SYNTHESIS OF BLEOMYCIN GROUP ANTIBIOTICS AND ANALOGUES

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DESCRIPTION: (Principal Investigator's) The long term goals of this research are i) synthesis of bleomycin group antibiotics and the development of new methods that facilitate their elaboration, and ii) synthesis of bleomycin analogues that have superior properties as therapeutic agents or which can be used to help define the mechanism of action of bleomycin. For the period of requested support, the specific aims include completion of the total synthesis of phleomycin and a stereocontrolled, total synthesis of tallysomycin. Also planned are the syntheses of bleomycin analogues that can help to define the mode of DNA binding, which bind and cleave RNA with greater affinity, and which exhibit greater efficiency in double-strand cleavage of B-form DNA. While bleomycin is an established member of the armamentarium of clinically used antitumor agents, there are nonetheless a number of deficiencies in the understanding of the way in which BLM functions as an antitumor agent. The studies proposed here should facilitate an understanding of the mechanism of BLM action and make it possible to identify BLM congeners exhibiting enhanced properties as antitumor agents.