Iridium(III) carbene complexes as potent girdin inhibitors against metastatic cancers.

Many cancer-driving protein targets remain undruggable due to a lack of binding molecular scaffolds. In this regard, octahedral metal complexes with unique and versatile three-dimensional structures have rarely been explored as inhibitors of undruggable protein targets. Here, we describe antitumor iridium(III) pyridinium-N-heterocyclic carbene complex 1a, which profoundly reduces the viability of lung and breast cancer cells as well as cancer patient-derived organoids at low micromolar concentrations. Compound 1a effectively inhibits the growth of non-small-cell lung cancer and triple-negative breast cancer xenograft tumors, impedes the metastatic spread of breast cancer cells, and can be modified into an antibody-drug conjugate payload to achieve precise tumor delivery in mice. Identified by thermal proteome profiling, an important molecular target of 1a in cellulo is Girdin, a multifunctional adaptor protein that is overexpressed in cancer cells and unequivocally serves as a signaling hub for multiple pivotal oncogenic pathways. However, specific small-molecule inhibitors of Girdin have not yet been developed. Notably, 1a exhibits high binding affinity to Girdin with a Kd of 1.3 µM and targets the Girdin-linked EGFR/AKT/mTOR/STAT3 cancer-driving pathway, inhibiting cancer cell proliferation and metastatic activity. Our study reveals a potent Girdin-targeting anticancer compound and demonstrates that octahedral metal complexes constitute an untapped library of small-molecule inhibitors that can fit into the ligand-binding pockets of key oncoproteins.

A promising future of metal-N-heterocyclic carbene complexes in medicinal chemistry: The emerging bioorganometallic antitumor agents.

Metal complexes based on N-heterocyclic carbene (NHC) ligands have emerged as promising broad-spectrum antitumor agents in bioorganometallic medicinal chemistry. In recent decades, studies on cytotoxic metal-NHC complexes have yielded numerous compounds exhibiting superior cytotoxicity compared to cisplatin. Although the molecular mechanisms of these anticancer complexes are not fully understood, some potential targets and modes of action have been identified. However, a comprehensive review of their biological mechanisms is currently absent. In general, apoptosis caused by metal-NHCs is common in tumor cells. They can cause a series of changes after entering cells, such as mitochondrial membrane potential (MMP) variation, reactive oxygen species (ROS) generation, cytochrome c (cyt c) release, endoplasmic reticulum (ER) stress, lysosome damage, and caspase activation, ultimately leading to apoptosis. Therefore, a detailed understanding of the influence of metal-NHCs on cancer cell apoptosis is crucial. In this review, we provide a comprehensive summary of recent advances in metal-NHC complexes that trigger apoptotic cell death via different apoptosis-related targets or signaling pathways, including B-cell lymphoma 2 (Bcl-2 family), p53, cyt c, ER stress, lysosome damage, thioredoxin reductase (TrxR) inhibition, and so forth. We also discuss the challenges, limitations, and future directions of metal-NHC complexes to elucidate their emerging application in medicinal chemistry.

The first evaluation of the in vitro effects of silver(I)-N-heterocyclic carbene complexes on Encephalitozoon intestinalis and Leishmania major promastigotes.

Encephalitozoon intestinalis is an opportunistic microsporidian parasite that primarily infects immunocompromised individuals, such as those with HIV/AIDS or undergoing organ transplantation. Leishmaniasis is responsible for parasitic infections, particularly in developing countries. The disease has not been effectively controlled due to the lack of an effective vaccine and affordable treatment options. Current treatment options for E. intestinalis infection and leishmaniasis are limited and often associated with adverse side effects. There is no previous study in the literature on the antimicrosporidial activities of Ag(I)-N-heterocyclic carbene compounds. In this study, the in vitro antimicrosporidial activities of previously synthesized Ag(I)-N-heterocyclic carbene complexes were evaluated using E. intestinalis spores cultured in human renal epithelial cell lines (HEK-293). Inhibition of microsporidian replication was determined by spore counting. In addition, the effects of the compounds on Leishmania major promastigotes were assessed by measuring metabolic activity or cell viability using a tetrazolium reaction. Statistical analysis was performed to determine significant differences between treated and control groups. Our results showed that the growth of E. intestinalis and L. major promastigotes was inhibited by the tested compounds in a concentration-dependent manner. A significant decrease in parasite viability was observed at the highest concentrations. These results suggest that the compounds have potential anti-microsporidial and anti-leishmanial activity. Further research is required to elucidate the underlying mechanisms of action and to evaluate the efficacy of the compounds in animal models or clinical trials.

