CHEMISTRY OF BIOLOGICALLY RELEVANT QUINONE IMINES

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Quinone imines are intermedites in the oxidation of a variety of biological systems, and various roles have been postulated for these species. Thus, the metabolism of a number of biologically important cathecholamines is postulated to involve quinone imine intermediates, and N-alkylated quinone imines may be involved in the side effects of long-term chloropromazine therapy. The toxicity of the analgesic paracetamol has been attributed to a metabolically formed quinone imine which binds cell macromolecules. Recent studies have invoked a quinone imine from N-methylellipticium acetate as the intermediate which arylates in vivo purine nucleosides and nucleotides; thus, this particular quinone imine may play an important role in the antitumor activity of ellipticene. Simple quinone imines as well as those involved in the biological effects noted above are usually quite unstable under the conditions used for their generation. This has prevented their isolation and a more detailed study of their chemistry, spectroscopy, and biology under carefully controlled conditions. Thus, a method for preparation and isolation of quinone imines would allow an in-depth study of their chemistry and biology. Our aim is to develop methods for the non-oxidative generation of quinone imines under highly controlled conditions, in the absence of the reduced form of the quinone imine, adventitious excess oxidant, metal salts from the oxidation, or large quantities of nucleophiles. These reaction conditions will allow the quinone imines to be isolated in pure form so that their chemistry and biology can be studied under well-defined conditions. Preliminary results have demonstrated that a simple derivative of quinone imines can be synthesized in good yield via chemistry we have developed. In the proposed research this approach will be adapted for the generation of biologically relevant quinone imines such as those formed in biological oxidation of catecholamines and 9-hydroxy-ellipticenium acetate (see above). A study of these systems under carefully defined conditions will establish the products and rates of their reactions with biologically important nucleophiles. Spectroscopic characterization of the quinone imines synthesized will allow evaluation of laser Raman spectroscopy for the study of the chemistry of these intermediates in vivo.