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

血红素硫醇盐结构的化学性质研究及其在药物化学中的应用

基本信息

批准号：
11470494
负责人：
HIGUCHI Tsunehiko
金额：
$ 8万
依托单位：
Nagoya City University (2000-2001)The University of Tokyo (1999)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

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

硫酸盐与血红素铁的配位是细胞色素P450的特征之一，对P450血红素的化学性质有很大影响。最近，P450和NOS活性位点的轴向配体与酰胺NH之间存在NH…S氢键。我们已经成功地合成了第一个在催化氧化过程中保持硫酸配合物的合成血红素硫酸配合物（SR）。因此，我们设计并合成了一种具有分子内NH…S氢键的新型铁卟啉-烷硫酸盐配合物，以评价NH…S氢键对催化氧化的影响。该配合物在烷烃-烯烃竞争氧化反应中表现出显著的催化性能，其活性中间体的亲电性优于其他铁卟啉-烷硫酸配合物。一氧化氮（NO）是一种具有多种生物活性的内源性化合物，血红素蛋白在一氧化氮的生物合成和一氧化氮介导的信号转导中起着重要作用。因此，研究合成铁卟啉与NO的结合有助于我们了解NO如何与含血红素的生物分子相互作用。通过光谱学证实了NO与SR的Fe原子可逆配位。我们研究了它的光谱和电化学特征，这些关于SR-NO的数据提供了对一氧化氮相关的血红素硫酸酶（如一氧化氮合酶）的重要见解。摘要研究了含s -烷基- l-异硫辛瓜氨酸（L-MIT）二肽对三种重组人一氧化氮合酶（NOS）同工酶的构效关系。在体外实验中，疏水l -氨基与L-MIF的结合显著改变了抑制模式，从而获得选择性的iNOS抑制剂。这些结果表明，人类NOS同工酶在l -精氨酸的c端结合位点附近存在不同大小的空腔，而iNOS的空腔是疏水的。因此，含有l - mit的二肽是人类iNOS的选择性抑制剂。少