SYNTHESIS OF SPECIFIC INHIBITORS OF CYTOCHROME P-450

设计细胞色素P-450自杀抑制剂的新技术 将会被探索。P-450底物的硫和硅类似物 参与关键生物作用的酶将被合成并 尽可能用纯化的酶系统进行测试。P-450‘抑制剂S 将被靶向切割胆固醇侧链，11 β-羟基化、17，20-裂解酶、芳香化酶、维生素D3 1 α-羟基酶。模型化合物将被制备并用肝脏进行测试 Ames试验中的微粒体P-450。该提案包括四个部分： 1)P-450scc作用机理和活性部位的研究。 2)提出的自杀化学的机理研究。 3)体内抑制剂的研究进展。 4)其他四种类固醇激素潜在自杀抑制剂的合成 P-450‘S和微粒体P-450。

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.