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.
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