Patek Marcel, Safar Pavel, Smrcina Martin, Wegrzyniak Eric, Bjergarde Kirsten, Weichsel Aleksandra, Strop Peter
Selectide-Combinatorial Technology Center of Aventis Pharmaceuticals, Inc., 1580 East Hanley Boulevard, Tucson, Arizona 85737, USA.
J Comb Chem. 2004 Jan-Feb;6(1):43-9. doi: 10.1021/cc0300311.
One of the key elements in the drug discovery process is the use of automation to synthesize libraries of compounds for biological screening. The "split-and-mix" approaches in combinatorial chemistry have been recognized as extremely powerful techniques to access large numbers of compounds, while requiring only few reaction steps. However, the need for effective encoding/deconvolution strategies and demands for larger amounts of compounds have somewhat limited the use of these techniques in the pharmaceutical industry. In this paper, we describe a concept of directed sort and combine synthesis with spatially arranged arrays of macroscopic supports. Such a concept attempts to balance the number of reaction steps, the confidence in compound identity, and the quantity of synthesized compounds. Using three-dimensional arrays of frames each containing a two-dimensional array of macroscopic solid supports, we have conceptualized and developed a modular semiautomated system with a capacity of up to 100 000 compounds per batch. Modularity of this system enables flexibility either to produce large diverse combinatorial libraries or to synthesize more focused smaller libraries, both as single compounds in 12-15 micromol quantities. This method using sortable and spatially addressed arrays is exemplified by the synthesis of a 15 360 compound library.
药物研发过程中的关键要素之一是利用自动化技术合成用于生物筛选的化合物库。组合化学中的“拆分与混合”方法被认为是获取大量化合物的极为强大的技术，同时仅需很少的反应步骤。然而，对有效编码/解卷积策略的需求以及对大量化合物的要求在一定程度上限制了这些技术在制药行业的应用。在本文中，我们描述了一种将定向分选与结合合成与宏观载体的空间排列阵列相结合的概念。这样的概念试图在反应步骤数量、化合物身份的确信度以及合成化合物的数量之间取得平衡。通过使用每个都包含宏观固体载体二维阵列的框架三维阵列，我们构思并开发了一个模块化的半自动化系统，每批能够合成多达100,000种化合物。该系统的模块化使其具有灵活性，既可以生成大量多样的组合库，也可以合成更具针对性的较小库，两者均为12 - 15微摩尔量的单一化合物。使用可分选和空间寻址阵列的这种方法通过合成一个包含15,360种化合物的库得到了例证。
