New Strategies for the Synthesis of Bioactive Molecules

生物活性分子合成新策略

基本信息

批准号：
7259289
负责人：
RAYMOND L. FUNK
金额：
$ 31.38万
依托单位：
PENNSYLVANIA STATE UNIVERSITY, THE
依托单位国家：
美国
项目类别：
财政年份：
1987
资助国家：
美国
起止时间：
1987-09-01 至 2011-02-28
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): The primary objective of this research is to continue to discover new strategies for the construction of complex carbocyclic or heterocyclic ring systems. Several new methods will be developed to meet this objective. Intramolecular cycloadditions of aza-ortho-xylylenes will be explored for the construction of the ring system of communesin B, a cytotoxic natural product that functions by disrupting microfilaments. It is hoped that anti-microfilament agents might represent a new class of anticancer agents and prove to be as effective as the well-established anti-microtubule agents. A novel method developed for the construction of indoles, a ubiquitous privileged structure found in numerous biologically active compounds, will be applied in the total synthesis of the cytotoxic, anti-microtubule agent welwistatin. This natural product has not been synthesized and is active against multiple drug resistant phenotypes. The versatility of this indole synthesis will be further demonstrated in the total synthesis of dragmacidin E. A strategy developed for the synthesis of erythrinan alkaloids that takes advantage of amidoacrolein-based methodology will be extended to a member of the homoerythrinan subclass of natural products. More importantly, additional analogs of the potent neuronal nicotinic acetylcholine antagonist, dihydro-p-erythroidine, will be prepared. The overall goal is to further define the pharmacophore and discover a subtype selective antagonist, of potential therapeutic value in the treatment of neurological diseases (for example, autism) as well as smoking cessation. A method featuring the cyclization of 2-silyloxyenals will be exploited for the first time in the rapid construction of the ring system of the potent, selective angiogenesis inhibitor, cortistatin A, an exciting new lead structure for the further development of this emerging class of anticancer agents. A completed total synthesis will permit subsequent construction of cortistatin A conjugates that will be used to discover the molecular target of this natural product. Finally, a new method of considerable promise for the construction of complex ring systems that involves the tandem vicinal difunctionalization of enecarbamates will be used to prepare gram quantities of the architecturally fascinating cytotoxin nakadomarin A. The biological investigation of this natural product has been severely restricted by its limited availability from the natural source, a marine sponge.

描述（由申请人提供）：这项研究的主要目的是继续发现建造复杂碳环或杂环环系统的新策略。将开发几种新方法来满足这一目标。将探索AZA-ORTHO-XYLYLENES的分子内环载物，以构建Communesin B的环系统，这是一种通过破坏微丝的细胞毒性天然产物。希望抗微丝剂可以代表一种新的抗癌药，并被证明与良好的抗微管剂一样有效。一种用于构造吲哚的新方法是在许多生物活性化合物中发现的无处不在的特权结构，将用于细胞毒性，抗微蛋白剂Welwistatin的总合成中。该天然产物尚未合成，并且对多种耐药表型具有活性。该吲哚合成的多功能性将在Dragmacidin E的总合成中进一步证明。一种用于合成erythrinan生物碱的策略，利用基于胺果蛋白的方法，将扩展到天然产物的同型雌雄同体子类的成员。更重要的是，将制备有效神经元烟碱乙酰胆碱拮抗剂二氢 - 甲状腺素蛋白的其他类似物。总体目标是进一步定义药效团并发现亚型选择性拮抗剂，该拮抗剂具有潜在的治疗神经系统疾病（例如自闭症）以及戒烟的治疗价值。在有效，选择性血管生成抑制剂Cortistatin A的快速构造中，将首次利用一种具有2个硅氧基环化的方法，这是一种令人兴奋的新铅结构，以进一步开发这种新兴的抗癌药物。完整的总合成将允许随后构造偶联物，该偶联物将用于发现该天然产物的分子靶标。最后，一种涉及ENECARBAMATES串联的杂化环节的新方法，用于建造复杂的环系统，该方法将用于制备革兰氏数量的建筑上令人着迷的细胞毒素Nakadomarin A.对这种自然产品的生物学研究受到了自然来源的有限限制。