Study of metalation of thioredoxin by gold(I) therapeutic compounds using combined liquid chromatography/capillary electrophoresis with inductively coupled plasma/electrospray MS/MS detection.

The reactivity of thioredoxin (Trx1) with the Au(I) drug auranofin (AF) and two therapeutic N-heterocyclic carbene (NHC)2-Au(I) complexes (bis [1-methyl-3-acridineimidazolin-2-ylidene]gold(I) tetrafluoroborate (Au3BC) and [1,3-diethyl-4,5-bis(4methoxyphenyl)imidazol-2-ylidene]gold(I) (Au4BC)) was investigated. Direct infusion (DI) electrospray ionization (ESI) mass spectrometry (MS) allowed information on the structure, stoichiometry, and kinetics of formation of Trx-Au adducts. The fragmentation of the formed adducts in the gas phase gave insights into the exact Au binding site within the protein, demonstrating the preference for Trx1 Cys32 or Cys35 of AF or the (NHC)2-Au(I) complex Au3BC, respectively. Reversed-phase HPLC suffered from the difficulty of elution of gold compounds, did not preserve the formed metal-protein adducts, and favored the loss of ligands (phosphine or NHC) from Au(I). These limitations were eliminated by capillary electrophoresis (CE) which enabled the separation of the gold compounds, Trx1, and the formed adducts. The ICP-MS/MS detection allowed the simultaneous quantitative monitoring of the gold and sulfur isotopes and the determination of the metallation extent of the protein. The hyphenation of the mentioned techniques was used for the analysis of Trx1-Au adducts for the first time.

Novel NHC-Based Au(I) Complexes as Precursors of Highly Pure Au(0) Nuggets under Oxidative Conditions.

The Lewis-acidic character and robustness of NHC-Au(I) complexes enable them to catalyze a large number of reactions, and they are enthroned as the catalysts of choice for many transformations among polyunsaturated substrates. More recently, Au(I)/Au(III) catalysis has been explored either by utilizing external oxidants or by seeking oxidative addition processes with catalysts featuring pendant coordinating groups. Herein, we describe the synthesis and characterization of N-heterocyclic carbene (NHC)-based Au(I) complexes, with and without pendant coordinating groups, and their reactivity in the presence of different oxidants. We demonstrate that when using iodosylbenzene-type oxidants, the NHC ligand undergoes oxidation to afford the corresponding NHC=O azolone products concomitantly with quantitative gold recovery in the form of Au(0) nuggets ~0.5 mm in size. The latter were characterized by SEM and EDX-SEM showing purities above 90%. This study shows that NHC-Au complexes can follow decomposition pathways under certain experimental conditions, thus challenging the believed robustness of the NHC-Au bond and providing a novel methodology to produce Au(0) nuggets.

Fluorescence vs. Phosphorescence: Which Scenario Is Preferable in Au(I) Complexes with Benzothiadiazoles?

The photoluminescence of Au(I) complexes is generally characterized by long radiative lifetimes owing to the large spin-orbital coupling constant of the Au(I) ion. Herein, we report three brightly emissive Au(I) coordination compounds, 1, 2a, and 2b, that reveal unexpectedly short emission lifetimes of 10-20 ns. Polymorphs 2a and 2b exclusively exhibit fluorescence, which is quite rare for Au(I) compounds, while compound 1 reveals fluorescence as the major radiative pathway, and a minor contribution of a microsecond-scale component. The fluorescent behaviour for 1-2 is rationalized by means of quantum chemical (TD)-DFT calculations, which reveal the following: (1) S0-S1 and S0-T1 transitions mainly exhibit an intraligand nature. (2) The calculated spin-orbital coupling (SOC) between the states is small, which is a consequence of overall small metal contribution to the frontier orbitals. (3) The T1 state features much lower energy than the S1 state (by ca. 7000 cm-1), which hinders the SOC between the states. Thus, the S1 state decays in the form of fluorescence, rather than couples with T1. In the specific case of complex 1, the potential energy surfaces for the S1 and T2 states intersect, while the vibrationally resolved S1-S0 and T2-S0 calculated radiative transitions show substantial overlap. Thus, the microsecond-scale component for complex 1 can stem from the coupling between the S1 and T2 states.

Computational Studies of Au(I) and Au(III) Anticancer MetalLodrugs: A Survey.

Owing to the growing hardware capabilities and the enhancing efficacy of computational methodologies, computational chemistry approaches have constantly become more important in the development of novel anticancer metallodrugs. Besides traditional Pt-based drugs, inorganic and organometallic complexes of other transition metals are showing increasing potential in the treatment of cancer. Among them, Au(I)- and Au(III)-based compounds are promising candidates due to the strong affinity of Au(I) cations to cysteine and selenocysteine side chains of the protein residues and to Au(III) complexes being more labile and prone to the reduction to either Au(I) or Au(0) in the physiological milieu. A correct prediction of metal complexes' properties and of their bonding interactions with potential ligands requires QM computations, usually at the ab initio or DFT level. However, MM, MD, and docking approaches can also give useful information on their binding site on large biomolecular targets, such as proteins or DNA, provided a careful parametrization of the metal force field is employed. In this review, we provide an overview of the recent computational studies of Au(I) and Au(III) antitumor compounds and of their interactions with biomolecular targets, such as sulfur- and selenium-containing enzymes, like glutathione reductases, glutathione peroxidase, glutathione-S-transferase, cysteine protease, thioredoxin reductase and poly (ADP-ribose) polymerase 1.

Cupriphication of gold to sensitize d10-d10 metal-metal bonds and near-unity phosphorescence quantum yields.

