This application is a request for support of our continuing research efforts with a number of naturally occuring antitumor compounds. Our proposal outlines extensive experiments with a focus on metabolic systems and the antineoplastic compounds which they transform. Our work will advance the understanding of antitumor agents in one or more of the following ways by: providing quantities of potentially active drug metabolites; providing metabolites as analytical standards to facilitate drug metabolism studies in mammalian systems; revealing new and important pathways of metabolism of structurally complex antitumor compounds; and by shedding new light on possible mechanisms of metabolic bioactivation, bioinactivation or increasing toxicities. Experiments will employ selected microorganisms; and microbial, mammalian and plant enzyme systems including the copper oxidases; peroxidases; other purified enzymes; and mammalian liver preparations. Mechanisms of oxidative transformations of Catharanthus alkaloids, aureolic acid, nogalamycin and quadrone will be explored using these metabolic systems. Metabolites will be isolated and identified. We have already obtained a biolgically active intermediate of quadrone biosynthesis, and will conduct further chemical and biotransformation experiments with the sesquiterpene. We intend to determine the generality and significance of a new type of biotransformation reaction catalyzed by copper oxidases involving beta-carbinolamine moieties found commonly in the structures of biologically active compounds. Through a combination of chemical and biochemical experimental approaches, we hope to establish structure-activity-relationships with compounds under investigation.
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