Didemnins and Ustiloxins as Probes of Cell Proliferation

描述(申请人提供)：这是我们的17年计划(CA-40081)的续展申请，重点是环肽和脱肽的总合成，对细胞增殖具有有效的调节作用。我们的研究主要集中在两类天然产物上，一类是来自海洋海鞘(被囊类)的白粉菌素/罗曼达多肽，另一类是植物来源的枯草杆菌毒素/褐孔菌素杂多肽。我们的方法开发了天然产物家族的全合成，作为SAR和蛋白质组分析的工具。我们之前的计划极大地促进了衣酸代谢物的合成化学，明确地建立了白鲜素/罗汉果素多肽的结构相似性和生物活性。这一领域的新举措将研究白粉菌素M和他芒柄花素M的亚皮下分子免疫抑制活性。设计在罗望子草素支架上的探针分子将使用先进的生化研究路线进行合成。正在准备第二代荧光和亲和类似物，以解开不同类型活性之间的关系。体内细胞分析与严格的蛋白质组学方法相结合，以阐明这些脱肽的分子受体。我们采用精细化的方法，通过对一整类天然产品的活性、目标和合成进行全面分析，继续努力了解海洋天然产品。在第二组研究中，我们将我们基于班级的方法应用于一组微管蛋白调节剂，即ustiloxins和phomopsins。我们已经证明了能够实现ustiloxins的简单合成，现在为开发类似物和同类物质的准确制备方法提供了一个良好的平台。目前正在进行的研究正在进行中，以转移通过我们的类似物和衍生物获得的知识，为这些异构肽的SAR和生物活性提供一个全面的模型。

DESCRIPTION (provided by applicant): This is a renewal application of our 17th-year program (CA-40081) focusing on the total synthesis of cyclic peptide and depsipeptides with potent regulation of cell proliferation. Our studies have focused on 2 classes of natural products the didemnin/tamandarin depsipeptides from marine ascidians (tunicates) and the ustiltoxin/phomopsin heterodetic peptides of plant origin. Our approach develops total synthesis of families of natural products as tools for SAR and proteomic analyses. Our previous program has considerably advanced the synthetic chemistry of the tunicate metabolites and established unequivocally the structural similarity and biological activity of didemnin/tamandarin depsipeptides. New initiatives in this area will investigate the subpicomolar immunosuppressive activity of didemnin M and tamandarin M. Probe molecules designed on the tamandarin scaffold will be synthesized using advanced routes for biochemical investigations. Second generation fluorescent and affinity analogs of the tamandarins, are being prepared to untangle the relationships among the different types of activity. In vivo cell analyses have been combined with a rigorous proteomics approach to elucidate the molecular receptors for these depsipeptides. Using a refined approach, we continue our efforts towards understanding marine natural products by developing a comprehensive analysis of the activity, target and synthesis of an entire class of natural products. In a second set of studies, we have applied our class based approach to a set of tubulin regulators, the ustiloxins and phomopsins. We have demonstrated the ability to achieve facile syntheses of the ustiloxins, and now offer a sound platform for development of accurate methods for analog and congener preparation. Ongoing studies are now underway to transfer the knowledge gained through our analogs and derivatives to provide a comprehensive model for the SAR and biological activities of these heterodetic peptides.