Effects of 2-Mercaptothiazoline Coordination Modes on Reactivity of Gold(I) Compounds with Thiols and Sulfur-Containing Proteins

Gold(I)-based drugs hold significant potential for medical applications. The facile ligand substitution in linear gold(I) compounds adds complexity to identifying active species. Ligands such as PR3 and CN−, with strong trans-directing properties, are likely carrier ligands, influencing substitution reactions. The N,S-heterocyclic compound 2-mercaptothiazoline (mtz) presents an exocyclic thiol sulfur and a heterocyclic nitrogen. Coordination of mtz to transition metals, modulated by the trans ligand, results in complexes like [NCAu(N-mtz)] (N-coordinated) and [(Ph3P)Au(S-mtz)] (S-coordinated). We investigated these complexes to compare the influence of CN− and PR3, as well as the coordination mode of the mtz ligand, on reactivity with thiols and sulfur-containing proteins.

Human serum albumin, egg white lysozyme, and the C-terminal zinc finger (ZF2) of the nucleocapsid NCp7 protein of HIV-1 were studied. Zinc finger studies revealed that coordination structure can determine reactivity toward biomolecules. Due to ligand scrambling, [NCAu(N-mtz)] forms highly reactive species, generating [NCyAux-biomolecule] adducts. Mass spectrometry observations confirmed [(CN)Au]-ZF formation, showcasing the ability of Au(I) compounds to form [(Ligand)Au] adducts on zinc fingers. Conversely, [(Ph3P)Au(S-mtz)] generates [(Ph3P)2Au]+ species, showing lower reactivity, likely due to steric hindrance. For this complex, [(Ph3P)Au-biomolecule] and [Au-biomolecule] adducts dominate. Results support the hypothesis that coordination modulation affects reactivity, dependent not only on the ligand but also the coordination mode.

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