Application of New Amination Reactions to Natural Product and Nonnatural Heterocy

新胺化反应在天然产物和非天然杂性中的应用

• 批准号: 7657219
• 负责人: Jeffrey Nicholas Johnston
• 金额: $ 31.42万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7657219
• 关键词: Acetylcholine; Alkaloids; Alkynes; Alzheimer' s Disease; Amination; Amines; Amino Acids; Aziridines; Biological Assay; Biological Factors; Budgets; Cancer cell line; Chemicals; DNA; Development; Disease; Exhibits; Follow-Up Studies; Free Radicals; Funding; Goals; Grant; Hand; Imines; Mediating; Metals; Methodology; Methods; Mitomycins; Pathway interactions; Pharmaceutical Chemistry; Pharmacologic Substance; Phase; Positioning Attribute; Public Health; Quinones; Reaction; Route; Screening procedure; Therapeutic; TimeLine; anticancer activity; antitumor agent; base; chemical synthesis; chemotherapy; crosslink; esterase; indoline; innovation; lycopodium alkaloid; member; neurochemistry; pharmacophore; programs; serratezomine A; skeletal; small molecule; tool

This program describes a chemical synthesis route to biologically active natural products. Mitomycin C is a clinically-used small molecule for chemotherapy that functions as a DNA cross-linking agent. No other known chemotherapeutic duplicates this mechanism of action. A short synthesis is being developed based on new reactions devleoped during the program's first phase: the aza-Darzens reaction of propargyl imines to produce the cis-aziridine diastereoselectively. A metal promoted amine-alkyne enamine synthesis is then paired with a quinone to conjoin the molecule's two halves. Completion of the synthesis will be accomplished via one of several intermediates this approach provides. Completion of the total synthesis of (+)-serratezomine A is also planned. Free radical-mediated vinyl amination is a key enabling reaction in this synthesis. Serratezomine A is a member of the lycopodium alkaloids; many constituents have exhibited acetycholine esterase inhibition and anticancer activity. The synthesis route allows general access to these members and unnatural derivatives through a common skeletal construction. Chemical synthesis of antitumor and potential Alzheimer's therapeutic leads will result from these studies. Additionally, new synthetic methods with more general impact in pharmaceutical synthesis are expected to result.

本程序描述了一种具有生物活性的天然产物的化学合成路线。 产品。丝裂霉素C是一种临床上用于化疗的小分子药物 起DNA交联剂的作用。没有其他已知的化疗复制品 这种作用机制。一种基于新反应的简短合成正在开发中 在该计划的第一阶段发展起来：炔丙基亚胺的aza-Darzens反应 非对映选择性地生产顺-氮杂环丙烷。一种金属催化胺-炔烃 然后将烯胺合成与苯二酚配对，将分子的两半连接在一起。 合成的完成将通过几个中间体中的一个完成 方法提供了。完成了(+)-Serratezomine A的全合成 有计划的。自由基介导的乙烯基胺化反应是这一反应的关键 综合。Serratezomine A是石松属生物碱的一员，有许多成分 具有乙酰胆碱酯酶抑制活性和抗癌活性。综合 路径允许对这些成员和非自然派生进行常规访问 常见的骨骼结构。 抗肿瘤和潜在阿尔茨海默病治疗线索的化学合成将 来自这些研究的结果。此外，具有更广泛影响的新合成方法 在药物合成方面有望取得成果。