Didemnins and Ustiloxins as Probes of Cell Proliferation

德德宁和乌斯蒂洛辛作为细胞增殖的探针

基本信息

批准号：
7845468
负责人：
MADELEINE M JOULLIE
金额：
$ 1.28万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-05 至 2009-10-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7845468
关键词：
Affinity Antimitotic Agents Area Aziridines Binding Binding Proteins Biochemical Biological Biological Factors Cell Cycle Stage Cell Proliferation Cell Proliferation Regulation Cell membrane Cells Cloning Collection Cyclic Peptides Depsipeptides Development Didemnin B Evaluation Family Generations Human Cell Line Hybrids Image Immunosuppressive Agents Investigation Knowledge Marines Methodology Methods Modeling Molecular Nitrogen Peptides Plants Preparation Proteomics Reaction Role Route Structure Synthesis Chemistry System Tubulin Urochordata Validation analog analytical tool antiproliferative agents ascidian base cell type cellular imaging chemical synthesis cytotoxicity design didemnin A didemnins improved in vivo marine natural product novel phomopsin programs receptor scaffold sound stereochemistry tamandarin B tool two-photon ustiloxin A ustiloxin D

项目摘要

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.

描述（由申请人提供）：这是我们的17年计划（CA-40081）的续签应用，重点介绍了环状肽和二肽的总合成，并具有有效的细胞增殖调节。我们的研究集中在两类天然产物上，来自海洋海鞘（外膜）和植物起源的ustiltoxin/phomoptin杂化肽的两类天然产物。我们的方法开发了天然产品家族作为SAR和蛋白质组学分析的工具的完全合成。我们以前的计划已大大推进了贴材代谢产物的合成化学，并明确地确定了didemnin/tamandarin depspepeptides的结构相似性和生物学活性。该领域的新举措将研究dodemnin m和tamandarin M.探针分子的亚摩尔免疫抑制活性，该分子将使用先进的生物化学研究途径合成。 tamandarins的第二代荧光和亲和力类似物正在准备解开不同类型的活动之间的关系。体内细胞分析已与严格的蛋白质组学方法结合使用，以阐明这些二肽的分子受体。使用精致的方法，我们通过对整个天然产品的活动，目标和综合进行全面分析，继续努力理解海洋天然产品。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，乌斯蒂洛蛋白和phomopsins。我们已经证明了能够实现ustiloxins易于合成的能力，现在为开发准确的模拟和同类器准备方法提供了一个合理的平台。现在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，以为这些异构肽的SAR和生物学活性提供全面的模型。