Exploring the Chemoselectivity towards Cysteine Arylation by Cyclometallated Au^III Compounds: New Mechanistic Insights

Abstract

To gain more insight into the factors controlling efficient cysteine arylation by cyclometallated Au III complexes, the reaction between selected gold compounds and different peptides was investigated by high-resolution liquid chromatography electrospray ionization mass spectrometry (HR-LC-ESI-MS). The deduced mechanisms of CÀ S cross-coupling, also supported by density functional theory (DFT) and quantum mechanics/molecular mechanics (QM/MM) calculations, evidenced the key role of secondary peptidic gold binding sites in favouring the process of reductive elimination. The use of metal-based catalysts within living systems is a research area that has gained significant attention for biological sensing, imaging, caging applications and therapy. [1] Among the possible reactions templated by metal compounds in biological environments, Suzuki-Miyaura, [2] Mizoroki-Heck and Sonogashira [3] cross-coupling reactions have been described for Pd II compounds and successfully applied to modify biomolecules, proteins in particular, and to study their function. [1c] Recently, some examples have appeared concerning the use of gold compounds for selective bioorthogonal transformations through CÀ C or CÀ X (X = heteroatom) bond formation for different applications in chemical biology. [1e] Many of the investigations exploit the propensity of both Au III and Au I ions to activate alkynes towards nucleophilic addition for catalysis. In this context, selective cysteine arylation using organogold reagents represents another important example of metalmediated bioconjugation reactions. Wong and co-workers [4] pioneered this approach forming CÀ S bonds on cysteine models using the cyclometallated Au III C^N complex A, featuring a N,N'-bis(methanesulfonyl)ethylene (msen) ligand (Figure 1) and derivatives. According to the authors, a compound's affinity for cysteine arylation was mainly determined [a

Comparing the Antileishmanial Activity of Gold(I) and Gold(III) Compounds in L. amazonensis and L. braziliensis in Vitro

“…The robustness of the scaffold could be exploited to functionalize the compound with parasite targeting moieties. Moreover, 7 was recently reported to selectively arylate cysteine residues in protein domains by Au III ‐templated reductive elimination, [40,41] leading to irreversible modification of the protein structure. We cannot exclude that a similar reactivity could account for the observed antiparasitic effects.…”

Tuning Cyclometalated Gold(III) for Cysteine Arylation and Ligand-Directed Bioconjugation

“…This can lead to a chemoselective reagent with favorable reaction rate with amino acids. Transition metal complexes such as Au, Ru, Pd, Ni, and Rh have been reported to modify amino acids via direct metalation or arylation. − Au complexes are known to modify cysteine significantly due to their inherent Lewis acidic character. , Au or Pd mediated cysteine arylation have been reported by Wong et al, Spokoyny et al , Casini et al, − and Buchwald–Pentelute et al Moreover, Au complex reactivity can be tuned to modify other amino acids as well . In our previous work, we reported lysine modification in c-MYC protein using Au-based probes .…”

Interfering with Metabolic Profile of Triple‐Negative Breast Cancers Using Rationally Designed Metformin Prodrugs

“…[20a] In the case of 3met,f urther gold-templated C-S cross coupling can also be hypothesized. [25] TheA u III complexes were tested against the aggressive poorly differentiated TNBC cell line,M DA-MB-231, as well as other human cancer cell lines,and exhibited high cytotoxicities in all cases (Supporting Information, Table S4, Figure S35). In contrast, metformin was devoid of cytotoxicity, while phenformin was only marginally cytotoxic, in agreement with the literature.…”