A graft-to strategy of poly(vinylphosphonates) on dopazide-coated gold nanoparticles using in situ catalyst activation.

A modular synthetic pathway for poly(diethyl vinylphosphonates) grafting-to gold nanoparticles is presented. Utilising an azide-dopamine derivative as nanoparticle coating agent, alkyne-azide click conditions were used to covalently tether the polymer to gold nanoparticles leading to stable and well distributed colloids for different applications.

Blockage of aquaporin-3 peroxiporin activity by organogold compounds affects melanoma cell adhesion, proliferation and migration.

Aquaporin-3 (AQP3) is a membrane channel with dual aquaglyceroporin/peroxiporin activity, facilitating the diffusion of water, glycerol and H2 O2 across cell membranes. AQP3 shows aberrant expression in melanoma and its role in cell adhesion, migration and proliferation is well described. Gold compounds were shown to modulate AQP3 activity with reduced associated toxicity, making them promising molecules for cancer therapy. In this study, we validated the phenotype resulting from AQP3-silencing of two melanoma cell lines, MNT-1 and A375, which resulted in decreased H2 O2 permeability. Subsequently, the AQP3 inhibitory effect of a new series of organogold compounds derived from Auphen, a potent AQP3 inhibitor, was first evaluated in red blood cells (RBCs) that highly express AQP3, and then in HEK-293T cells with AQP3 overexpression to ascertain the compounds' specificity. The first screening in RBCs unveiled two organogold compounds as promising blockers of AQP3 permeability. Moderate reduction of glycerol permeability but drastic inhibition of H2 O2 permeability was detected for some of the gold derivatives in both AQP3-overexpressing cells and human melanoma cell lines. Additionally, all compounds were effective in impairing cell adhesion, proliferation and migration, although in a cell type-dependent manner. In conclusion, our data show that AQP3 peroxiporin activity is crucial for melanoma progression and highlight organogold compounds as promising AQP3 inhibitors with implications in melanoma cell adhesion, proliferation and migration, unveiling their potential as anticancer drugs against AQP3-overexpressing tumours. KEY POINTS: AQP3 affects cellular redox balance. Gold compounds inhibit AQP3 permeability in melanoma cells. AQP3 is involved in cell adhesion, proliferation and migration of melanoma. Blockage of AQP3 peroxiporin activity impairs melanoma cell migration. Gold compounds are potential anticancer drug leads for AQP3-overexpressing cancers.

Organogold(III)-dithiocarbamate compounds and their coordination analogues as anti-tumor and anti-leishmanial metallodrugs.

The limited chemical stability of gold(III)-based compounds in physiological environment has been a challenge in drug discovery, and organometallic chemistry might provide the solution to overcome this issue. In this work, four novel cationic organogold(III)-dithiocarbamate complexes of general structure [(C^N)AuIIIDTC]PF6 (C1a - C4a, DTC = dithiocarbamate, L1 - L4, C^N = 2-anilinopyridine) are presented, and compared to their coordination gold(III)-dithiocarbamate analogues [AuIIIDTCCl2] (C1b - C4b), as potential anti-cancer and anti-leishmanial drugs. Most of the complexes effectively inhibited cancer cell growth, notably C3a presented anti-proliferative effect in the nanomolar range against breast cancer (MCF-7 and MDA-MB-231 cells with moderate selectivity. Pro-apoptotic studies on treated MCF-7 cells showed a high population of cells in early apoptosis. Reactivity studies of C3a towards model thiols (N-acetyl-L-cysteine) refer to a possible mode of action involving bonding between the organogold(III)-core and the thiolate. In the scope of neglected diseases, gold complexes are emerging as promising therapeutic alternatives against leishmaniasis. In this regard, all gold(III)-dithiocarbamate complexes presented anti-leishmanial activity against at least one Leishmania species. Complexes C1a, C4a, C1b, C4b were active against all tested parasites with IC50 values varying between 0.12 and 42 µM, and, overall, organometallic compounds presented more intriguing inhibition profiles. For C4a selectivity over 500-fold for L. braziliensis; even higher than the reference anti-leishmanial drug amphotericin B. Overall, our findings revealed that the organogold(III) moiety significantly amplified the anti-cancer and anti-leishmanial effects with respect to the coordination analogues; thus, showing the great potential of organometallic chemistry in metallodrug-based chemotherapy for cancer and leishmaniasis.

