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.

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With the aim of exploiting new organometallic species for cross‐coupling reactions, we report here on the AuIII‐mediated Caryl−P bond formation occurring upon reaction of C^N cyclometalated AuIII complexes with phosphines. The [Au(C^N)Cl2] complex 1 featuring the bidentate 2‐benzoylpyridine (CCON) scaffold was found to react with PTA (1,3,5‐triaza‐7‐phosphaadamantane) under mild conditions, including in water, to afford the corresponding phosphonium 5 through C−P reductive elimination. A mechanism is proposed for the title reaction based on in situ 31P{1H} NMR and HR‐ESI‐MS analyses combined with DFT calculations. The C−P coupling has been generalized to other C^N cyclometalated AuIII complexes and other tertiary phosphines. Overall, this work provides new insights into the reactivity of cyclometalated AuIII compounds and establishes initial structure–activity relationships to develop AuIII‐mediated C−P cross‐coupling reactions.

Within the framework of designing new self-assembled metallosupramolecular architectures for drug delivery, seven [Pd 2 L 4 ] 4+ metallacages (L = 2,6-bis(pyridine-3-ylethynyl)pyridine) featuring different groups in exo -position, selected to enhance the cage solubility in aqueous environment, were synthesized. Thus, carboxylic acids, sugars, and PEG groups were tethered to the bispyridyl ligands directly or via disulfide bond formation, as well as via click chemistry. The ligands and respective cages were characterized by different methods, including NMR spectroscopy and high-resolution electrospray mass spectrometry (HR-ESI-MS). While the two ligands featuring carboxylic acid-functionalized groups showed improved solubility in water, the other ligands were soluble only in organic solvents. Unfortunately, all the respective self-assembled cages were also insoluble in water. Afterwards, the encapsulation properties of the anticancer drug cisplatin in selected [Pd 2 L 4 ]X 4 cages (X = , ) were studied by 1 H, 1 H DOSY, and 195 Pt NMR spectroscopy. The effect of the counter ions as well as of the polarity of the solvent in the drug encapsulation process were also investigated, and provided useful information on the host-guest properties of these experimental drug delivery systems. Our results provide further experimental support for previous studies that suggest the desolvation of guests from surrounding solvent molecules and the resulting solvent rearrangement may actually be the primary driving force for determining guest binding affinities in metallacages, in the absence of specific functional group interactions.

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