The tyloindicines F-I, structurally novel promising tumor selective cytotoxic agents, are under study. They apparently act via mechanisms of action unrelated to currently known anticancer agents. Therefore, they are an exciting lead for development as potential chemotherapeutic agents. This proposal describes a multidisciplinary, collaborative effort towards the synthesis of the tyloindicines and related analogues, the elucidation of the molecular mechanism(s) of action, and the characterization of the interaction between the compounds and the molecular target(s). This interdisciplinary approach involves medicinal chemistry, molecular biology, and biochemistry approaches. Since the tyloindicines are not readily available from natural sources, their synthesis is proposed as well as the synthesis of analogues to be used as biological probes. The identification of the receptor for the tyloindicines will be examined by photolabeling of the receptor(s), by a cDNA-phage display technique, by the drug-western method, and affinity column purification. Their cytotoxicity and cellular mechanisms will be studied as well. In addition it is proposed to characterize the interaction of the tyloindicines with their biological targets with the help of photoaffinity labels.
