DIDEMNINS AND USTILOXINS AS PROBES OF CELL PROLIFERATION

摘要：这是一个为期12年的项目（CA-40081）的更新申请，重点是天然产物和类似物的全合成，具有抗增殖药物的潜在用途。我们所选择的化合物已经并将继续成为理解和开发控制细胞增殖过程的有价值的工具。它们在研究可能是新颖的或知之甚少的抗增殖机制，以及在确定治疗性疾病（如癌症）的可能的新途径方面尤其重要。选择了两组不同的天然产物进行研究。我们首先描述了我们的程序，以进一步了解大环沉积肽的dideminin家族的生物学特性。我们以前的努力已经大大促进了这些化合物的合成化学。didemnin领域的新动向将集中在合成探针分子上：(1)了解某些didemnin惊人的亚皮莫勒免疫抑制活性，(2)鉴定相关受体蛋白，(3)阐明凋亡，细胞毒性，免疫抑制和蛋白质生物合成抑制活性之间的关系，以及(4)开发毒性较小的didemnin前药。作为一个新的冒险，我们提出探索ustiloxins，大环肽是微管蛋白聚合的有效抑制剂。在微管蛋白结合位点、对有丝分裂的影响和细胞毒性水平方面，对乌斯替洛素的了解甚少。这些化合物的合成化学也不是很发达。因此，我们提出了两种合成乌斯蒂洛素的方法。我们的战略是我们在环肽生物碱领域的成就的产物。除了最初的全合成ustiloxin D之外，我们将披露一种灵活的方法，适用于(a) ustiloxin同系物的合成，(B)密切相关的磷光素，以及(C)一组类似物的合成，这些类似物将用于探索结合位点和结构-活性关系。除了作为合成靶点的吸引力外，ustiloxins还有望作为抗微管蛋白天然产物的整个肽类的重要探针。

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.