Exploring the Anticancer Activity of Tamoxifen-Based Metal Complexes Targeting Mitochondria.

Two new 'hybrid' metallodrugs of Au(III) (AuTAML) and Cu(II) (CuTAML) were designed featuring a tamoxifen-derived pharmacophore to ideally synergize the anticancer activity of both the metal center and the organic ligand. The compounds have antiproliferative effects against human MCF-7 and MDA-MB 231 breast cancer cells. Molecular dynamics studies suggest that the compounds retain the binding activity to estrogen receptor (ERα). In vitro and in silico studies showed that the Au(III) derivative is an inhibitor of the seleno-enzyme thioredoxin reductase, while the Cu(II) complex may act as an oxidant of different intracellular thiols. In breast cancer cells treated with the compounds, a redox imbalance characterized by a decrease in total thiols and increased reactive oxygen species production was detected. Despite their different reactivities and cytotoxic potencies, a great capacity of the metal complexes to induce mitochondrial damage was observed as shown by their effects on mitochondrial respiration, membrane potential, and morphology.

Bottom-up Synthesis of Water-Soluble Gold Nanoparticles Stabilized by N-Heterocyclic Carbenes: From Structural Characterization to Applications.

N-heterocyclic carbenes (NHCs) have become attractive ligands for functionalizing gold nanoparticle surfaces with applications ranging from catalysis to biomedicine. Despite their great potential, NHC stabilized gold colloids (NHC@AuNPs) are still scarcely explored and further efforts should be conducted to improve their design and functionalization. Here, the 'bottom-up' synthesis of two water-soluble gold nanoparticles (AuNP-1 and AuNP-2) stabilized by hydrophilic mono- and bidentate NHC ligands is reported together with their characterization by various spectroscopic and analytical methods. The NPs showed key differences likely to be due to the selected NHC ligand systems. Transmission electron microscopy (TEM) images showed small quasi-spherical and faceted NHC@AuNPs of similar particle size (ca. 2.3-2.6 nm) and narrow particle size distribution, but the colloids featured different ratios of Au(I)/Au(0) by X-ray photoelectron spectroscopy (XPS). Furthermore, the NHC@AuNPs were supported on titania and fully characterized. The new NPs were studied for their catalytic activity towards the reduction of nitrophenol substrates, the reduction of resazurin and for their photothermal efficiency. Initial results on their application in photothermal therapy (PTT) were obtained in human cancer cells in vitro. The aforementioned reactions represent important model reactions towards wastewater remediation, bioorthogonal transformations and cancer treatment.

C-C Cross-Couplings from a Cyclometalated Au(III) C ∧ N Complex: Mechanistic Insights and Synthetic Developments.

In recent years, the reactivity of gold complexes was shown to extend well beyond π-activation and to hold promises to achieve selective cross-couplings in several C-C and C-E (E=heteroatom) bond forming reactions. Here, with the aim of exploiting new organometallic species for cross-coupling reactions, we report on the Au(III)-mediated C(sp2 )-C(sp) occurring upon reaction of the cyclometalated complex [Au(CCH2 N)Cl2 ] (1, CCH2 N=2-benzylpyridine) with AgPhCC. The reaction progress has been monitored by NMR spectroscopy, demonstrating the involvement of a number of key intermediates, whose structures have been unambiguously ascertained through 1D and 2D NMR analyses (1 H, 13 C, 1 H-1 H COSY, 1 H-13 C HSQC and 1 H-13 C HMBC) as well as by HR-ESI-MS and X-ray diffraction studies. Furthermore, crystallographic studies have serendipitously resulted in the authentication of zwitterionic Au(I) complexes as side-products arising from cyclization of the coupling product in the coordination sphere of gold. The experimental work has been paralleled and complemented by DFT calculations of the reaction profiles, providing valuable insight into the structure and energetics of the key intermediates and transition states, as well as on the coordination sphere of gold along the whole process. Of note, the broader scope of the cross-coupling at the Au(III) CCH2 N centre has also been demonstrated studying the reaction of 1 with C(sp2 )-based nucleophiles, namely vinyl and heteroaryl tin and zinc reagents. These reactions stand as rare examples of C(sp2 )-C(sp2 ) cross-couplings at Au(III).

