Dinuclear Gold Complexes Research Articles

Novel dinuclear gold(i) complexes containing bis(diphenylphosphano)alkanes and (biphenyl-2-yl)(di-tert-butyl)phosphane: synthesis, structural characterization and anticancer activity

Four novel dinuclear phosphanegold(I) complexes containing bis(diphenylphosphano)alkanes and related phosphano alkanes were synthesized and characterized by elemental analysis, FTIR, NMR spectroscopy, and X-ray crystallography.

Aggregation versus Biological Activity in Gold(I) Complexes. An Unexplored Concept.

The aggregation process of a series of mono- and dinuclear gold(I) complexes containing a 4-ethynylaniline ligand and a phosphane at the second coordination position (PR3-Au-C≡CC6H4-NH2, complexes 1-5, and (diphos)(Au-C≡CC6H4-NH2)2, complexes 6-8), whose biological activity was previously studied by us, has been carefully analyzed through absorption, emission, and NMR spectroscopy, together with dynamic light scattering and small-angle X-ray scattering. These experiments allow us to retrieve information about how the compounds enter the cells. It was observed that all compounds present aggregation in fresh solutions, before biological treatment, and thus they must be entering the cells as aggregates. Inductively coupled plasma atomic emission spectrometry measurements showed that mononuclear complexes are mainly found in the cytosolic fraction; the dinuclear complexes are mainly found in a subsequent fraction composed of nuclei and cytoskeleton. Additionally, dinuclear complex 8 affects the actin aggregation to a larger extent, suggesting a cooperative effect of dinuclear compounds.

Synthesis, characterization, in vitro cytotoxic activity and molecular docking of dinuclear gold(I) complexes with terephthalaldehyde bis(thiosemicarbazones)

Four new bis(thiosemicarbazones) were synthesized and, by reaction with AuI, four dinuclear gold(I) complexes were obtained. Cytotoxic activity of both the ligands and the complexes against NCI-H460 (lung), A2780 and A2780cisR (ovarian) cancer cell lines and normal renal LLC-PK1 cells has been evaluated. The results indicate that the ligands do not show antiproliferative activity in the cell lines evaluated and the NCI-H460 line is only sensitive to the complex bearing cyclohexyl substituents. On the other hand, the four complexes display high cytotoxic activity towards A2780 and A2780 cisR and the complex with thiosemicarbazide could circumvent resistance to cisplatin. By contrast, none of the complexes show significant inhibition against the normal renal cell line LLC-PK1. Docking studies with carboxamide ribonucleotide formyltransferase (AICARFT) and cyclin-dependent kinases (CDK2) for lung and ovarian cancer, respectively, show that the best binding affinity corresponds to complex 4, which is in agreement with the in vitro cytotoxicity.

Assembly of Heterometallic AuICu2I2 Cores on the Scaffold of NPPN-Bridging Cyclic Bisphosphine.

The row of metallocyclic dinuclear gold(I) complexes with cyclic diphosphines, namely, P-pyridylethyl-substituted 1,5-diaza-3,7-diphosphacyclooctanes, has been obtained. Further interaction of the dinuclear gold(I) complexes with copper(I) iodide gave the first examples of hexanuclear AuI/CuI complexes containing two unusual trinuclear AuICu2I2 fragments. The structures of di- and hexanuclear complexes were confirmed by NMR spectroscopy, ESI mass spectrometry, elemental analysis, and single-crystal X-ray diffraction. All of the obtained complexes are moderate emitters in the solid state. Dinuclear gold(I) complexes displayed a greenish emission with the maxima in the emission spectra at ca. 550 nm. The obtained hexanuclear heterobimetallic AuI/CuI complexes are triplet solid-state blue emitters with the maximum in the emission spectra at 463 and 484 nm. According to the TD-DFT calculations, the observed emission of all studied complexes had a triplet origin and was caused by the 3CC or 3(MLCT) T1 → S0 transitions for dinuclear and hexanuclear complexes, respectively.

Light in Gold Catalysis.

