Investigation on the Chemical Property of Heme Thiolate Structure and Application to Medicinal Chemistry

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Thiolate coordination to the heme iron is one of the characteristic features of cytochrome P450 and affects greatly the chemistry of heme of P450. Recently, the presence of an NH…S hydrogen bond between the axial ligand and amide NH in the active site of P450 and NOS has been proposed. We have already succeeded in the syntesis of the first syntetic heme thiolate complex (SR) which retains thiolate coordination during catalytic oxidation. Therefore we designed and synthesized a novel iron porphyrin-alkanethiolate complex with an intramolecular NH…S hydrogen bond to evaluate the influence of the NH…S hydrogen bond on catalytic oxidation. This complex showed significant catalytic properties in the alkane-alkene competitive oxidation that its active intermediate reacts more electrophilically than those of the other iron porphyrin-alkanethiolate complexes.Nitric oxide (NO) is an endogenous compound that has various bioactivities, and heme proteins play important roles in the biosynthesis of … More NO and in signal transduction mediated by NO. Therefore studies into the binding of NO by synthethic iron porphyrins should aid our understanding of how NO interacts with heme-containing biomolecules. We have confirmed that NO coordinates reversibly to the Fe atom of SR by spectroscopies. We have investigated its spectroscopic and electrochemical features, and these date on SR-NO provide significant insight into nitric oxide-related heme-thiolate enzymes such as nitric oxide synthase.The aim of this study was to investigate the structure-activity relationship of S-alkyl-L-isothiocitrulline (L-MIT)-containing dipeptides towards three recombinant human nitric oxide synthase (NOS) isozymes. In an in vitro assay, the combination of hydrophobic L-amino with L-MIF dramatically altered the inhibition pattern to give selective iNOS inhibitors. These results suggest that the human NOS isozymes have different-sized cavities in the binding site near the position to which the C-terminal of L-arginine binds and the cavity of iNOS is hydrophobic. Thus, L-MIT-containing dipeptides are selective inhibitors of human iNOS. Less