PALYTOXIN PRODRUG SYNTHESIS, PURIFICATION, AND ANALYSES

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During Phase I research, two palytoxin-derived prodrugs were prepared. The prodrugs were up to 1000-fold less cytotoxic to cells in culture than palytoxin. In the presence of activating enzyme, full conversion of the prodrug to palytoxin was demonstrated. Anti-tumor monoclonal antibody conjugates of the activating enzyme conferred antigen-selective cytotoxicity to the prodrugs of up to 100-fold, against cells in culture. In mixed populations of antigen-positive and -negative cells, a potent "bystander-cell" killing effect was observed. This is the first marine toxin derivative used as a prodrug. The Phase II research effort will further optimize synthetic, purification, and analytical methodology for palytoxin-derived prodrugs. Additional congeners of the palytoxin derivatives will be prepared and evaluated against cells in culture. Preclinical antitumor activity will be investigated under a collaborative research agreement.