AZINOMYCIN TOTAL SYNTHESIS AND MECHANISM OF ACTION

描述：主要研究者报告说，阿奇霉素A和 B是从培养液中分离的抗肿瘤抗生素剂 灰褐链霉菌，这些代理商具有复杂的 含有前所未有的氮丙啶（1，2-）的官能化结构 a）吡咯烷环系统。 注意到，azinomycin A和B表现出 对L5178 Y细胞具有有效的体外细胞毒活性， 对小鼠P388白血病的体内抗肿瘤活性， 试剂已经显示出共价交联DNA，推测是通过 亲电氮丙啶和环氧化物体系，以与 临床上重要的抗肿瘤药物丝裂霉素C。 据称， 本提案的具体目标是为以下方面制定方法： 本文报道了抗肿瘤药物azinomycin A的全合成， 专门为处理有关的综合问题而设计的方法 问题. 首席研究员还指出，他建议探索 在设计的研究中， 以确定它们与寡核苷酸相互作用的分子机制。 他说，他的研究计划将包括开发新的 取代萘环体系的合成策略， 对环氧化物片段的对映选择性方法， 用于引入脱氢氨基酸的官能化膦酸酯 双键，立体控制合成1- 氮杂双环（3.1.0）己烷环体系，包括 介绍了分化的1，2-二醇，以及收敛的方法 偶联阿奇霉素的各个片段，其中 引入反应性氮丙啶并（1，2-a）吡咯烷作为最终产物， 合成操作

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.