Cytotoxic Nitrogen Heterocycles

本项目将探索与重要的实验抗癌药物FK317、FR900482、丝裂霉素C、端粒菌素和重氮酰胺A相关的复杂杂环结构的合成。在FK317/FR900482中，将完成导致DMA交联剂形成的中间体的合成，并将评估其在DMA烷基化反应中的作用。相关结构将与D.H.Sherman教授合作，测试它们作为丝裂霉素C或FR900482生物合成的可能后期中间体所起的作用。 将开始合成与端粒酶抑制剂端粒酶相关的多恶唑。我们的重点将是开发在重复链中连接简单恶唑单元的方法。重氮酰胺A的合成将按照一条访问关键氨基和大环亚单位的路线完成，并已开发出控制氧化吲哚中季碳构型的技术。该方法允许大环肽环的后期引入和修饰。方法学方面的进展将继续进行，包括进一步研究锂化氮杂环、恶唑活化、芳基三氟代偶联以在复杂环境中组装氨基酸、烯醇胺化和大环肽环闭合。

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.