This project proposes the preparation and preliminary studies of selenazoidine carboxylic acids as novel selenium delivery agents. Selenium is of growing importance in human health beyond its well-recognized role as a micronutrient. For example, selenium has exhibited exciting activity as a cancer chemopreventive agent against disease in several organs, caused by a variety of carcinogens. Selenium is also known for its toxicity, however, making the development of clinically valuable agents a distinct challenge that must be accomplished with extreme care and creativity. The selenocysteine and were designed to provide a continuous supply of the amino acid over time at levels high and sustained enough to have therapeutic value but not high enough to produce toxicity. The current application will accomplish two specific aims: (1) synthesizing two prototype selenazolidine prodrugs; and (2) conducting pilot studies in a mouse model to explore: (a) the toxicity of the novel agents; (b) their effect on the selenium content in blood and tissue; (c) their ability to provide biologically available selenium as measured by increased activity of the selenium-dependent enzyme, glutathione peroxidase; and (d) their ability to function as chemopreventive agents against nitrosamine-induced lung cancer. These analogs are completely novel. It appears to be an entirely new approach in the selenium field and may allow the potential of selenium as a preventive and/or therapeutic agent in human disease to be clinically realized.