Within the wide family of gold-catalyzed reactions, gold photocatalysis intrinsically features unique elementary steps. When gold catalysis meets photocatalysis, a valence change of the gold center can easily be achieved via electron transfer and radical addition, avoiding the use of stoichiometric sacrificial external oxidants. The excellent compatibility of radicals with gold catalysts opens the door to a series of important organic transformations, including redox-neutral C-C and C-X coupling, C-H activation, and formal radical-radical cross-coupling. The photocatalysis with gold complexes nicely complements the existing photoredox catalysis strategies and also opens a new avenue for gold chemistry. This review covers the achieved transformations for both mononuclear gold(I) catalysts (with and without a photosensitizer) and dinuclear gold(I) photocatalysts. Various fascinating methodologies, their value for organic chemists, and the current mechanistic understanding are discussed. The most recent examples also demonstrate the feasibility of both, mononuclear and dinuclear gold(I) complexes to participate in excited state energy transfer (EnT), rather than electron transfer. The rare applications of gold(III) photocatalysts, both homogeneous and heterogeneous, are also summarized.

Dinuclear gold(I) complexes with N-phosphanyl, N-heterocyclic carbene ligands: synthetic strategies, luminescence properties and anticancer activity.

A small library of dinuclear gold(I) complexes with the title ligands has been prepared, encompassing neutral, mono- and dicationic complexes. The luminescence properties of the complexes in the solid state have been evaluated, and it turns out that neutral and monocationic complexes not presenting a rigid metallamacrocyclic structure can exhibit rather strong emissions that extend towards the red region of the visible spectrum. The in vitro anticancer activity of the complexes has been also preliminarly evaluated; cytotoxicity seems to correlate with complex lipophilicity, whereas selectivity towards cancer cells can be apparently enhanced upon a judicious choice of the ligands.

Intramolecular aurophilic interactions in dinuclear gold(i) complexes with twisted bridging 2,2′-bipyridine ligands

Elimination of the chloride ion from the [(PPh3)AuCl] complex using silver triflate (AgOTf) in the presence of 2,2'-bipyridine R2bpy (the Au : R2bpy molar ratio is 2 : 1) in dichloromethane at room temperature leads to dinuclear gold(I) complexes [(PPh3Au)2(μ-R2bpy)](OTf)2 (R2bpy = bpy (1), dbbpy (2), CH3Obpy (3), 3-CO2CH3bpy (4), 4-CO2CH3bpy (5)) in high yields. The crystal structures for all compounds were determined using X-ray diffraction analysis. In all structures, gold ions are in a typical linear environment, and the bipyridine molecule is twisted, which allows intramolecular aurophilic interactions. Relatively short Au(I)⋯Au(I) contacts (3.1262 (2)-3.400 (1) Å) are found in structures 3-5. DFT calculations show the presence of bond critical points (3, -1) for aurophilic interactions in these structures. In structures 1 and 2, the Au(I)⋯Au(I) distances are noticeably larger and equal to 4.479 (1) and 4.589 (1) Å respectively; there are no bond critical points (3, -1) for aurophilic interactions. All complexes show photoluminescence in solid state at room temperature when excited at 300 nm in a wide spectral range: from blue or blue-green emission (400-460 nm) for 1-4 to orange emission (580 mn) for 5. The lifetimes of the excited state are in the microsecond range which is characteristic of phosphorescence. TD-DFT calculations reveal that electronic transitions of different nature are responsible for the photoluminescence of these compounds.

Mononuclear and dinuclear gold(i) complexes with a caffeine-based di(N-heterocyclic carbene) ligand: synthesis, reactivity and structural DFT analysis

Two gold(i) complexes with caffeine-based di(N-heterocyclic carbene) ligands were synthesised and fully characterised.

Synthesis and Biological Studies on Dinuclear Gold(I) Complexes with Di-(N-Heterocyclic Carbene) Ligands Functionalized with Carbohydrates.

The design of novel metal complexes with N-heterocyclic carbene (NHC) ligands that display biological activity is an active research field in organometallic chemistry. One of the possible approaches consists of the use of NHC ligands functionalized with a carbohydrate moiety. Two novel Au(I)–Au(I) dinuclear complexes were synthesized; they present a neutral structure with one bridging diNHC ligand, having one or both heterocyclic rings decorated with a carbohydrate functionality. With the symmetric diNHC ligand, the dicationic dinuclear complex bearing two bridging diNHC ligands was also synthesized. The study was completed by analyzing the antiproliferative properties of these complexes, which were compared to the activity displayed by similar mononuclear Au(I) complexes and by the analogous bimetallic Au(I)–Au(I) complex not functionalized with carbohydrates.

