Proteases are enzymes that effect the degradation of proteins by catalyzing the hydrolysis of peptide bonds. Proteases play important roles in numerous physiological processes and are important factors in the pathogenesis of disease states involving tissue destruction such as emphysema, rheumatoid arthritis, tumor metastasis, and the cardia muscle necrosis that accompanies myocardial ischemia. There is a need for development of inhibitors of cysteine and serine proteases because of the potential application of such compounds as therapeutic agents and because of their utility as investigative tools for the elucidation of the biochemical properties and physiological functions of this group of enzymes. The purpose of the research described in this proposal is to synthesize and evaluate three series of substituted N-hydroxybenzolactams as mechanism based inhibitors of cysteine and serine proteases. The three series of compounds to be prepared consist of substituted 1-hydroxy-2-oxo- 2,3-diydroindoles (I), substituted 1-hydroxy-2-oxo-1,2,3,4- tetrahydroquinolines (II), and substituted 1-hydroxy-2-oxo-2,3,4,5- tetrahydrobenzazepines (III). The corresponding benzolactams will also be synthesized. The newly synthesized compounds will be evaluated for their abilities to inhibit the cysteine protease papain and the two serine proteases chymotrypsin and elastase. Those compounds that are found to be effective protease inhibitors will be evaluated in a series of biochemical experiments designed to provide information with regard to the reversibility, kinetic characteristics and mechanism of enzyme inhibition.
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