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: 6605781
• 负责人: ANNALIESE K FRANZ
• 金额: $ 4.16万
• 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 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6605781
• 关键词: aldehydes; allyl compound; chemical genetics; 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，但尚未实现多种硅基功能化文库的潜力。提出的研究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环化策略在固体载体。烯丙硅烷的分支Sakurai，[3+2]环化和分子内环化途径将与各种构建块一起使用，以生成各种天然产物样支架。这一策略将提供快速获取具有生物活性的杂环和碳环的途径，如四氢呋喃、吡罗烷、吡罗烷酮、异恶唑烷、醌衍生物、四氢喹啉、内酰胺和环戊烷环，以及同丙烯醇和拟肽物。该文库将有四个产生多样性的步骤：1)装载醛底物，2)形成烯丙基硅烷功能，3)烯丙基硅烷的分支途径以提供结构多样化的杂环和均烯丙基底物，以及4)从固相裂解小分子产物以保留产品中的硅基或提供羟基取代的杂环。这种策略将提供一个结构独特的库，至少有200,000个硅基和羟基功能化化合物。这些不同的小分子配体将用于化学遗传学方法来探索生物功能和疾病途径。表型和蛋白质结合分析将为药物开发和癌症治疗提供直接线索。癌症相关表型筛选的例子包括细胞分裂抑制、运动蛋白抑制、细胞周期进展和细胞凋亡抑制。