4 RECENT STUDIES IN CYTOCHROME-P450 MODELINGS - A STABLE IRON PORPHYRIN COORDINATED BY A THIOLATE LIGAND - A ROBUST RUTHENIUM PORPHYRIN-PYRIDINE N-OXIDE DERIVATIVES SYSTEM - POLYPEPTIDE-BOUND IRON PORPHYRIN - APPLICATION TO DRUG-METABOLISM STUDIES

(1) A distinctive structural feature of P450 is the unusual thiolate c oordination to heme. We have succeeded in the preparation of the first synthetic thiolato-iron porphyrin (SR complex) which retains its stru cture during catalytic oxidation. Experiments using SR complex have re vealed that the thiolate ligand greatly accelerates the rate of the O- O bond cleavage and its heterolysis even in highly hydrophobic media. (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 and sulfides to afford epoxides and sulfoxides, respectively, in high yields. The s ystem in the presence of hydrogen halide effectively oxidized unactiva ted alkanes and arenes to give alcohols (or ketones) and p-quinones in high yields with high selectivity and an extremely high catalyst turn over number (up to 1.2 X 10(5)). (3) A polypeptide-bound porphyrinatoi ron complex was prepared. The polymer complex exhibited greater P450-l ike activity than non-bound Fe(TPP)Cl in the oxidation of olefin and a niline derivatives. (4) P450 mimics were applied to drug metabolism st udies. These model systems were effective for one-step preparation of unstable metabolic intermediates, 'candidate metabolites', and for the discovery of novel modes of metabolism.