Cyclometalated Au^III Complexes for Cysteine Arylation in Zinc Finger Protein Domains: towards Controlled Reductive Elimination

Abstract

With the aim of exploiting the use of organometallic species for the efficient modification of proteins through C‐atom transfer, the gold‐mediated cysteine arylation through a reductive elimination process occurring from the reaction of cyclometalated Au III C^N complexes with a zinc finger peptide (Cys 2 His 2 type) is here reported. Among the four selected Au III cyclometalated compounds, the [Au(C CO N)Cl 2 ] 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 ionization mass spectrometry. DFT and quantum mechanics/molecular mechanics (QM/MM) studies permitted 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 ‐catalyzed reductive elimination in aqueous media.

Carbon–Phosphorus Coupling from C^N Cyclometalated AuIII Complexes

“…To rationalize the results of the experimental investigations, DFT calculations were performed on the reaction of 1 with PTA. Based on the previously reported results on the CÀSbond formation, [10] and on the aforementioned experimental evidences,w ep ostulated that PTAf irst coordinates to gold to form either [Au(C^N)Cl(PTA)] + or [Au(C^N)(PTA) 2 ] 2 + and that CÀPc oupling then occurs through reductive elimination. In the case of [Au(C^N)Cl(PTA)] + ,i ti sm ostl ikely that the CÀP bond formation involves the complex with the aryl group and the phosphine in cis arrangement, due to the strong prefer-ence for reductive elimination to occur between groups located in cis position.…”

“…The latter observation is in line with the previously reported Cys arylatione fficiency of the same cyclometalated Au III complexes. [10] In the case of compounds 1-3 not even ad etailed computational analysis of the electronic and steric features of the three compounds could rationalize the observedd ifferences in reactivity. [10] Instead, in the case of compound 4,D FT calculations showedt hat the higher steric demand nearbyt he C atom of the aryl group approaching the cysteinate residue, increases the activation barrier for CÀSc oupling.…”

“…[10] In the case of compounds 1-3 not even ad etailed computational analysis of the electronic and steric features of the three compounds could rationalize the observedd ifferences in reactivity. [10] Instead, in the case of compound 4,D FT calculations showedt hat the higher steric demand nearbyt he C atom of the aryl group approaching the cysteinate residue, increases the activation barrier for CÀSc oupling. [10] The same effect may accountfor the low yield of the herewith investigated CÀPc ross-coupling.…”

“…[9] Following these promising results, we recently reported on the cysteine arylation by as eries of C^N cyclometalated Au III complexes upon reaction with am odel of az inc finger domain. [10] By combining mass spectrometry and DFT calculations, initial mechanistic insights and structure-activity relationships were obtained, enabling the control of the reductive elimination in aqueous environment. [10] As reported hereafter, we have now discovered that Au III C^N complexes achieveC À Pc ross-coupling reactions under mild conditions.…”

“…[10] By combining mass spectrometry and DFT calculations, initial mechanistic insights and structure-activity relationships were obtained, enabling the control of the reductive elimination in aqueous environment. [10] As reported hereafter, we have now discovered that Au III C^N complexes achieveC À Pc ross-coupling reactions under mild conditions.…”