SYNTHESIS OF BIOLOGICALLY ACTIVE CYCLODEPSIPEPTIDES

这是提案2R01 CA40081-05A1的重新提交。校长 我们研究计划的目标是开发高效的、立体控制的 合成具有重要生物意义的环多肽的合成路线 研究它们潜在的活动地点。我们之前已经 对二氢杨梅素的化学和合成进行了研究。一个 这一时期的重大成就是修订了 髋部单元的立体化学。我们还开发了一种通用的 综合战略和方法，使我们能够 在大环或线性侧链中的修饰。 这些侧链对生物活性至关重要。我们的 合成方法非常适合于修饰氨基酸。 因此，为了研究多肽链的特定方面， 结构-活性关系(SARS)。非典很重要，不仅仅是 对于改进药物的设计，也是为了更好地了解 生物活性的机制。使用分子建模程序和 化学直觉，我们设计了一些类比作为合理的进入 我们已经制定了建设这些目标的战略。这个 计划中的调查还将有助于制定 具有重要生物学意义的环多肽。的结构简单性 白粉菌素及其有效和多样的生物活性，以及它们的 目前的稀缺性使得对这些化合物的合成研究成为可能 这是一项重要的努力。

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.