AZINOMYCIN TOTAL SYNTHESIS AND MECHANISM OF ACTION

描述：首席调查员报告说，氮霉素A和 B是从发酵液中分离出来的抗肿瘤抗生素。 以及这些菌剂拥有错综复杂的 官能化结构，含有前所未有的氮杂环(1，2- A)吡咯烷环系。值得注意的是，奇霉素A和B展示了 体外对L5178Y细胞有较强的细胞毒活性 小鼠体内对P388白血病的抗肿瘤活性 已有研究表明，药物可能通过DNA分子间的 亲电的氮杂环丙烷和环氧化物体系，其方式可与 临床上重要的抗肿瘤药物丝裂霉素C，据介绍， 这项提案的具体目标是为 抗肿瘤药物阿奇霉素A的全合成 专门设计的方法来处理相关的合成 问题。首席调查员还指出，他提议探索 在设计的研究中，试剂的结构/功能关系 以确定它们与寡核苷酸相互作用的分子机制。 他表示，他的研究计划将涉及开发新的 取代萘环体系的合成策略， 环氧化物片段的对映选择性研究进展 用于引入脱氢氨基酸的官能化磷酸盐 双键，立体控制合成1-二氢呋喃的研究 氮杂双环(3.1.0)正己烷环系，包括有效的方法 1，2-二元醇的差别化及其收敛方法 链霉菌素的单个片段的偶联，其中 引入反应性氮杂环(1，2-a)吡咯烷作为最终产物。 综合作业。

DESCRIPTION: The principal investigator reports that azinomycins A and B are antitumor-antibiotic agents that were isolated from culture broths of Streptomyces griseofuscus and that these agents possess an intricately functionalized structure that contains the unprecedented aziridino(1,2- a)pyrrolidine ring system. It is noted that azinomycins A and B exhibit potent in vitro cytotoxic activity against L5178Y cells and significant in vivo antitumor activity against P388 leukemia in mice and that the agents have been shown to covalently cross-link DNA presumably via the electrophilic aziridine and epoxide systems, in a manner comparable to the clinically important antitumor agent mitomycin C. It is stated that the specific aims of this proposal are to develop methodology for the total synthesis of the antitumor agent azinomycin A, using new methodology specifically designed to deal with the relevant synthetic issue. The principal investigator also notes that he proposes to explore the structure/function relationships of the agents, in studies designed to define their molecular mechanism of interaction with oligonucleotides. He states that his research plan will involve the development of new strategies for the synthesis of substituted naphthalene ring systems, an enantioselective approach to the epoxide fragment, the development of functionalized phosphonates for introduction of the dehydroamino acid double bond, studies on the stereocontrolled synthesis of the 1- azabicyclo(3.1.0)hexane ring system, including effective methods for introduction of the differentiated 1,2-diol, and methods for convergent coupling of the individual fragments of the azinomycins, where the reactive aziridino(1,2-a)pyrrolidine is introduced as the final synthetic operation.