Acyclic Boryl Complexes of Copper(I).

Reaction of (6-Dipp)CuOtBu (6-Dipp=C{NDippCH2 }2 CH2 , Dipp=2,6-iPr2 C6 H3 ) with B2 (OMe)4 provided access to (6-Dipp)CuB(OMe)2 via σ-bond metathesis. (6-Dipp)CuB(OMe)2 was characterised by NMR spectroscopy and X-ray crystallography and shown to be a monomeric acyclic boryl of copper. (6-Dipp)CuB(OMe)2 reacted with ethylene and diphenylacetylene to provide insertion compounds into the Cu-B bond which were characterised by NMR spectroscopy in both cases and X-ray crystallography in the latter. It was also competent in the rapid catalytic deoxygenation of CO2 in the presence of excess B2 (OMe)4 . Alongside π-insertion, (6-Dipp)CuB(OMe)2 reacted with LiNMe2 to provide a salt metathesis reaction at boron, giving (6-Dipp)CuB(OMe)NMe2 , a second monomeric acyclic boryl, which also cuproborated diphenylacetylene. Computational interrogation validated these acyclic boryl species to be electronically similar to (6-Dipp)CuBpin.

Electrochemical Synthesis of Gold-N-Heterocyclic Carbene Complexes.

An electrochemical synthesis of gold(I)-N-heterocyclic carbene (Au-NHC) complexes has been developed. The electrochemical methodology uses only imidazolium salts, gold metal electrodes, and electricity to produce these complexes with hydrogen gas as the only by-product. This high-yielding and operationally simple procedure has been used to produce eight mononuclear and three dinuclear Au-NHC complexes. The electrochemical procedure facilitates a clean reaction with no by-products. As such, Au-NHC complexes can be directly transferred to catalytic reactions without work-up or purification. The Au-NHC complexes were produced on-demand and tested as catalysts in a vinylcyclopropanation reaction. All mononuclear Au-NHC complexes performed similarly to or better than the isolated complexes.

Reversible Coupling of Germylone with Isocyanates.

The germylone dimNHCGe (5, dimNHC=diimino N-heterocyclic carbene) undergoes a [2+2] cycloaddition with isocyanates RNCO (R=4-tolyl or 3,5-xylyl) to furnish novel alkyl carboxamido germylenes 7 (R=4-tolyl) and 8 (R=3,5-xylyl), featuring a C-C bond between the former carbene carbon and the isocyanate moiety. Heating a mixture of 8 with 4-tolyl isocyanate to 100 °C results in isocyanate metathesis, demonstrating reversible C-C bond formation on the reduced germanium compound. DFT calculations suggest that this process occurs via the reductive dissociation of isocyanate from 8 that regenerates the parent Ge(0) compound 5.

Electrochemical Synthesis of Metal Complexes Using Dissolving Anodes.

The use of dissolving metal electrodes for the direct electrochemical synthesis of metal complexes has been used widely in the last decade. A major benefit of the electrochemical approach is the minimal by-products resulting from the synthesis. As such, metal complexes can be produced on-demand and used directly in catalysis without the need for purification. Furthermore, the electrochemical method enables the production of metal complexes that cannot be synthesized using other methods, including those with base-sensitive ligands. General principles of the electrochemical method and recent advances in the field are discussed.

Mesoionic Janus-Type Dicarbene: Complexes, Adducts, and Catalytic Studies.

The preparations of homo- and hetero-bimetallic complexes as well as thiourea and selenourea derivatives of a mesoionic Janus-type N-heterocyclic dicarbene (diNHC) are reported. Analogues of its monocationic intermediate NHC have also been obtained for comparison. Using the main group adducts, the π-acceptor properties of both NHCs were determined using low temperature 77Se NMR spectroscopy completing their stereoelectronic profiling. Moreover, catalytic investigations reveal that the mesoionic dipalladium Janus-diNHC complex can be used in the sequential C2- and C5-arylation of 1-methylpyrrole for the preparation of non-symmetrical 2,5-diarylpyrroles.