Dinuclear Gold(I) Complexes Bearing Alkyl-Bridged Bis(N-heterocyclic carbene) Ligands as Catalysts for Carboxylative Cyclization of Propargylamine: Synthesis, Structure, and Kinetic and Mechanistic Comparison to the Mononuclear Complex [Au(IPr)Cl

Eight new dinuclear gold(I) complexes, [Au-2(L)X-2] (1-8), were synthesized using a straightforward synthetic procedure under very mild conditions. The complexes have been characterized by NMR spectroscopy, elemental analysis, and single-crystal X-ray structure analysis. Their catalytic activity was investigated in the carboxylative cyclization of propargylamine (PPA). A superior performance in comparison to [Au(IPr)Cl] (9) was obtained for complexes 1 and 2 having an eight-methylene bridge connecting two NHCs with an arene bearing an isopropyl substituent for X = Cl, Br. This prompted more detailed kinetic and mechanistic studies by FTIR comparing dinuclear complex 2 of X = Cl to complex 9. Fortuitously the FTIR studies allowed monitoring of the formation of the products carbamic acid (CA) and carbamate salt (CS), as well as a key cyclized intermediate first discovered by Ikariya. These data allow additional insight into the mechanism as well as the central role which may be played by Au(I) carbamate formation as a higher energy resting state present in the catalytic cycle. The crystal structures of four of the new complexes and a detailed computational study relevant to the role of carbamic acid (CA) and carbamates in the catalytic cycle are also reported.

Quantitative Selection of the Axially Chiral Conformation in a Flexible Dinuclear Gold(I) di(N-Heterocyclic Carbene) Complex via Chlorine Oxidative Addition

A novel dinuclear gold(II) complex with two-fold rotational symmetry 2 of general formula [Au2Cl2(diNHC)2](PF6)2 (diNHC=di(N-heterocyclic carbene)) has been obtained in quantitative yield via chlorine (in the form of PhICl2) oxidative addition to the parent gold(I) complex 1 [Au2(diNHC)2](PF6)2. The novel compound has been characterized by 1H and 13C NMR and single crystal x-ray structure analysis. The oxidation of the two gold(I) centres to gold(II), with the formation of a covalent bond between them, imposes to the complex an axis of chirality, along the Au–Au bond, leading to a chiral propeller arrangement. Structural characterization of a novel dinuclear gold(II) complex with di(N-heterocyclic carbene) ligands, the formation of the gold(II)-gold(II) bond imposes to the complex coordination chirality.

Synthesis and Photophysical Properties of Laterally Asymmetric Digold(I) Alkynyls and Triazolyl: Ancillary Ligand and Organic Functionality Dictate Excited-State Dynamics

Four new laterally asymmetric dinuclear gold(I) complexes made from a new chromophoric ligand (Au-DiBTF0–3) have been characterized. Changing the organic ancillary ligand from a phosphine ((Au-DiBT...

Photoluminescent properties and molecular structures of dinuclear gold(I) complexes with bridged diphosphine ligands: near-unity phosphorescence from 3XMMCT/3MC.

The gold(i) complexes [μ-LiPr(AuX)2] {X = Cl (1D), Br (2D), and I (3D); LiPr = 1,2-bis[bis(2-isopropylphenyl)phosphino]benzene} were synthesised to investigate the photoluminescence properties of dinuclear Au complexes comprising weak Au(i)-Au(i) bonds. Single crystals of the tetrahydrofuran (THF) adducts 1DOR, 2DOR, and 3DOR were obtained by recrystallisation of 1D, 2D, and 3D from a mixed solution of THF and n-hexane. These THF adducts afford orange emission, with peak wavelengths ranging from 597 to 630 nm, in the crystalline state at 293 K. Recrystallisation of 3D from a mixed solution of acetone and n-hexane afforded single crystals of the acetone adduct 3DGR, which exhibits blue-green emission at 293 K. No crystals of the acetone adduct were obtained from 1D and 2D. The emission spectra and lifetimes of 1DOR, 2DOR, 3DOR, and 3DGR measured in the temperature range 77-293 K indicate that emission from these complexes in the solid state is due to phosphorescence. Notably, although the molecular structure of 3D in the 3DOR crystal is near-similar to that of 3DGR, the phosphorescence spectrum of 3DOR differs markedly from that of 3DGR, with peak wavelengths at 597 and 506 nm, respectively. Theoretical studies revealed that (1) phosphorescence occurs via the electronic transition from the excited triplet state, which is mainly composed of halogen-to-metal-metal charge transfer and metal-centered transitions and (2) the T1-optimised structure of 3D in the 3DGR crystals differs markedly from that in 3DOR, and the differences in the phosphorescence colour observed between 3DGR and 3DOR are ascribed to the differences in their stabilised structures in the excited triplet state.

