Allylsilane Annulation Strategy for Diversity Synthesis

描述（由申请人提供）：尽管已经观察到几种有机硅化合物的抗肿瘤特性，但尚未实现多样化甲硅烷基官能化文库的潜力。本研究的目标是开发和合成一个不同的小分子库，利用一种新的烯丙基硅烷成环策略的固体支持。Sakurai的分支，[3+2]成环和烯丙基硅烷的分子内环化途径将与各种构建块一起使用，以产生不同的天然产物样支架。该策略将提供快速获得具有生物活性的杂环和碳环的途径，例如四氢呋喃、吡咯烷、吡咯烷酮、异恶唑烷、醌衍生物、四氢喹啉、内酰胺和环戊烷环，以及高烯丙型醇和肽模拟物。该库将有四个多样性生成步骤：1）加载醛底物，2）形成烯丙基硅烷官能团，3）烯丙基硅烷的分支途径以提供结构上不同的杂环和高烯丙基底物，以及4）从固相裂解小分子产物以保留产物中的甲硅烷基或提供羟基取代的杂环。该策略将提供具有最少200，000个甲硅烷基和羟基官能化化合物的结构上不同的库。这些不同的小分子配体将用于化学遗传学方法，以探索生物功能和疾病途径。将进行表型和蛋白质结合试验，以产生药物开发和癌症治疗的直接线索。癌症相关表型筛选的实例包括细胞分裂抑制、运动蛋白抑制、细胞周期进展和细胞凋亡抑制。

DESCRIPTION (provided by applicant): Although anti-tumor properties have been observed for several organosilicon compounds, the potential for a diverse silyl-functionalized library has not yet been realized. The goal of the proposed research is to develop and synthesize a library of diverse small molecules exploiting a novel allylsilane annulation strategy on solid support. Branching Sakurai, [3+2] annulation and intramolecular cyclization pathways of allylsilanes will be employed with various building blocks to generate diverse natural product-like scaffolds. This strategy will provide rapid access to biologically active heterocycles and carbocycles such as tetrahydrofurans, pyrrolidines, pyrrolidinones, isoxazolidines, quinone derivatives, tetrahydroquinolines, lactams, and cyclopentane rings, as well as homoallylic alcohols and peptidomimetics. There will be four diversity-generating steps for this library: 1) loading the aldehyde substrate, 2) formation of the allylsilane functionality, 3) branching pathways of allylsilanes to afford structurally diverse heterocycles and homoallylic substrates, and 4) cleavage of the small molecule product from the solid phase to either retain the silyl group in the product or provide a hydroxy substituted heterocycle. This strategy will afford a structurally distinct library with a minimum of 200,000 silyl- and hydroxy-functionalized compounds. These diverse small molecule ligands will be utilized in a chemical genetics approach to explore biological function and disease pathways. Both phenotypic and protein-binding assays will be performed to generate direct leads for drug development and cancer treatment. Examples of cancer-relevant phenotypic screens include inhibition of cell division, motor protein inhibition, cell cycle progression, and inhibition of apoptosis.