Development of Chemical Models of Cytochrome P450 Aiming Application to Medicinal Chemistry

(1)P450的独特结构特征是与血红素的不寻常的硫醇配位。我们首次合成了硫醇铁卟啉（SR）配合物，该配合物在催化氧化过程中能保持原有结构。使用SR的实验，针对轴向配体的相对效果，已经揭示了硫醇盐配体大大加速了O-O键裂解的速率，并且即使在高度疏水的介质中也能使其异裂解。此外，我们已经确定，硫醇配体具有显着的影响，高价铁氧卟啉中间体的反应性。(2)杂芳族N-氧化物被发现是很好的氧化剂在钌卟啉的存在下。2，6-二取代吡啶N-氧化物加上催化量的钌卟啉氧化烯烃，硫化物，烯丙基或苄醇，分别得到环氧化合物，亚砜，和醛，在高产率。在这些酸的存在下，该体系有效地氧化未活化的烷烃和芳烃，以高产率、高选择性和极高的催化剂周转数（高达1.2 x 10^5）生成醇（或酮）和对苯醌。这是杂芳族N-氧化物在没有光活化的情况下用作烃的氧化剂的第一个实例。(3)P450模拟物应用于药物代谢研究。模型系统的使用是有效的一步制备不稳定的代谢中间体，“候选代谢物”，并发现新的模式的代谢。在该化学体系中，γ、δ-或β、γ-不饱和羧酸分别以高产率和高立体选择性转化为δ-或β-羟基-γ-内酯化合物。

(1) The distinctive structural features of P450 are the unusual thiolate coordination to heme. We have succeeded in the preparation of the first synthetic thiolato-iron porphyrin (SR complex) which can keep its original structure during catalytic oxidation. Experiments using SR,directed toward relative effect of axial ligand, have revealed that a thiolate ligand greatly accelerates the rate of the O-O bond cleavage, and its heterolysis even in highly hydrophobic media. Further, we have established that the thiolate ligand has a marked influence on the reactivity of high-valent iron-oxo porphyrin intermediate.(2) Heteroaromatic N-oxides were found to be excellent oxidants in the presence of ruthenium porphyrin.2,6-Disubstituted pyridine N-oxides plus a catalytic amount of Ru porphyrin oxidized olefins, sulfides, and allyl or benzyl alcohols to afford epoxides, sulfoxides, and aldehydes, respectively, in high yields. The system in the presence of these acids effectively oxidized unactivated alkanes and arenes to give alcohols (or ketones) and p-quinones in high yields with high selectivity and an extremely high catalyst turnover number (up to 1.2 x 10^5). This is the first example that a heteroaromatic N-oxide works as an oxidant for hydrocarbon without photoactivation.(3) P450 mimics were applied to drug metabolism studies. The uses of model systems were effective for one-step preparation of unstable metabolic intermediates, "candidate metabolites", and for the discovery of novel modes of metabolism. In the chemical system, gamma, delta-or beta, gamma-unsaturated carboxylic acids are converted to the delta-or beta-hydroxy-gamma-lactone compound, respectively in high yield with high stereoselectivity.