Dinuclear gold(i) complexes: from bonding to applications

The last two decades have seen a veritable explosion in the use of gold(i) complexes bearing N-heterocyclic carbene (NHC) and phosphine (PR3) ligands. Both ligand families have significantly contributed to the stability and design of a plethora of gold complexes. Design is oftentimes associated with application. Here, we wish to present an overview of the synthesis and structural properties of dinuclear gold(i) complexes reported to date with their applications across numerous research areas.

Rearrangement of two 8-membered 1,5-diaza-3,7-diphosphacyclooctane rings into 16-membered P4N4 ligand on the gold(i) template

The reaction of gold(i) chloride with two molecules of 1,5-diaza-3,7-diphosphacyclooctane derivative causes their reorganization into 16-membered macrocyclic tetraphosphine ligand. The structure of the trinuclear gold(i) complex obtained was confirmed by X-ray analysis. The dynamic equilibrium between dinuclear gold(i) complexes with eight-membered cyclic ligands and the trinuclear gold(i) complex with 16-membered ones has been revealed.

Hydroalkoxylation of Terminal and Internal Alkynes Catalyzed by Dinuclear Gold(I) Complexes with Bridging Di(N-Heterocyclic Carbene) Ligands

A series of six dinuclear gold(I) complexes with bridging bidentate N-heterocycic carbene ligands (NHCs) of general formula Au2Br2LX (L = diNHC, X = 1–6) have been studied as catalysts in the intermolecular hydroalkoxylation of terminal and internal alkynes. The best catalytic results have been obtained by using Au2Br2L4, characterized by 2,6-diisopropylphenyl wingtip substituents and a methylene bridging group between the two NHC donors. Complex Au2Br2L4 has been structurally characterized for the first time in this work, showing the presence of intramolecular aurophiclic interaction in the solid state. In the adopted reaction conditions Au2Br2L4 is able to convert challenging substrates such as diphenylacetylene. Comparative catalytic tests by using the mononuclear gold(I) complexes AuIL7 and IPrAuCl have been performed in order to determine the possible presence of cooperative effects in the catalytic process.

Abstract C043: Targeting TXNRD1 with a competitive inhibitor exposes an Achilles heel of SCLC

