Cyclometalated Au(III) Complexes for Cysteine Arylation in Zinc Finger Protein Domains: Towards Controlled Reductive Elimination

With the aim of exploiting the use of organometallic species for the efficient modification of proteins through C-atom transfer, we report here on the gold-mediated cysteine arylation via reductive elimination process occurring from the reaction of cyclometalated Au(III) C^N complexes with a zinc finger peptide (Cys2His2 type). Among the four selected Au(III) cyclometallated compounds, the [Au(C CO N)Cl2] complex featuring the 2-benzoylpyridine (C CO N) scaffold was identified as the most prone to reductive elimination and Cys arylation in buffered aqueous solution (pH 7.4) at 37°C by high-resolution-LC-electrospray mass spectrometry. DFT and QM/MM studies allowed to propose a mechanism for the title reaction that is in line with the experimental results. Overall, the results provide new insights into the reactivity of cytotoxic organogold compounds with biologically important zinc finger domains and identify initial structure-activity relationships to enable Au(III)-catalysed reductive elimination in aqueous media.