MIXED N,S-METAL COMPLEXES AS MODELS FOR METALLOHYDROLASE

产品说明：（改编自申请人的摘要）一大类金属蛋白利用混合的氮/硫配位环境将金属离子（Fe、Ni、Co、Cu、Zn）保持在活性位点，包括蓝铜蛋白、腈水合酶、醇脱氢酶和肽脱甲酰基酶（PDF）。 拟议研究的长期目标是开发新的氮/硫金属络合物的配位化学，因为它涉及某些金属蛋白的结构和功能。 特别是，这个建议的主题涉及的合成和反应性的一个新的家庭的混合氮/硫金属络合物，被设计为肽脱甲酰基酶的结构和功能模型。 肽脱甲酰基酶（PDF）是一种具有四面体Fe（II）中心的细菌金属水解酶。 它目前正被审查为新抗生素药物的一个有吸引力的目标。 L（N，S）-M（M = Fe，Ni，Co，Zn）配合物的研究有助于阐明PDF和其他相关金属水解酶的重要结构/功能关系。 这些化合物还应该表现出新的性质和反应性，这将为研究生物学中的其他N，S-金属位点提供有价值的信息，例如腈水合酶，醇脱氢酶或碳酸酐酶的突变形式。 该研究的目的包括设计用于模拟PDF中发现的2 His，1 Cys连接的配体的合成。 发展新的有机合成方法，制备三配位、三脚架结构的二吡啶基和二咪唑基硫醇盐配体。 [L（M（II）X]型络合物（L = N2硫醇盐; M = Fe、Ni、Co、Zn; X =卤素、单阴离子、溶剂等）应该是可访问的。 将测定这些复合物对酰胺和酯底物的水解能力。 将进行机理研究（例如中间体的分离、动力学研究）。 光谱分析（NMR，EPR，UV-vis，电化学）将被用来表征基态配合物以及中间体沿着反应路径。[LM（II）OH]配合物的分离和表征将被强调，假定它们在水解裂解过程中作为活性亲核试剂的作用。

DESCRIPTION: (Adapted from applicant's abstract)A large class of metalloproteins utilize a mixed nitrogen/sulfur coordination environment to hold the metal ion (Fe, Ni, Co, Cu, Zn) in the active site, including blue copper proteins, nitrile hydratase, alcohol dehydrogenase, and peptide deformylase (PDF). The long term objective of the proposed research is the development of the coordination chemistry of new nitrogen/sulfur metal complexes as it relates to the structure and functioning of certain of these metalloproteins. In particular, the theme of this proposal concerns the synthesis and reactivity of a new family of mixed nitrogen/sulfur metal complexes that are designed to be structural and functional models of peptide deformylase. Peptide deformylase (PDF) is a bacterial metallohydrolase enzyme with a tetrahedral Fe(II) center. It is currently under scrutiny as an attractive target for new antibiotic drugs. Study of the new class of L(N,S)-M (M = Fe, Ni, Co, Zn) complexes designed here should shed light on important structure/function relationships concerning PDF and other related metallohydrolases. These compounds should also exhibit new properties and reactivity that will provide valuable information in the study of other N,S-metal sites in biology such as nitrile hydratase, alcohol dehydrogenase, or mutant forms of carbonic anhydrase. Objectives of the propose research include the synthesis of ligands designed to mimic the 2 His, 1 Cys ligation found in PDF. New organic syntheses will be developed to prepare three-coordinate, tripodal dipyridyl- and diimidazolyl-alkylthiolate ligands. Complexes of the type [L(M(II)X] (L = N2Sthiolate; M = Fe, Ni, Co, Zn; X = halogen, monoanion, solvent, etc.] should be accessible. The hydrolytic capabilities of these complexes toward amide, and ester substrates will be determined. Mechanistic investigations (e.g. isolation of intermediates, kinetic studies) will be undertaken. Spectroscopic analysis (NMR, EPR, UV-vis, electrochemistry) will be used to characterize ground state complexes as well intermediates along the reaction path. The isolation and characterization of [LM(II)OH] complexes will be emphasized, given their presumed role as the active nucleophilic agent during hydrolytic cleavage.