Allylsilane Annulation Strategy for Diversity Synthesis

用于多样性合成的烯丙基硅烷成环策略

• 批准号: 6552261
• 负责人: ANNALIESE K FRANZ
• 金额: $ 3.66万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6552261
• 关键词: aldehydes; allyl compound; chemical registry /resource; chemical synthesis; combinatorial chemistry; cyclic compound; intermolecular interaction; postdoctoral investigator; silanes; technology /technique development

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.

描述（由申请人提供）：虽然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库的潜力。拟议研究的目标是开发和合成多种小分子库，利用固体支持物上的新型烯丙基硅烷成环策略。烯丙基硅烷的分支樱井、[3+2]环化和分子内环化途径将与各种构建模块一起使用，以生成多种天然产物状支架。该策略将提供快速获得生物活性杂环和碳环的途径，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，以及高烯丙醇和拟肽。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多样的杂环和同烯丙基底物，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。该策略将提供一个结构独特的库，其中至少包含 200,000 个甲硅烷基和羟基官能化化合物。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测定，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细胞分裂的抑制、运动蛋白抑制、细胞周期进程和细胞凋亡的抑制。