Access to NHC-Boryl Mono- and Bis-Selenide and Utility as Mild Selenium Transfer Reagent Including to the C-F Bond.

Reactions of 5-SIDipp ⋅ BH3 (5-SIDipp=1,3-bis(2,6-diisopropylphenyl)-imidazolin-2-ylidene) (1) with diphenyldiselenide provide access to 5-SIDipp-boryl mono- (5-SIDipp ⋅ BH2 SePh) (2) and bis-selenide (5-SIDipp ⋅ BH(SePh)2 ) (3). The facile cleavage of the B-Se bond makes 2 a neutral source of selenium nucleophiles in substitutions reactions with benzyl bromides, and provide access to the corresponding selenoethers. The direct transformations of one of the C(sp2 )-F bonds of C5 F5 N and C6 F5 CF3 to C-Se bonds have also been achieved by the use of 2 without employing transition-metal catalysts. While it was previously established that C6 F6 could undergo complete defluoroselenation under harsh conditions, we successfully achieved partial defluorination of C6 F6 by employing 2 as a mild selenide transfer reagent. During the formation of C-Se bonds through the cleavage of C-F bonds, the potential by-product NHC ⋅ BH2 F undergoes ring expansion of the NHC, leading to the formation of the six-membered diaazafluoroborinane (7).

(Benz)imidazo[1,2-a]quinolinium Salts: Access via Unprecedented Regiospecific non-AAIPEX Strategy and Study of Their Tunable Properties.

An unprecedented non-AAIPEX protocol has been developed to access diverse monosubstituted cationic polycyclic heteroaromatic compounds (cPHACs) from the readily available azolium salts and phenacyl bromides via Ru(II)-catalyzed tandem annulation cum aromatization. This atom-economic protocol executes a range of intermediate steps e. g. double C-H activation, nucleophilic addition, annulation, and dehydration cum aromatization in one-pot manner under the generation of H2O as the sole byproduct. Moreover, the systematic tunability of photo-physical and electrochemical properties of these new class of cPHACs can be authenticated from the DFT calculated frontier molecular orbital energies that might be beneficial for their potential applications in optoelectronics and DNA intercalation.

Unmasking the Electrochemical Stability of N-Heterocyclic Carbene Monolayers on Gold.

N-heterocyclic carbene (NHC) monolayers are transforming electrocatalysis and biosensor design via their increased performance and stability. Despite their increasing use in electrochemical systems, the integrity of the NHC monolayer during voltage perturbations remains largely unknown. Herein, we deploy surface-enhanced Raman spectroscopy (SERS) to measure the stability of two model NHCs on gold in ambient conditions as a function of applied potential and under continuous voltammetric interrogation. Our results illustrate that NHC monolayers exhibit electrochemical stability over a wide voltage window (-1 V to 0.5 V vs Ag|AgCl), but they are found to degrade at strongly reducing (< -1 V) or oxidizing (>0.5 V) potentials. We also address NHC monolayer stability under continuous voltammetric interrogation between 0.2 V and -0.5 V, a commonly used voltage window for sensing, showing they are stable for up to 43 hours. However, we additionally find that modifications of the backbone NHC structure can lead to significantly shorter operational lifetimes. While these results highlight the potential of NHC architectures for electrode functionalization, they also reveal potential pitfalls that have not been fully appreciated in electrochemical applications of NHCs.

Chiral NHC Ligands for Enantioselective Gold(I) Catalysis Under Aerobic Conditions: the Importance of Conformational Flexibility and Steric Hindrance of NHC Ligand on Reactivity.

Gold(I) catalysis has been recognized as a valuable tool for the unique transformation of multiple carbon-carbon bonds. Enantioselective π-catalysis based on gold(I) complexes is, however, still underdeveloped due to lack of privileged ligands. Herein, we present an accessible method to a new family of stable yet catalytically active chiral NHC-Au(I)-Cl complexes. The key to preserving a simultaneous fine balance between reactivity and stability in this newly developed family appears to be sterically hindered, but conformationally flexible NHC ligands. These could be easily accessed on a multigram scale by merging sterically hindered anilines with commercially available amino alcohols and amines via a four-steps synthetic sequence without the need for chromatographic purification. Further investigations of the catalytic activity of NHC-Au-Cl complexes identified the OH functionality incorporated into the NHC core as crucial for the level of enantioselectivity as well as the TsO- anion responsible for the activation of NHC-Au(I)-Cl. Finally, NMR studies and X-ray investigations revealed for the first time that the widely accepted ion metathesis (NHC-Au-Cl to NHC-Au-OSO2 R) responsible for the activation of NHC-Au-Cl complexes does not take place (or it is very slow) in commonly used MeNO2 in contrast to DCM.

