The objective of this project is the kinetic and mechanistic characterization of reactions of N-alkyl porphyrin complexes. These results will be applied to the development of efficacious anti-tumor agents and the rapid synthesis of radiolabelled metalloporphyrins for therapeutic and diagnostic use. N-alkyl porphyrin complexes have the potential for tumor localization and cytotoxic activity by alkylation at a controllable rate. Kinetic control can be achieved by proper choice of metal ion in the N-alkyl porphyrin complex. Very limited kinetic data for these reactions in vitro are available and no controlled in vivo experiments have been carried out. We propose to prepare a series of N-alkyl porphyrin complexes and to determine the variation of rates and activation parameters for dealkylation reactions as functions for the bound metal atom and alkyl group. We will undertake mechanistic studies to determine the site selectivity for alkylation of a number of biologically important nucleophiles in aqueous and non-aqueous media. We will compare these reactions with reactions between the N-alkyl metalloporphyrins and cells in culture. In addition, we will ascertain the integrity of N-alky; porphyrin complexes and the localization of the alkyl group in vivo (in mice) using radiolabelled compounds. As new classes of compounds with different reactivity are synthesized for the kinetic studies, gram-scale samples will be made available for testing under the auspices of the National Cancer Institute.
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