Synthesis of Biologically Significant Cyclopropanes

具有生物学意义的环丙烷的合成

• 批准号: 0517389
• 负责人: Richard Taylor
• 金额: $ 39.2万
• 依托单位: University of Notre Dame
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=0517389&HistoricalAwards=false
• 关键词: Synthesis; Biologically; Significant; Cyclopropanes

This renewal project centers on the development of synthetic methodology and its application towards the synthesis of biologically relevant cyclopropane-containing targets including histone deacetylase inhibitors, histamine H3 antagonists, and the anti-fungal natural product ambruticin. Cationic cyclopropanation reactions with benzylic and cyclopropylmethyl alcohol derivatives will be investigated, including a detailed study of the stereochemical integrity of the ring closure reaction, with emphasis on the effect of reaction conditions (solvent polarity and leaving group effects). This methodology will be applied in the synthesis of novel cyclopropyl-substituted histone deacetylase inhibitors. The effect of alpha-heteroaromatic substitution on the stereochemical integrity of the cation cyclization process will be investigated, and this chemistry will be applied toward the synthesis of a series of H3 receptor antagonists. The activation and ring closure of allylic alcohols will be investigated, and this chemistry will be applied toward the synthesis of the architecturally complex anti-fungal polyketide ambruticin.With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Dr. Richard E. Taylor of the Department of Chemistry and Biochemistry at the University of Notre Dame. Professor Taylor and his students will devise and develop new methods for the controlled synthesis of organic molecules containing cyclopropane (three-membered ring) units. Such compounds often require special techniques for their synthesis, given the strain present in the three-membered ring, yet form the basis of a number of interesting naturally occurring compounds as well as potential pharmaceutical agents, including therapeutic agents for disorders involving sleep, food intake, thermoregulation, and memory formation. The PI's initial discoveries in this area are already transitioning into the chemical industry, where they are being used to facilitate the discovery of new drug candidates.

该更新项目的重点是合成方法的开发及其在合成生物相关的含环丙烷靶点方面的应用，包括组蛋白脱乙酰酶抑制剂，组胺H3拮抗剂和抗真菌天然产物ambruticin。阳离子环丙烷化反应与苄基和环丙基甲醇衍生物将进行调查，包括闭环反应的立体化学完整性的详细研究，重点是反应条件的影响（溶剂极性和离去基团的影响）。此方法将应用于合成新的环丙基取代的组蛋白去乙酰化酶抑制剂。将研究α-杂芳取代对阳离子环化过程的立体化学完整性的影响，并且这种化学将被应用于一系列H3受体拮抗剂的合成。该项目将研究烯丙醇的活化和闭环反应，并将此化学反应应用于结构复杂的抗真菌聚酮化合物ambruticin的合成。圣母大学化学和生物化学系的泰勒说。 泰勒教授和他的学生将设计和开发控制合成含有环丙烷（三元环）单元的有机分子的新方法。考虑到三元环中存在的应变，此类化合物通常需要特殊的合成技术，但仍形成许多令人感兴趣的天然存在的化合物以及潜在的药物制剂的基础，包括用于涉及睡眠、食物摄入、体温调节和记忆形成的疾病的治疗剂。PI在这一领域的初步发现已经过渡到化学工业，在那里它们被用来促进新候选药物的发现。