Allylsilane Annulation Strategy for Diversity Synthesis

描述(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，但尚未实现不同硅基功能化文库的潜力。这项拟议研究的目标是开发和合成一个不同的小分子文库，利用一种新的固体载体上的烯丙基硅烷环化策略。烯丙基硅烷的分支樱花、[3+2]环化和分子内环化途径将与不同的构筑块一起使用，以生成不同的天然产物类支架。这一策略将提供快速获得生物活性杂环和碳环的途径，如四氢呋喃、吡咯烷、吡咯烷酮、异恶唑烷、苯醌衍生物、四氢喹啉、内酰胺和环戊烷环，以及高烯丙醇和肽类化合物。该文库将有四个多样性产生步骤：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多样化的杂环和高烯丙基底物，以及4)从固相中裂解小分子产物以保留产物中的硅基或提供羟基取代的杂环。这一策略将提供一个结构截然不同的库，至少有200,000个硅基和羟基官能化化合物。这些不同的小分子配体将被用于化学遗传学方法，以探索生物功能和疾病途径。将进行表型分析和蛋白质结合分析，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例子包括抑制细胞分裂、抑制运动蛋白、细胞周期进展和抑制凋亡。

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.