SYNTHESIS OF SPECIFIC INHIBITORS OF CYTOCHROME P-450

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New technology for the design of suicide inhibitors of cytochrome P-450 will be explored. Sulfur and silicon analogues of the substrates fo P-450 enzymes involved in critical biological roles will be synthesized and tested with purified enzyme systems, where possible. Inhibitors of P-450's will be targeted for cholesterol side chain cleavage, 11 Beta-hydroxylation, 17,20-lyase, aromatase, vitamin D3 1 Alpha-hydroxylase. Model compounds will be prepared and tested with liver microsomal P-450 in the Ames test. The proposal has four parts: 1) Studies relating to the mechanism and active site of P-450scc. 2) Mechanistic studies of proposed suicide chemistry. 3) The development of In vivo inhibitors. 4) Synthesis of potential suicide inhibitors of four other steroid hormone P-450's and microsomal P-450.