadian Period
详细信息 查看全文
- 作者：Konstantina Vougogiannopoulou ; Yoan Ferandin ; Karima Bettayeb ; Vassilios Myrianthopoulos ; Olivier Lozach ; Yunzhen Fan ; Carl Hirschie Johnson ; Prokopios Magiatis ; Alexios-Leandros Skaltsounis ; Emmanuel
- 刊名：Journal of Medicinal Chemistry
- 出版年：2008
- 出版时间：October 23, 2008
- 年：2008
- 卷：51
- 期：20
- 页码：6421-6431
- 全文大小：388K
- 年卷期：v.51,no.20(October 23, 2008)
- ISSN：1520-4804
文摘
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.