Mechanistic insight into hydroxamate transfer reaction mimicking the inhibition of zinc-containing enzymes

Abstract

A hydroxamate transfer reaction between metal complexes has been investigated by a combination of experimental and theoretical studies. A hydroxamate-bound cobalt(II) complex bearing a tetradentate macrocyclic ligand, [Co^II(TBDAP)(CH₃C(–NHO)O)]⁺ (1), is prepared by the reduction of a hydroximatocobalt(III) complex with a biological reductant. Alternatively, 1 is accessible via a synthetic route for the reaction between the cobalt(II) complex and acetohydroxamic acid in the presence of a base. 1 was isolated and characterized by various physicochemical methods, including UV-vis, IR, ESI-MS, and X-ray crystallography. The hydroxamate transfer reactivity of 1 was examined with a zinc complex, which was followed by UV-vis and ESI-MS. Kinetic and activation parameter data suggest that the hydroxamate transfer reaction occurs via a bimolecular mechanism, which is also supported by DFT calculations. Moreover, 1 is able to inhibit the activity against a zinc enzyme, i.e., matrix metalloproteinase-9. Our overall investigations of the hydroxamate transfer using the synthetic model system provide considerable insight into the final step involved in the inhibition of zinc-containing enzymes.