DIDEMNINS AND USTILOXINS AS PROBES OF CELL PROLIFERATION

摘要：这是一项为期12年的计划(CA-40081)的更新应用，该计划侧重于天然产物及其类似物的全合成，具有潜在的抗增殖剂用途。我们所选择的化合物一直是并将继续是理解和利用控制细胞增殖的过程的宝贵工具，它们在研究可能是新的或知之甚少的抗增殖机制以及确定可能的治疗干预癌症等增殖性疾病的新途径方面尤其重要。已经选择了两组不同的天然产品进行研究。我们首先描述我们的计划，以进一步了解大环脱脂肽的Ddemnin家族的生物学特性。我们以前的努力大大推进了这些化合物的合成化学。该领域的新举措将集中在合成探针分子上：(1)了解某些白粉菌素显著的亚皮下分子免疫抑制活性，(2)鉴定相关的受体蛋白，(3)理清细胞凋亡、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)开发毒性较低的白粉菌素前体药物。作为一项新的冒险，我们计划探索大环肽Utiloxins，这是一种有效的微管蛋白聚合抑制剂。关于曲霉毒素在微管蛋白结合部位(S)、对有丝分裂的影响(S)以及细胞毒性水平方面，人们知之甚少。这些化合物的合成化学也不发达。因此，我们提出了两种合成曲霉毒素的方法。我们的战略是我们在环肽生物碱领域取得的成就的产物。除了最初的Utilooxin D的全合成外，我们还将公开一种灵活的方法，适用于(A)Utilooxin同系物，(B)密切相关的根霉毒素，和(C)一系列类似物的合成，这些类似物将用于探索结合部位和构效关系。除了它们作为合成靶标的吸引力外，ustiloxins还有望成为整个抗微管蛋白天然产品多肽类的重要探针。

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.