Didemnins and Ustiloxins as Probes of Cell Proliferation

描述（由申请人提供）：这是我们第17年项目（CA-40081）的更新申请，重点是具有有效调节细胞增殖的环肽和沉积肽的总合成。我们的研究主要集中在两类天然产物，即来自海洋海鞘动物（被囊动物）的海鞘素/毛檀素沉积肽和来自植物的海鞘毒素/毛檀素异源肽。我们的方法开发了天然产物家族的全合成，作为SAR和蛋白质组学分析的工具。我们之前的项目已经在很大程度上推进了被囊动物代谢物的合成化学，并明确地建立了dididmin /tamandarin沉积肽的结构相似性和生物活性。在这一领域，新的研究方向将是研究红皮素M和红皮素M的亚皮摩尔免疫抑制活性。在红皮素支架上设计探针分子将采用先进的途径进行生化研究。第二代荧光和亲和类似物的红皮苷，正准备解开不同类型的活动之间的关系。体内细胞分析已经结合了严格的蛋白质组学方法来阐明这些沉积肽的分子受体。通过一种精细的方法，我们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，我们将基于类的方法应用于一组微管蛋白调节剂，ustiloxins和phoomopsin。我们已经证明了实现ustiloxins的快速合成的能力，现在为开发类似物和同系物制备的精确方法提供了一个良好的平台。目前正在进行的研究正在转移通过我们的类似物和衍生物获得的知识，为这些异源肽的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.