Abstract Targeting TXNRD1 to kill cancer cells has long been discussed as a promising strategy for the following reasons: 1) TXNRD1 over-expression was repeatedly identified as having a statistically significant association with poor prognosis. 2) It is suggested to be a key player in redox regulation, with a lower dependency in most normal adult cells and tissues than in cancer cells. Last but not least, potent inhibitors of TXNRD1 activity cause cytotoxicity in cancer cells. Despite this highly plausible and promising target profile, the success rate of TXNRD1 inhibitors has been disappointing in preclinical and clinical studies. One reason for this lack of success might be the physicochemical shortcomings of lead compounds, which pose liabilities in the area of bioavailability, stability, and dose limiting side effects. Auranofin, so far the most studied inhibitor of TXNRD1, is a prominent example for these kind of problems, but there are also more recent reports which show that it is demanding to improve the balance between cytotoxicity and selectivity in order to achieve more efficacious and durable tumor suppression. In addition, it is possible that TXNRD1 is not a critical target for all cancer entities, but rather plays critical roles only in a limited set of cancer entities or subtypes thereof. We have identified a class of dinuclear dithiocarbamate gold complexes, with superior efficacy and selectivity for TrxR1, which bind in competition with the TrxR1 substrate thioredoxin-1 (Trx1). Consequently, cells which express higher levels of Trx1, like most cancer and normal cells, are resistant while cells expressing low levels of Trx1, like SCLC, are hypersensitive to the drug. Our data show that all tested SCLC-derived cell lines and primary isolates are hypersensitive to the drug, independent of their resistance status to cisplatin. Unlike most other gold complexes, our drug is devoid of activity on the glutathione system and the proteasome at concentrations cytotoxic to cells. Most importantly, we observe oxidative stress only in the cytoplasm, but not in mitochondria, contributing to a low general toxicity profile. Finally, in SCLC animal models, the inhibitor eradicates residual tumor cells surviving first line therapy and completely prevents tumor recurrence. The safety profile in mouse is favorable for long term treatment and is compatible with first line therapy (cisplatin/etoposide). We present data describing the discovery of the lead compound and its optimization towards improved formulation and on-target activity as well as enhanced cytotoxicity on large 3-D aggregates of tumor cells. We also present a biomarker concept which explains the susceptibility of SCLC but also shows a rational to extend the use of our drug for other cancer (sub-) entities. Citation Format: Nikolas Peter Gunkel, Eberhard Amtmann, Pjotr Fabrowski, Sanaz Taromi, Tobias Dick. Targeting TXNRD1 with a competitive inhibitor exposes an Achilles heel of SCLC [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C043. doi:10.1158/1535-7163.TARG-19-C043

Dinuclear Gold Complexes Supported by Wide Bite Angle Diphosphines for Preorganization-Induced Selective Dual-Gold Catalysis

The synthesis, reactivity, and potential of well-defined dinuclear gold complexes as precursors for dual-gold catalysis is explored. Using the preorganizing abilities of well-known wide bite angle diphosphine ligands, DBFPhos and DPEPhos, dinuclear Au(I)–Au(I) complexes 1 and 2 are used as precursors to form well-defined monocationic species with either a chlorido- or acetylido-ligand bridging the two gold centers. These compounds are active catalysts for the dual-gold heterocycloaddition of a urea-functionalized alkyne, and the preorganization of both Au-centers affords efficient σ,π-activation of the substrate, even at high dilution, significantly outperforming benchmark mononuclear catalysts.

Structural and Luminescent Properties of Homoleptic Silver(I), Gold(I), and Palladium(II) Complexes with nNHC-tzNHC Heteroditopic Carbene Ligands.

Novel silver(I), gold(I), and palladium(II) complexes were synthesized with bidentate heteroditopic carbene ligands that combine an imidazol-2-ylidene (nNHC) with a 1,2,3-triazol-5-ylidene (tzNHC) connected by a propylene bridge. The silver(I) and gold(I) complexes were dinuclear species, [M2(nNHC-tzNHC)2](PF6)2 (M = Ag or Au), with the two bidentate ligands bridging the metal centers, whereas in the palladium(II) complex [Pd(nNHC-tzNHC)2](PF6)2, the two ligands were chelated on the same metal center. Because of the presence of two different carbene units, isomers were observed for the gold(I) and palladium(II) complexes. The molecular structures of the head-to-tail isomer for gold(I) complexes, with a twisted or folded-syn conformation of the bridge between the carbene units, were determined by X-ray diffraction analysis. The study was completed with a systematic structural investigation through density functional theory (DFT) calculations. For palladium(II) species, the head-to-head form was structurally characterized. The dinuclear gold(I) complexes were emissive in the solid state in the blue region (PLQY up to 8%); time-dependent density functional theory (abbreviated as TD-DFT) calculations disclosed that the absorption bands have metal-to-ligand-charge-transfer character and evidenced that the emission occurs from the T1 level (phosphorescence).

A HELIXOL‐Derived Bisphosphinite Ligand: Synthesis and Application in Gold‐Catalyzed Enynes Cycloisomerization

The synthesis, optical resolution through derivatization, characterization, and utilization of a new helical bis(phosphinite gold) complex derived from HELIXOL are described. By using an efficient cobalt catalyst, neither irradiation nor high catalytic loading was required to access the helicene of interest. The latter was phosphorylated to afford a new chiral ligand that was studied. Especially, treatment with AuCl(SMe2) gives a dinuclear gold complex that was used in cycloisomerization reactions.