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 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.
Highlights
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
The past decade has witnessed new ways of tagging proteins with fluorophores or other probes based on palladium-mediated reactions that played a major role in modern organic synthesis, such as the Suzuki–Miyaura, Mizoroki–Heck, and Sonogashira cross-coupling reactions.[3]
The results show the coexistence of apo-zinc finger domain (ZF)
Summary
Solvents and reagents (reagent grade) were all commercially available and used without further purification. The zinc finger precursor peptides were obtained from Peptide Specialty Laboratories GmbH and had the sequence 1PYKCPECGKSFSQKSDLVKHQRTHTG[26] (ZF). Dimethyl sulfoxide (DMSO), zinc acetate dihydrate, water (molecular biology grade) were purchased from Fisher. 1H and 13C NMR spectra were recorded in [d6]DMSO solution, with TMS as the internal reference, on Bruker Avance 400 or 500 MHz NMR spectrometers. HR-ESI-MS spectra were recorded on Synapt G2-Si time-of-flight (TOF) mass spectrometer (Waters) by high-pressure liquid chromatography (HPLC). HPLC was performed with an Acquity UPLC system (Waters) and by using an Acquity UPLC protein BEH C4 column (300 , 1.7 mm, 2.1 mm 100 mm). Mass spectra were acquired and processed using MassLynx V4.1 (Waters). Compounds 1–4 have been synthesized by following procedures already reported in the literature.[19,24] The purity of the compounds was confirmed by elemental analysis, which showed purity > 98 %
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