The proposed research program is aimed at several objectives. Firstly, studies will be directed at the characterization, synthesis and elucidation of the mode of action of the neocarzinostatin chromophore, the biologically active subunit of a compound which is used in the treatment of human tumors. Secondly, research will be conducted on the characterization and synthesis of aplysiatoxin and its analogues, the third and newest group of super tumor promoters. Computer modelling work will also be done to establish the relationship of these promoters with phorbol promoters, a task which is the starting point for understanding tumor promotion and thereby for establishing a basis for the development of cancer chemopreventatives, i.e. tumor promoter inhibitors. Thirdly, a new approach to the synthesis of analogues of mitomycin C, a clinically used antitumor drug, will be developed based on benztriazole photochemistry. This new methodology is also expected to have wide applicability to other problems including the synthesis of pyrrolizidine derivative now in development at NCI. Fourthly, efforts based on a novel arene olefin cycloaddition method will be continued in connection with the synthesis of analogues of the antitumor agent coriolin, and the antibiotic pentalenolactone, and the antileukemic rudmollin. Fifthly, research on the synthesis of biologically active large ring compounds will be pursued in connection with studies on the use of the photothermal olefin metathesis method for melampolidin synthesis, on the use of macroexpansion chemistry for the synthesis of the cytotoxic cembrane crassin acetate, and on a novel onium ion ring expansion process. These programs are expected to advance our understanding of certain classes of cancer active drugs, providing thereby for the design of more effective chemotherapeutics and to refine our understanding of crucial biological processes involved in the development of cancer. Many analogues of the active compounds will be produced and submitted for assay.
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