N-Heterocyclic Carbene/Transition Metal Dual Catalysis.

N-heterocyclic carbene catalysis has been developed as a versatile method for the enantioselective synthesis of complex organic molecules in organic chemistry. Merging of N-heterocyclic carbene catalysis with transition metal catalysis holds the potential to achieve unprecedented transformations with broad substrate scope and excellent stereoselectivity, which are unfeasible with individual catalyst. Thus, this dual catalysis has attracted increasing attention, and numerous elegant dual catalytic systems have been established. In this review, we summarize the recent achievements of dual NHC/transition metal catalysis, including the reaction design, mechanistic studies and practical applications.

C-H Activation and Hydrogen Isotope Exchange of Aryl Carbamates using Iridium(I) Complexes Bearing Chelating NHC-Phosphine Ligands.

Hydrogen isotope exchange (HIE) via C-H activation constitutes an efficient method for the synthesis of isotopically-enriched compounds, which are crucial components of the drug discovery process and are extensively employed in mechanistic studies. A series of iridium(I) complexes, bearing a chelating phosphine-N-heterocyclic carbene ligand, was designed and synthesized for application in the catalytic HIE of challenging N- and O-aryl carbamates. A broad range of substrates were labeled efficiently, and applicability to biologically-relevant systems was demonstrated by labeling an ʟ-tyrosine-derived carbamate with excellent levels of deuterium incorporation. Combined theoretical and experimental studies unveiled intriguing mechanistic features within this process, in comparison to C-H activation and hydrogen isotope exchange catalysed by monodentate Ir(I) NHC/phosphine complexes.

Modular Synthesis of Azines Bearing a Guanidine Core from N-Heterocyclic Carbene (NHC)-Derived Selenoureas and Diazo Reagents.

N-Heterocyclic carbene (NHC)-derived selenoureas comprise a fundamentally important class of NHC derivatives, with key applications in coordination chemistry and the determination of NHC electronic properties. Considering the broad reactivity of chalcogen-containing compounds, it is surprising to note that the use of NHC-derived selenoureas as organic synthons remains essentially unexplored. The present contribution introduces a novel, straightforward transformation leading to azines bearing a guanidine moiety, through the reaction of a wide range of NHC-derived selenoureas with commercially available diazo compounds, in the presence of triphenylphosphine. This transformation offers a new approach to such products, having biological, materials chemistry, and organic synthesis applications. The guanidine-bearing azines are obtained in excellent yields, with all manipulations taking place in air. A reaction mechanism is proposed, based on both experimental mechanistic findings and density functional theory (DFT) calculations. A one-pot, multicomponent transesterification reaction between selenoureas, α-diazoesters, alcohols, and triphenylphosphine was also developed, providing highly functionalized azines.

N-Heterocyclic Carbene Enabled Functionalization of Inert C(Sp3)-H Bonds via Hydrogen Atom Transfer (HAT) Processes.

Developing methods to directly transform C(sp3) -H bonds is crucial in synthetic chemistry due to their prevalence in various organic compounds. While conventional protocols have largely relied on transition metal catalysis, recent advancements in organocatalysis, particularly with radical NHC catalysis have sparked interest in the direct functionalization of "inert" C(sp3) -H bonds for cross C-C coupling with carbonyl moieties. This strategy involves selective cleavage of C(sp3) -H bonds to generate key carbon radicals, often achieved via hydrogen atom transfer (HAT) processes. By leveraging the bond dissociation energy (BDE) and polarity effects, HAT enables the rapid functionalization of diverse C(sp3)-H substrates, such as ethers, amines, and alkanes. This mini-review summarizes the progress in carbene organocatalytic functionalization of inert C(sp3)-H bonds enabled by HAT processes, categorizing them into two sections: 1) C-H functionalization involving acyl azolium intermediates; and 2) functionalization of C-H bonds via reductive Breslow intermediates.

Acetylated galactopyranosyl N-heterocyclic monocarbene complexes of Silver(I) as novel anti-proliferative agents in a rhabdomyosarcoma cell line.