Outer-shell s0/p0 orbital mixing with d10 orbitals and symmetry reduction upon cupriphication of cyclic trinuclear trigonal-planar gold(I) complexes are found to sensitize ground-state Cu(I)-Au(I) covalent bonds and near-unity phosphorescence quantum yields. Heterobimetallic Au4Cu2 {[Au4(µ-C2,N3-EtIm)4Cu2(µ-3,5-(CF3)2Pz)2], (4a)}, Au2Cu {[Au2(µ-C2,N3-BzIm)2Cu(µ-3,5-(CF3)2Pz)], (1) and [Au2(µ-C2,N3-MeIm)2Cu(µ-3,5-(CF3)2Pz)], (3a)}, AuCu2 {[Au(µ-C2,N3-MeIm)Cu2(µ-3,5-(CF3)2Pz)2], (3b) and [Au(µ-C2,N3-EtIm)Cu2(µ-3,5-(CF3)2Pz)2], (4b)} and stacked Au3/Cu3 {[Au(µ-C2,N3-BzIm)]3[Cu(µ-3,5-(CF3)2Pz)]3, (2)} form upon reacting Au3 {[Au(µ-C2,N3-(N-R)Im)]3 ((N-R)Im = imidazolate; R = benzyl/methyl/ethyl = BzIm/MeIm/EtIm)} with Cu3 {[Cu(µ-3,5-(CF3)2Pz)]3 (3,5-(CF3)2Pz = 3,5-bis(trifluoromethyl)pyrazolate)}. The crystal structures of 1 and 3a reveal stair-step infinite chains whereby adjacent dimer-of-trimer units are noncovalently packed via two Au(I)⋯Cu(I) metallophilic interactions, whereas 4a exhibits a hexanuclear cluster structure wherein two monomer-of-trimer units are linked by a genuine d10-d10 polar-covalent bond with ligand-unassisted Cu(I)-Au(I) distances of 2.8750(8) Å each-the shortest such an intermolecular distance ever reported between any two d10 centers so as to deem it a "metal-metal bond" vis-à-vis "metallophilic interaction." Density-functional calculations estimate 35-43 kcal/mol binding energy, akin to typical M-M single-bond energies. Congruently, FTIR spectra of 4a show multiple far-IR bands within 65-200 cm-1, assignable to vCu-Au as validated by both the Harvey-Gray method of crystallographic-distance-to-force-constant correlation and dispersive density functional theory computations. Notably, the heterobimetallic complexes herein exhibit photophysical properties that are favorable to those for their homometallic congeners, due to threefold-to-twofold symmetry reduction, resulting in cuprophilic sensitization in extinction coefficient and solid-state photoluminescence quantum yields approaching unity (ΦPL = 0.90-0.97 vs. 0-0.83 for Au3 and Cu3 precursors), which bodes well for potential future utilization in inorganic and/or organic LED applications.

Coordination Chemistry of Bis-Cyclic Alkyl(Amino) Carbene (cAAC)-Supported Di-Phosphorus (P2 ): An Efficient Route to Donor Base-Stabilized Elusive Di-Phosphorus-Monoxide(P2 O)-Gold Complex.

The stability and reactivity studies of heavier di-atomic group-15 congeners of alkynes, e. g., the di-phosphorus (P≡P) compounds have been the topic of huge interest because of their contrasting transient properties and lower stability compared to those of the stable molecular di-nitrogen (N≡N). Herein, we depict the reactivity studies of the bis-cAAC-stabilized di-phosphorus (P2 ) having an inversely polarized phosphaalkene nature featuring the C=P double bonds with Au(I)Cl. Both the mono-, and the di-aurated phosphaalkenes with the formulae [(Me2 -cAAC=P)2 (AuCl)] (2), and [(Me2 -cAAC=P)2 (AuCl)2 ] (3), respectively have been isolated in the solid state. Moreover, for the first time, we have been able to isolate the cAAC-stabilized tetra-aurated elusive di-phosphorus-monoxide (P2 O) with the formula [(Cy-cAAC=P)-O-(P=cAAC-Cy)(AuCl)4 ] (5) in presence of oxygen. Complexes 2-3, 5 have been structurally characterized by single crystal X-ray diffraction, and further studied by NMR spectroscopy. Our findings reveal significant elongation of the CcAAC -P bonds in 2-3, 5, and the presence of aurophilic interaction in 5. Quantum chemical calculations, including density functional theory (DFT), and energy decomposition analysis coupled with natural orbitals for chemical valence (EDA-NOCV) have been performed to study the electron densities distribution and nature of bonding in 2-3, 5.

Novel gold(I) complexes induce apoptosis in leukemia cells via the ROS-induced mitochondrial pathway with an upregulation of Harakiri and overcome multi drug resistances in leukemia and lymphoma cells and sensitize drug resistant tumor cells to apoptosis in vitro.

Gold complexes could be promising for tumor therapy because of their cytotoxic and cytostatic properties. We present novel gold(I) complexes and clarify whether they also show antitumor activity by studying apoptosis induction in different tumor cell lines in vitro, comparing the compounds on resistant cells and analyzing the mechanism of action. We particularly highlight one gold complex that shows cytostatic and cytotoxic effects on leukemia and lymphoma cells already in the nanomolar range, induces apoptosis via the intrinsic signaling pathway, and plays a role in the production of reactive oxygen species. Furthermore, not only did we demonstrate a large number of resistance overcomes on resistant cell lines, but some of these cell lines were significantly more sensitive to the new gold compound. Our results show promising properties for the gold compound as anti-tumor drug and suggest that it can subvert resistance mechanisms and thus targets resistant cells for killing.