Application of Chemical Cytochrome P-450 Model System to Studies on Drug Metabolism.

细胞色素P-450在生物大分子和外源生物的代谢中起着重要作用，其催化活性的机理一直是人们广泛研究的课题。最近，人们进行了许多尝试，试图用简单的金属卟啉重现化学体系中的反应性。我们已经完成了许多有效的P-450模拟物的合成，并阐明了它们的功能，目的是开发与天然P-450系统高度相似的人工酶来研究药物代谢。在这里，我们三年的研究结果如下：(1)稳定的烷基硫醇连接的铁卟啉即使在疏水溶剂中也能极大地促进过氧酸的O-O键的异解断裂。异解裂解产生了被认为是强氧化剂的Fe^&lt；5+&gt；-型活性物种。(2)修饰细胞色素c，固定化细胞色素c和微过氧化物酶-11，催化了一些类P-450底物的氧化。这些N-和S-氧化反应的反应机理与P-450本身的反应机理相似。(3)建立了催化烯烃环氧化反应的Ru-卟啉/2，6-二取代吡啶N-氧化物体系。在酸存在下，该体系有效地催化了未活化烷烃的氧化，催化剂的转化率为18800。(4)与天然的P-450体系相比，许多P-450模型体系对多种药物的代谢能力进行了测试，发现苯胺衍生物的偶联反应、哌啶衍生物的β-氧代反应和苯乙酸衍生物的氧化脱羧基反应是依赖于P-450的新的代谢途径。这些结果清楚地表明，P-450模型对于识别次要/新/不稳定的代谢物是有用的。

Cytochrome P-450 plays an important role in metabolizing biomolecules and xenobiotics, and the mechanism of its catalytic activities has been the subject of extensive investigation. Recently many attempts have been made to reproduce the reactivity in chemical systems with a simple metalloporphyrin. We have achieved the synthesis of many effective P-450 mimics and clarified their functions with the aim of developing artificial enzymes having high similarity to the native P-450 system for investigation of drug metabolism.Here we present the results of our studies for three years.(1) The stable iron porphyrin ligated by alkyl thiolate showed enormously accelerated heterolytic O-O bond cleavage of peracids even in hydrophobic solvents. The heterolytic cleavage gives Fe^<5+>-oxenoid type active species which is thought to be a strong oxidant.(2) Modified cytochrome c, immobilized cytochrome c and microperoxidase-11, catalyzed some P-450-like substrate oxidations. The reaction mechanisms of these N- and S-oxidations were similar to those of P-450itself.(3) Ru-porphyrin/2,6-disubstituted pyridine N-oxide system was developed for olefin epoxidation. In the presence of acid, this system effectively catalyzed a oxidation of unactivated alkane and turn over number of the catalyst was 18800.(4) Many P-450 model systems were tested for ability to metabolize various drugs compared with the native P-450 system and coupling reactions of aniline derivatives, beta-oxo formation of piperidine derivatives, and oxidative decarboxylation of phenylacetic acid derivatives were found to be new P-450 dependent metabolic pathways. These results clearly show that P-450 model is useful for identification of minor/new/unstable metabolites.