Turner David M, Tom Christopher T M B, Renslo Adam R
Small Molecule Discovery Center, and Department of Pharmaceutical Chemistry, University of California, San Francisco , San Francisco, California 94158, United States.
ACS Comb Sci. 2014 Dec 8;16(12):661-4. doi: 10.1021/co500132q. Epub 2014 Nov 12.
Disulfide exchange screening is a site-directed approach to fragment-based lead discovery that requires a bespoke library of disulfide-containing fragments. Previously, we described a simple one-pot, two-step synthesis of disulfide fragments from amine- or acid-bearing starting materials. Here, we describe the synthesis of disulfide fragments that bear a 1,4-substituted-1,2,3-triazole linkage between disulfide and molecular diversity element. This work establishes the compatibility of copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) chemistry with a one-pot, two-step reaction sequence that can be readily parallelized. We performed 96 reactions in a single deep-well microtiter plate, employing 48 alkynes and two different azide linker reagents. From this effort, a total of 81 triazole-containing disulfide fragments were obtained in useful isolated yields. Thus, CuAAC chemistry offers an experimentally convenient method to rapidly prepare disulfide fragments that are structurally distinct from fragments accessed via amide, sulfonamide, or isocyanate chemistries.
二硫键交换筛选是一种基于片段的先导化合物发现的定点方法，需要一个定制的含二硫键片段库。此前，我们描述了一种从含胺或含酸的起始原料简单一锅两步合成二硫键片段的方法。在此，我们描述了在二硫键和分子多样性元素之间带有1,4-取代-1,2,3-三唑连接的二硫键片段的合成。这项工作确立了铜（I）催化的叠氮化物-炔烃环加成（CuAAC）化学与易于平行化的一锅两步反应序列的兼容性。我们在单个深孔微量滴定板中进行了96个反应，使用了48种炔烃和两种不同的叠氮连接试剂。通过这项工作，总共获得了81个含三唑的二硫键片段，并具有有用的分离产率。因此，CuAAC化学提供了一种实验方便的方法，可快速制备结构上不同于通过酰胺、磺酰胺或异氰酸酯化学方法获得的片段的二硫键片段。
