DIDEMNINS AND USTILOXINS AS PROBES OF CELL PROLIFERATION

地德米宁和乌斯蒂洛辛作为细胞增殖的探针

• 批准号: 6512349
• 负责人: MADELEINE M JOULLIE
• 金额: $ 31.57万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-30 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6512349
• 关键词: X ray crystallography; affinity chromatography; affinity labeling; antineoplastics; antiviral agents; biological products; circular dichroism; conformation; cyclic peptides; drug design /synthesis /production; drug receptors; immunosuppressive; molecular dynamics; nuclear magnetic resonance spectroscopy; oligopeptides; peptide analog; peptide chemical synthesis; prodrugs; protein structure function; receptor binding; stereochemistry; tubulin

ABSTRACT: This is a renewal application of a twelve-year program (CA-40081) focusing on the total synthesis of natural products and analogs have potential use as anti-proliferative agents. The compounds we have chosen have been and will continue to be valuable tools for understanding and exploiting the processing which control cell proliferation They are especially important in study anti-proliferative mechanisms which may be novel or poorly understood, and in identifying possible new avenues for therapeutic intervention in proliferative diseases such as cancer. Two separate groups of natural products have been selected for study. We describe first our program to understand further the biological properties of the didemnin family of macrocyclic depsipeptides. Our previous efforts have considerably advanced the synthetic chemistry of these compounds. New initiatives in the didemnin area will focus on synthetic probe molecules: (1) to understand the striking sub-picomolar immunosuppressive activity of certain didemnins, (2) to identify the relevant receptor proteins, (3) to untangle the relationships between apoptotic, cytotoxic, immunosuppressive and protein biosynthesis inhibition activities, and (4) to develop less toxic didemnin pro-drugs. As a new venture, we propose to explore the ustiloxins, macrocyclic peptides which are potent inhibitors of tubulin polymerization. The ustiloxins are poorly understood in terms of tubulin binding site(s), effect(s) on mitosis, and levels of cytotoxicity. The synthetic chemistry of these compounds is also not well-developed. Therefore, we propose two synthetic approaches to the ustiloxins. Our strategy is an outgrowth of our accomplishments in the cyclopeptide alkaloid field. Beyond the initial total synthesis of ustiloxin D, we will disclose a flexible approach suitable for the synthesis of (A) ustiloxin congeners, (B) the closely-related phomopsins, and (C) a set of analogs which will be used to explore binding sites and structure-activity relationships. In addition to their appeal as synthetic targets, the ustiloxins hold promise as important probes for the entire peptide class of anti-tubulin natural products.

摘要：这是针对天然产物和类似物的总合成的十二年计划（CA-40081）的续订应用。我们选择的化合物已经并且将继续是理解和利用处理哪种控制细胞增殖的有价值的工具，它们在研究抗增殖机制中尤为重要，这些机制可能是新颖或不理理解的，并且在识别诸如癌症之类的增殖性疾病中的治疗性干预方面可能是新的治疗方法。已经选择了两个单独的天然产品进行研究。我们首先描述了我们的程序，以进一步了解大环肽depspeptides的Didemnin家族的生物学特性。我们以前的努力已经大大推动了这些化合物的合成化学。 Didemn地区的新举措将集中在合成探针分子上：（1）了解某些dodemnins的惊人的亚曲线的免疫抑制活性，（2）确定相关的受体蛋白，（3）解开对质毒性，蛋白毒性，蛋白质抑制和蛋白质抑制的较少的关系（4）的关系（3）亲毒品。作为一项新事业，我们提议探索乌斯特洛昔候，大环肽是微管蛋白聚合的有效抑制剂。从微管蛋白结合位点，效应对有丝分裂的作用和细胞毒性水平方面，乌斯霉素的理解很少。这些化合物的合成化学也没有发达。因此，我们提出了两种合成方法，用于乌斯特洛毒素。我们的策略是我们在环肽生物碱领域成就的产物。除了最初的USTILOXIN D总合成之外，我们还将披露一种适用于（a）乌斯特洛毒素同源物，（b）密切相关的phomopsins的柔性方法，以及（c）一组类似物，这些类似物将用于探索结合位点和结构 - 活性关系。除了吸引合成靶标外，乌斯利洛毒素还具有对整个抗微管蛋白天然产物类别的重要探针的希望。