一个基于立体选择性三组件合反应的螺旋氧indoles图书馆
Michael M-C Lo1, Christopher S Neumann, Satoshi Nagayama
1Program in Chemical Biology, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02138, USA.
Journal of the American Chemical Society
|December 9, 2004
概括
研究人员使用分池方法合成了3000多种不同的螺旋氧indoles. 这种化学库有助于探索细胞电路,并确定了增强活性抑制剂细胞作用的化合物.
科学领域:
- 药用化学 医学化学
- 化学生物学 化学生物学
- 有机合成 有机合成
背景情况:
- 结构复杂和化学多样化的小分子对于探测细胞机制至关重要.
- 开发大型化合物库的高效合成策略对于药物发现和化学生物学研究至关重要.
研究的目的:
- 报告在高容量宏观弹头上开发了超过3000个螺旋氧indoles的分池合成.
- 证明本图书馆在识别细胞过程调节者的实用性,特别是latrunculin B.的作用.
主要方法:
- 使用了威廉姆斯三组件合器的易斯酸变体,用于立体选择性螺旋氧醇核心组装.
- 采用了索诺加希拉合物,胺形成反应和玛-乳酸盐的N-化,用于图书馆编制.
- 通过使用双项置信限度分析了库的纯度,并对合成的化合物进行了高通量选.
主要成果:
- 成功合成了超过3000个螺旋氧indoles的图书馆,这些化合物的纯度估计至少为82%.
- 从图书馆中确定了几个积极的结果,这些结果增强了拉特伦库林B的细胞效应,它是一种活性蛋白聚合的抑制剂.
- 通过再合成确认了一种已识别的化合物,在酵母细胞中显示亚微分子EC50值.
结论:
- 开发的分池合成策略是有效的产生大型,多样化的图书馆的复杂的小分子,如spirooxindoles.
- 合成的spiroxindole库是化学遗传选的宝贵工具,可以发现新的细胞路径调节器.
- 已识别的拉特伦林B作用增强剂突显了该库在发现新生物活性化合物的潜力.
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