Didemnins and Ustiloxins as Probes of Cell Proliferation

描述（由申请人提供）：这是我们第17年计划（CA-40081）的更新申请，重点是环肽和缩肽的全合成，具有有效的细胞增殖调节作用。我们的研究主要集中在两类天然产物：海洋海鞘（被囊动物）的didemnin/tamandarin缩肽和植物来源的ustiltoxin/phomopsin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。我们以前的计划已经大大推进了被囊动物代谢物的合成化学，并明确建立了didemnin/tamandarin缩肽的结构相似性和生物活性。这一领域的新举措将研究didemnin M和tamandarin M的亚皮摩尔免疫抑制活性。在tamandarin支架上设计的探针分子将使用先进的生化研究路线合成。第二代荧光和亲和性的tamandarins类似物，正在准备解开不同类型的活动之间的关系。在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缩肽的分子受体。我们使用改进的方法，通过对整个天然产品类别的活性，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，我们已经将我们基于类的方法应用于一组微管蛋白调节剂，ustiloxins和根视素。我们已经证明了能够实现简单的合成的ustiloxins，现在提供了一个良好的平台，为开发准确的方法，类似物和同源物的制备。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，以提供这些杂合肽的SAR和生物活性的综合模型。

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.