Herein, four silver(I) complexes bearing acetylated d-galactopyranoside-based N-heterocyclic carbene ligands were synthesized and fully characterized by elemental analysis, NMR, and X-ray photoelectron spectroscopy. All complexes were obtained with an anomeric ß-configuration and as monocarbene species. In this study, we investigated the biological effects of the silver(I) complexes 2a-d on the human rhabdomyosarcoma cell line, RD. Our results show concentration-dependent effects on cell density, growth inhibition, and activation of key signaling pathways such as Akt 1/2, ERK 1/2, and p38-MAPK, indicating their potential as anticancer agents. Notably, at 35.5 µM, the complexes induced mitochondrial network disruption, as observed with 2b and 2c, whereas with 2a, this disruption was accompanied by nuclear content release. These results provide insight into the utility of carbohydrate incorporated NHC complexes of silver(I) as new agents in cancer therapy.

New palladium complexes with N-heterocyclic carbene and morpholine ligands: Synthesis, characterization, crystal structure, molecular docking, and biological activities.

This work includes the synthesis of a new series of palladium-based complexes containing both morpholine and N-heterocyclic carbene (NHC) ligands. The new complexes were characterized using NMR (1 H and 13 C), FTIR spectroscopic, and elemental analysis techniques. The crystal structure of complex 1b was obtained by utilizing the single-crystal X-ray diffraction method. X-ray studies show that the coordination environment of palladium atom is completed by the carbene carbon atom of the NHC ligand, the nitrogen atom of the morpholine ring, and a pair of bromide ligand, resulting in the formation of slightly distorted square planar geometry. All complexes were determined for some metabolic enzyme activities. Results indicated that all the synthetic complexes exhibited powerful inhibitory actions against all aims as compared to the control molecules. Ki values of new morpholine-liganded complexes bearing 4-hydroxyphenylethyl group 1a-e for hCA I, hCA II, AChE, BChE, and α-glycosidase enzymes were obtained in the ranges 0.93-2.14, 1.01-2.03, 4.58-10.27, 7.02-13.75, and 73.86-102.65 µM, respectively. Designing of reported complexes is impacted by molecular docking study, and interaction with the current enzymes also proclaimed that compounds 1e (-12.25 kcal/mol for AChE and -11.63 kcal/mol for BChE), 1c (-10.77 kcal/mol and -9.26 kcal/mol for α-Gly and hCA II, respectively), and 1a (-8.31 kcal/mol for hCA I) are showing binding affinity and interaction from the synthesized five novel complexes.

Platinum(II) N-heterocyclic carbene complexes arrest metastatic tumor growth.

Vimentin is a cytoskeletal intermediate filament protein that plays pivotal roles in tumor initiation, progression, and metastasis, and its overexpression in aggressive cancers predicted poor prognosis. Herein described is a highly effective antitumor and antimetastatic metal complex [PtII(C^N^N)(NHC2Bu)]PF6 (Pt1a; HC^N^N = 6-phenyl-2,2'-bipyridine; NHC= N-heterocyclic carbene) that engages vimentin via noncovalent binding interactions with a distinct orthogonal structural scaffold. Pt1a displays vimentin-binding affinity with a dissociation constant of 1.06 µM from surface plasmon resonance measurements and fits into a pocket between the coiled coils of the rod domain of vimentin with multiple hydrophobic interactions. It engages vimentin in cellulo, disrupts vimentin cytoskeleton, reduces vimentin expression in tumors, suppresses xenograft growth and metastasis in different mouse models, and is well tolerated, attributable to biotransformation to less toxic and renal-clearable platinum(II) species. Our studies uncovered the practical therapeutic potential of platinum(II)‒NHC complexes as effective targeted chemotherapy for combating metastatic and cisplatin-resistant cancers.

Eco-Friendly Functionalization of Ynals with Thiols under Mild Conditions.

A new eco-friendly method for the synthesis of mono- and multifunctional organosulfur compounds, based on the process between ynals and thiols, catalyzed by bulky N-heterocyclic carbene (NHC), was designed and optimized. The proposed organocatalytic approach allows the straightforward formation of a broad range of thioesters and sulfenyl-substituted aldehydes in yields above 86%, in mild and metal-free conditions. In this study, thirty-six sulfur-based derivatives were obtained and characterized by spectroscopic methods.