Kappel Joseph C, Fan Yi C, Lam Kit S
Division of Hematology and Oncology, Department of Internal Medicine, University of California Davis Cancer Center, 4501 X Street, Sacramento, California 95817, USA.
J Comb Chem. 2008 Mar-Apr;10(2):333-42. doi: 10.1021/cc700165s. Epub 2008 Jan 9.
In "one-bead-one-compound" (OBOC) combinatorial chemistry, a compound-bead library with hundreds of thousands to millions of diversities can be rapidly generated such that each bead displays only one chemical entity. The highly efficient "libraries-from-libraries" approach involves the global transformation of a peptide library into many small molecule solution-phase mixture libraries, but this approach has never been successfully applied to OBOC libraries. Here we report a novel approach that allows us to combine these two enabling technologies to efficiently generate OBOC encoded small molecule bead libraries. By using a topologically segregated bilayer bead and a "ladder-synthesis" method, we can prepare peptide libraries with the peptide on the bead surface and a series of peptide ladders in the bead interior. Various global transformation reactions can then be employed to transform the starting peptide library into a variety of peptidomimetic libraries. During the transformation reactions, the peptide ladders in the bead interior are also transformed in a predictable manner. As a result, individual compound bead can be decoded by analyzing the hydrogen fluoride-released encoding tags with matrix-assisted laser desorption ionization Fourier transform mass spectrometry. Using this novel approach, a random encoded dipeptide library was prepared and subsequently transformed into polyamine and poly- N-acetylamine sublibraries. Random beads isolated from these sublibraries were reliably decoded.
在“一珠一化合物”（OBOC）组合化学中，可以快速生成具有数十万至数百万种多样性的化合物珠文库，使得每个珠子仅展示一种化学实体。高效的“文库-文库”方法涉及将肽文库整体转化为许多小分子溶液相混合物文库，但这种方法从未成功应用于OBOC文库。在此，我们报告一种新方法，该方法使我们能够将这两种使能技术结合起来，以高效生成OBOC编码的小分子珠文库。通过使用拓扑隔离的双层珠子和“阶梯合成”方法，我们可以制备在珠子表面带有肽且在珠子内部带有一系列肽阶梯的肽文库。然后可以采用各种整体转化反应将起始肽文库转化为多种拟肽文库。在转化反应过程中，珠子内部的肽阶梯也以可预测的方式发生转化。结果，通过用基质辅助激光解吸电离傅里叶变换质谱分析氟化氢释放的编码标签，可以对单个化合物珠进行解码。使用这种新方法，制备了一个随机编码的二肽文库，随后将其转化为多胺和聚-N-乙酰胺子文库。从这些子文库中分离出的随机珠子得到了可靠的解码。
