COMBINATORIAL APPROACHES TO DNA AND TUBULIN BINDING MOLECULES

DNA 和微管蛋白结合分子的组合方法

• 批准号: 6563923
• 负责人: K. C. NICOLAOU
• 金额: $ 19.71万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6563923
• 关键词: DNA binding protein; DNA topoisomerases; alkenes; antineoplastics; chemical registry /resource; chemical synthesis; drug design /synthesis /production; drug screening /evaluation; nucleic acid sequence; oligosaccharides; tubulin

This grant application describes a program directed at the development of DNA sequence specific molecules by combinatorial molecular imprinting techniques. Appropriately functionalized calicheamicin oligosaccharides with olefinic appendages of various sizes will be allowed to bind into the minor grove of duplex DNA containing two (or more) binding sites, and those who fit will be ligated via the olefin metathesis reaction. Through this and related strategies we hope to develop a series of sequence specific oligosaccharides for certain DNA sequences that can be used as vehicles for specific DNA cleavage and cross-linking as well as for modulating gene expression and suppression as a means to cancer chemotherapy. A second project will involve the construction of an apothilone B library using a combination of solution and solid phase chemistry techniques. The synthesized library will be screened in tubulin polymerization and cytotoxicity assays. Potential anticancer agents are expected to be identified from these studies.

本拨款申请描述了一个旨在开发 DNA序列特异性分子的组合分子印迹 技术.适当官能化的加利车霉素寡糖 具有各种尺寸的烯属附属物将被允许结合到 含有两个（或多个）结合位点的双链体DNA的小格罗夫，和 通过烯烃复分解反应连接那些适合的分子。通过 我们希望以此和相关策略制定出一系列的序列 某些DNA序列的特异性寡糖， 用于特异性DNA切割和交联以及用于 调节基因表达和抑制作为癌症的手段 化疗 第二个项目将涉及构建apothilone B文库 使用溶液和固相化学技术的组合。的 将在微管蛋白聚合中筛选合成文库， 细胞毒性测定。潜在的抗癌药物预计将 从这些研究中发现。