Exploring the Chemoselectivity towards Cysteine Arylation by Cyclometallated AuIII Compounds: New Mechanistic Insights.

To gain more insight into the factors controlling efficient cysteine arylation by cyclometallated AuIII 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 C-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.

Gold compounds for catalysis and metal-mediated transformations in biological systems.

One of the challenges of modern inorganic chemistry is translating the potential of metal catalysts to living systems to achieve controlled non-natural transformations. This field poses numerous issues associated with the metal compounds biocompatibility, stability, and reactivity in complex aqueous environment. Moreover, it should be noted that although referring to 'metal catalysis', turnover has not yet been fully demonstrated in most of the examples within living systems. Nevertheless, transition metal catalysts offer an opportunity of modulating bioprocesses through reactions that are complementary to enzymes. In this context, gold complexes, both coordination and organometallic, have emerged as promising tools for bio-orthogonal transformations, endowed with excellent reactivity and selectivity, compatibility within aqueous reaction medium, fast kinetics of ligand exchange reactions, and mild reaction conditions. Thus, a number of examples of gold-templated reactions in a biologically relevant context will be presented and discussed here in relation to their potential applications in biological and medicinal chemistry.

Carbon-Phosphorus Coupling from C

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 (CCO N) 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 31 P{1 H} 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.

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 (Cys2 His2 type) is here reported. Among the four selected AuIII cyclometalated compounds, the [Au(CCO N)Cl2 ] complex featuring the 2-benzoylpyridine (CCO 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 AuIII -catalyzed reductive elimination in aqueous media.

Exo-Functionalized Metallacages as Host-Guest Systems for the Anticancer Drug Cisplatin.

Within the framework of designing new self-assembled metallosupramolecular architectures for drug delivery, seven [Pd2L4]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 [Pd2L4]X4 cages (X = NO 3 - , BF 4 - ) were studied by 1H, 1H DOSY, and 195Pt 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.

Insights into the Mechanisms of Aquaporin-3 Inhibition by Gold(III) Complexes: the Importance of Non-Coordinative Adduct Formation.

Following our recent reports on the inhibition of the water and glycerol channel aquaglyceroporin-3 (AQP3) by the coordination complex [AuIII(1,10-phenanthroline)Cl2] (Auphen), a series of six new Au(III) complexes featuring substituted 1,10-phenanthroline ligands (1-6) have been synthesized and characterized. The speciation of the compounds studied in buffered solution by UV-visible spectrophotometry showed that most of the complexes remain stable for several hours. Quantum mechanics (QM) studies of the hydrolysis processes of the compounds suggest that they are thermodynamically less prone to exchange the chlorido ligands with H2O or OH- in comparison to Au(III) bipyridyl complexes. Preliminary data on the antiproliferative activity against A549 human lung cancer cells indicate that the compounds are able to inhibit cell proliferation in vitro. Stopped-flow spectroscopy showed that these complexes potently inhibit glycerol permeation in human red blood cells (hRBC) through AQP3 blockage. The QM investigation of the ligand exchange with methanethiol, used as a model of Cys40 of AQP3, was carried out for some derivatives and showed that the affinity of the compounds' binding for thiols is higher in comparison to the Aubipy complex ([AuIII(bipy)Cl2]PF6, bipy = 2,2'-bipyridine). In addition, both noncovalent and coordinative binding of complex 3 ( [AuIII(5-chloro-1,10-phenanthroline)Cl2]PF6) to the protein channel has been investigated in comparison to the benchmark Auphen and Aubipy using a computational workflow, including QM, molecular dynamics (MD), and quantum mechanics/molecular mechanics (QM/MM) approaches. Finally, atoms in molecules (AIM) and natural bond orbital (NBO) analyses corroborate the MD predictions, providing quantification of the noncoordinative interactions between the compounds and AQP3. AQP3 inhibition is the result of protein conformational changes, upon coordinative gold binding, which induce pore closure. The importance of noncoordinative adducts in modulating the AQP3 inhibition properties of the investigated Au(III) compounds has been elucidated, and these interactions should be further considered in the future design of isoform-selective AQP inhibitors.