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发生不同程度的硫代配位。我们成功地合成了第一个能够在催化氧化过程中保持原有结构的硫代铁卟啉(SR)配合物。针对轴向配体的相对效应进行的SR实验表明，即使在高度疏水的介质中，硫代配体也能极大地加快O-O键的断裂和异解速度。此外，我们还发现硫酸盐配体对高价铁氧基卟啉中间体的反应活性有显著的影响。(2)杂芳族氮氧化物是一种很好的氧化剂。2，6-二取代吡啶氮氧化物和催化量的Ru卟啉氧化烯、硫化物和烯丙基或苯甲醇分别高产率地合成了环氧化物、亚硫醚和醛。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1.2×10^5)得到醇(或酮)和对苯二酚。这是首次将杂芳烃N-氧化物作为碳氢化合物的氧化剂而不需要光活化。(3)将P450模拟物应用于药物代谢研究。模型系统的使用对于不稳定的代谢中间体“候选代谢物”的一步制备和发现新的代谢模式是有效的。在化学体系中，伽马、β-或β-不饱和羧酸分别转化为β-或β-羟基-伽马-内酯化合物，产率高，立体选择性高。

(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.