SYNTHESIS OF BIOLOGICALLY ACTIVE CYCLODEPSIPEPTIDES

这是提案2 R 01 CA 40081 - 05 A1的重新提交。 校长 我们的研究计划的目标是开发高效，立体控制， 生物学上重要的环缩酚肽和 研究他们潜在的活动地点 我们先前已经 研究了didemnins的化学和合成。 一 这一期间的一项重大成就是修订了 Hip单元的立体化学。 我们还开发了一个通用的 综合战略和方法，使我们能够 在一些实施方案中，大环化合物可以在大环或直链侧链中进行修饰。 这些侧链对生物活性至关重要。 我们 合成方法非常适合于修饰蛋白质中的氨基酸。 肽链，并因此检查其特定方面 构效关系（SAR）。 SAR很重要，不仅 用于设计改进的药物，也用于更好地了解 生物活性的机制。 使用分子模拟程序， 化学直觉，我们设计了一些类似物作为合理的入口， 目标，并制定了实现这些目标的战略。 的 计划中的调查还将有助于发展 生物学上重要的环缩酚肽。 结构简单， didemnins，其有效和多样的生物活性，以及它们的 目前缺乏这些化合物的合成研究， 重要的奋进。

This is a resubmission of proposal 2R01 CA40081-05A1. The principal goal of our research program is to develop efficient, stereocontrolled synthetic routes to biologically important cyclodepsipeptides and to study their potential sites of activity. We have previously investigated the chemistry and synthesis of the didemnins. A significant accomplishment during this period was the revision of the stereochemistry of the Hip unit. We have also developed a general synthetic strategies and methodologies that will enable us to make modifications, either in the macrocycle or in the linear side chains. These side chains are of utmost importance for biological activity. Our synthetic approach id eminently suited for modifying amino acids in the peptide chain, and to, therefore, examine specific aspects of the structure-activity relationships (SARs). SARs are important, not only for the design of improved drugs, but also for better understanding of the mechanism of bioactivity. Using molecular modeling programs and chemical intuition, we have designed some analogs as reasonable entry targets and we have devised strategies for their construction. The planned investigations will also contribute to the development of biologically important cyclodepsipeptides. The structural simplicity of the didemnins, their potent and diverse biological activities, and their present scarcity make synthetic investigations of these compounds an important endeavor.