A library of spirooxindoles based on a stereoselective three-component coupling reaction
A library of spirooxindoles based on a stereoselective three-component coupling reaction
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DOI：
10.1021/ja045089d
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发表时间：
2004-12-15
影响因子：
15
通讯作者：
Schreiber, SL
中科院分区：
文献类型：
--
作者：
Lo, MMC;Neumann, CS;Schreiber, SL
一系列结构复杂和化学多样的小分子是探索细胞回路的有用工具。在这篇文章中，我们报道了3000多个螺羟吲哚的高容量大珠上的分裂池合成。立体选择性组装螺羟吲哚核心的关键反应是威廉姆斯三组分偶联的刘易斯酸变体。形成后，使用Sonogashira偶联、酰胺形成反应和γ-内酰胺的N-酰化来阐述骨架。通过对单个大珠进行采样并使用二项式置信限分析最终文库。经确定，至少82%的库化合物的纯度应高于80%。为了证明我们的发现过程的实用性，使用所得产物的储备溶液进行高通量化学遗传修饰剂筛选。许多阳性被鉴定为肌动蛋白聚合抑制剂latrunculin B的细胞作用的增强剂。通过再合成，我们确认了其中一种阳性物质，并证明在酵母细胞中，它的EC 50在亚微摩尔范围内。
A collection of structurally complex and chemically diverse small molecules is a useful tool to explore cell circuitry. In this article, we report the split-pool synthesis of more than 3000 spirooxindoles on high capacity macrobeads. The key reaction to assemble the spirooxindole core stereoselectively is a Lewis acid variant of the Williams' three-component coupling, After formation, the skeleton was elaborated using Sonogashira couplings, amide forming reactions, and N-acylations of gamma-lactams. The final library was analyzed by sampling individual macrobeads and by using binomial confidence limits. It was determined that at least 82% of the library compounds should have better than 80% purity. To demonstrate the utility of our discovery process, a high-throughput chemical genetic modifier screen was performed using stock solutions of the resultant products. A number of positives were identified as enhancers of the cellular actions of latrunculin B, an actin polymerization inhibitor. Through resynthesis, we confirmed one of the positives and demonstrated that, in yeast cells, it has an EC50 in the sub-micromolar range.