Modeling substrate- and inhibitor-bound forms of liver alcohol dehydrogenase: Chemistry of mononuclear nitrogen/sulfur-ligated zinc alcohol, formamide, and sulfoxide complexes

摘要

Using a mixed nitrogen/sulfur ligand possessing a single internal hydrogen bond donor (N,N-bis-2-(methylthio)ethyl-N-(6-amino-2-pyridylmethyl)amine (bmapa)), we prepared and structurally and spectroscopically characterized a series of zinc complexes possessing a single alcohol ((bmapa)Zn(MeOH)(ClO4)(2) (1)), formamide ((bmapa)Zn-(DMF)(ClO4)(2) (3), (bmapa)Zn(NMF)(ClO4)(2) (4)), or sulfoxide ((bmapa)Zn(DMSO)(ClO4)(2) (7), (bmapa)Zn(TMSO)-(ClO4)(2) (8)) ligand. X-ray crystallographic characterization was obtained for 1-MeOH, 3, 4, 7-DMSO, and 8. To enable studies of the influence of the single hydrogen bond donor amino group of the bmapa ligand on the chemistry of zinc/neutral oxygen donor binding interactions, analogous alcohol ((bmpa)Zn(MeOH)(ClO4)2 (2)), formamide ((bmpa)Zn(DMF)(ClO4)2 (5), (bmpa)Zn(NMF)(ClO4)(2) (6)), and sulfoxide ((bmpa)Zn(DMSO)(ClO4)(2) (9), (bmpa)-Zn(TMSO)(ClO4)(2) (10)) complexes of the bmpa (N,N-bis-2-(methylthio)ethyl-N-(2-pyridylmethyl)amine) ligand system were generated and characterized. Of these, 2, 5, 6, and 9.2DMSO were characterized by X-ray crystallography. Solution spectroscopic methods (H-1 and C-13 NMR, FTIR) were utilized to examine the formamide binding properties of 3-6 in CH3CN and CH3NO2 solutions. Conclusions derived from this work include the following: (1) the increased donicity of formamide and sulfoxide donors (versus alcohols) makes these competitive ligands for a cationic N/S-ligated zinc center, even in alcohol solution, (2) the inclusion of a single internal hydrogen bond donor, characterized by a heteroatom distance of similar to2.80-2.95 Angstrom, produces subtle structural perturbations in N/S-ligated zinc alcohol, formamide, or sulfoxide complexes, (3) the heteroatom distance of a secondary hydrogen-bonding interaction involving the oxygen atom of a zinc-coordinated alcohol, formamide, and sulfoxide ligand is reduced with increasing donicity of the exogenous ligand, and (4) formamide displacement on a N/S-ligated zinc center is rapid, regardless of the presence of an internal hydrogen bond donor. These results provide initial insight into the chemical factors governing the binding of a neutral oxygen donor to a N/S-ligated zinc center. References: 30