Cytotoxic Nitrogen Heterocycles

细胞毒性氮杂环

• 批准号: 7223417
• 负责人: EDWIN VEDEJS
• 金额: $ 26.84万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1978
• 资助国家: 美国
• 起止时间: 1978-07-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7223417
• 关键词: Accounting; Alkylation; Amination; Amino Acids; Anabolism; Antineoplastic Agents; Aziridines; Carbon; Closure; Collaborations; Complex; Coupling; DNA; Evaluation; FR 900482; Methodology; Methods; Mitomycin; Modification; Nitrogen; Oxazoles; Peptides; Role; Route; Staging; Structure; Techniques; Telomerase Inhibitor; Testing; analog; animation; aziridine; crosslink; cytotoxic; diazonamide A; enolate; mitosene; oxindole; programs; telomestatin

This program will explore the synthesis of complex heterocyclic structures related to important experimental anticancer agents including FK317, FR900482, mitomycin C, telomestatin, and diazonamide A. In the FK317/FR900482, a synthesis of the intermediate proposed to cause DMA crosslink formation will be completed, and its role in DMA alkylation will be evaluated. Related structures will be prepared to test their role as possible late stage intermediates in the biosynthesis of mitomycin C or FR900482 in collaboration with Prof. D.H. Sherman. A synthesis of polyoxazoles related to the telomerase inhibitor telomestatin will be initiated. Our focus will be to develop methods for connecting simple oxazole units in a repeating chain. A synthesis of diazonamide A will be completed, following a route that has accessed the key aminal and macrocycle subunits, and has developed techniques for controlling configuration at a quaternary carbon in an oxindole. The approach allows late stage introduction and modification of the macrocyclic peptide ring. Advances in methodology will be pursued, including further studies of lithiated aziridines, oxazole activation, aryl triflate coupling to assemble amino acids in a complex setting, enolate amination, and macrocyclic peptide ring closure.

This program will explore the synthesis of complex heterocyclic structures related to important experimental anticancer agents including FK317, FR900482, mitomycin C, telomestatin, and diazonamide A. In the FK317/FR900482, a synthesis of the intermediate proposed to cause DMA crosslink formation will be completed, and its role in DMA alkylation will be evaluated.相关的结构将准备好与D.H. Sherman教授合作测试其在丝裂霉素C或FR900482的生物合成中的后期中间体。 将启动与端粒酶抑制剂端粒蛋白有关的多恶唑的合成。我们的重点是开发在重复链中连接简单的恶唑单元的方法。遵循已访问关键aminal和大环亚基的途径，将完成重18zonamide A的合成，并开发了用于控制Oxindole中第四纪碳的构型的技术。该方法允许后期引入和修饰大环肽环。将取得进展，包括进一步研究锂化氮氨酸，恶唑活化，芳基三叶酸酯偶联，以在复杂的环境中组装氨基酸，酸性胺化和大环肽环的关闭。