Cyclometalated AuIII 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, the gold‐mediated cysteine arylation through a reductive elimination process occurring from the reaction of cyclometalated AuIII C^N complexes with a zinc finger peptide (...

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Published inChemistry : a European journal Vol. 25; no. 32; pp. 7628 - 7634
Main Authors Wenzel, Margot N., Bonsignore, Riccardo, Thomas, Sophie R., Bourissou, Didier, Barone, Giampaolo, Casini, Angela
Format Journal Article
LanguageEnglish
Published Weinheim Wiley Subscription Services, Inc 07.06.2019
John Wiley and Sons Inc
Subjects
Aqueous solutions
catalysis
Chemistry
Communication
Communications
Cysteine
cysteine arylation
Cytotoxicity
Gold
gold complexes
Ionization
Ions
Mass spectrometry
Mass spectroscopy
Proteins
Quantum mechanics
reductive elimination
Zinc
Zinc finger proteins
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Summary: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 AuIII C^N complexes with a zinc finger peptide (Cys2His2 type) is here reported. Among the four selected AuIII cyclometalated compounds, the [Au(CCON)Cl2] complex featuring the 2‐benzoylpyridine (CCON) 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 AuIII‐catalyzed reductive elimination in aqueous media. The mechanism of cysteine arylation of zinc finger protein domains by cyclometalated AuIII C^N complexes was studied by using mass spectrometry and DFT methods.
Bibliography:These authors contributed equally to this work.
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ISSN:0947-6539
1521-3765
1521-3765
DOI:10.1002/chem.201901535