Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 25, Issue 32, Pages 7628-7634Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201901535
Keywords
catalysis; cysteine arylation; gold complexes; reductive elimination; zinc finger proteins
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Funding
- Cardiff University
- Hans Fischer Senior Fellowship of the Technical University of Munich, Institute for Advanced Study - German Excellence Initiative
- European Union Seventh Framework Program [291763]
- European Union Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant [663830]
- EPSRC [EP/L016443/1]
- CDT in Catalysis [EP/L016443/1]
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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 (CN)-N-boolean AND complexes with a zinc finger peptide (Cys(2)His(2) type) is here reported. Among the four selected Au-III cyclometalated compounds, the [Au((CN)-N-CO)Cl-2] complex featuring the 2-benzoylpyridine ((CN)-N-CO) scaffold was identified as the most prone to reductive elimination and Cys arylation in buffered aqueous solution (pH 7.4) at 37 degrees 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.
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