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.

An organometallic hybrid antibiotic of metronidazole with a Gold(I) N-Heterocyclic Carbene overcomes metronidazole resistance in Clostridioides difficile.

Antimicrobial resistance (AMR) has been emerging as a major global health threat and calls for the development of novel drug candidates. Metal complexes have been demonstrating high efficiency as antibacterial agents that differ substantially from the established types of antibiotics in their chemical structures and their mechanism of action. One strategy to exploit this potential is the design of metal-based hybrid organometallics that consist of an established antibiotic and a metal-based warhead that contributes an additional mechanism of action different from that of the parent antibiotic. In this communication, we describe the organometallic hybrid antibiotic 2c, in which the drug metronidazole is connected to a gold(I) N-heterocyclic carbene warhead that inhibits bacterial thioredoxin reductase (TrxR). Metronidazole can be used for the treatment with the obligatory anaerobic pathogen Clostridioides difficile (C. difficile), however, resistance to the drug hampers its clinical success. The gold organometallic conjugate 2c was an efficient inhibitor of TrxR and it was inactive or showed only minor effects against eucaryotic cells and bacteria grown under aerobic conditions. In contrast, a strong antibacterial effect was observed against both metronidazole-sensitive and -resistant strains of C. difficile. This report presents a proof-of-concept that the design of metal-based hybrid antibiotics can be a viable approach to efficiently tackle AMR.

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.

Understanding the Remarkable Stability of Well-Defined Dinuclear Copper(I) Carbene Complexes.

The synthesis of a well-defined dicopper carbene complex supported by the PNNP (2,7-bis(di-tert-butylphosphaneyl)methyl-1,8-naphthyridine) expanded pincer ligand is reported. This carbene complex is remarkably stable, even in the presence of air and water. The reactivity of this complex was explored towards typical carbene transfer substrates and its electronic structure was investigated. Using a combination of experiments and DFT calculations, the principles that underly the stability of dinuclear carbene complexes are probed.

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.

Asymmetric Carbene Transfer: Enhancing Chemical Diversity for Drug Discovery.

The quest to explore chemical space is vital for identifying novel disease targets, impacting both the effectiveness and safety profile of therapeutic agents. The tangible chemical space, currently estimated at a conservative 108 synthesized compounds, pales in comparison to the theoretically conceivable diversity of 1060 molecules. To bridge this vast gap, organic chemists are spearheading innovative methodologies that promise to broaden this limited chemical diversity. A beacon of this progressive wave is Asymmetric Carbene Transfer (ACT), a burgeoning strategy that significantly boosts molecular diversity with efficient bond-formation and precise chiral control. This review focuses on the capabilities of ACT in creating pharmaceutically significant molecules, encompassing an array of natural products and bioactive compounds. Through the lens of ACT, we discern its substantial influence on drug discovery, paving the way for novel therapeutic avenues by expanding the boundaries of molecular diversity. This review will shed light on prospective methodological developments of ACT and articulate their conceivable contributions to the medicinal chemistry arena.

Catalytic Epoxidation of Carbonyl Compounds via Carbonyl Ylides: from Racemic to Enantioselective.

Transition metal-catalyzed epoxidation of carbonyl compounds through carbonyl ylides represents a highly effective method for synthesizing a diverse range of valuable epoxides. This review offers an in-depth overview of the latest developments in inter- and intramolecular epoxidation reactions involving metal carbenes and carbonyl compounds, encompassing both racemic to enantioselective transformations. These catalytic epoxidations are reviewed by highlighting their product selectivity, diversity and applicability, and the related mechanistic rationale is showcased where possible.

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.

Ferrocene-Based N-Heterocyclic Silylenes: Monomeric Silanechalcogenones, Silanimines, Silirenes, and Insertion Products with P4.

The stable ferrocene-based N-heterocyclic silylenes fc[(N{B})2Si] (A; fc=1,1'-ferrocenylene, {B}=(HCNDipp)2B, Dipp=2,6-diisopropylphenyl) and fc[(NDipp)2Si] (B) are compared in a study focussing on their reactivity towards a range of small to moderately sized molecular substrates, viz. P4, S8, Se8, MesN3 (Mes=mesityl), RC≡CH, and RC≡CR (R=Ph, SiMe3). The Dipp-substituted congener B exhibits a more pronounced ambiphilicity and is sterically less congested than its 1,3,2-diazaborolyl-substituted relative A, in line with the higher reactivity of the former. The difference in reactivity is obviously due more to electronic than to steric reasons, as is illustrated by the fact that both A and B react with the comparatively bulky substrate MesN3 under mild conditions to afford the corresponding silanimine fc[(N{B})2Si=NMes] and fc[(NDipp)2Si=NMes], respectively. The heavier ketone analogues fc[(N{B})2Si=E] (E=S, Se, Te) are readily available from A and the corresponding chalcogen. In contrast, the reaction of the more reactive silylene B with elemental sulfur or selenium is unspecific, affording product mixtures. However, fc[(NDipp)2Si=Se] is selectively prepared from B and (Et2N)3PSe; the Te analogue is also accessible, but crystallises as head-to-tail dimer.

(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.

Access to a peri-Annulated Aluminium Compound via C-H Bond Activation by a Cyclic Bis-Aluminylene.

Carbocyclic aluminium halides [(ADC)AlX2]2 (2-X) (X=F, Cl, and I) based on an anionic dicarbene (ADC=PhC{N(Dipp)C}2, Dipp = 2,6-iPr2C6H3) framework are prepared as crystalline solids by dehydrohalogenations of the alane [(ADC)AlH2]2 (1). KC8 reduction of 2-I affords the peri-annulated Al(III) compound [(ADCH)AlH]2 (4) (ADCH=PhC{N(Dipp)C2(DippH)N}, DippH=2-iPr,6-(Me2C)C6H3)) as a colorless crystalline solid in 76 % yield. The formation of 4 suggests intramolecular insertion of the putative bis-aluminylene species [(ADC)Al]2 (3) into the methine C-H bond of HCMe2 group. Calculations predict singlet ground state for 3, while the conversion of 3 into 4 is thermodynamically favored by 61 kcal/mol. Compounds 2-F, 2-Cl, 2-I, and 4 have been characterized by NMR spectroscopy and their solid-state molecular structures have been established by single crystal X-ray diffraction.

Asymmetric Carbene Transformations for the Construction of All-Carbon Quaternary Centers.

Asymmetric catalytic carbene reactions have been well documented in the last few decades for the expeditious assembly of chiral molecules with structural diversity. However, the enantioselective construction of all-carbon quaternary centers remains a challenge in this area. In this review article, two types of asymmetric carbene reactions that beyond cyclopropanation, cyclopropenation, and Büchner reaction, have been summarized for the construction of all-carbon quaternary centers: 1) using carbene species as a 1C synthon that reacts with a trisubstituted prochiral center; 2) sequential installation of two different C-C bonds on the carbene position, which features a gem-difunctionalization reaction. Especially, the asymmetric metal carbene gem-dialkylation process, which has emerged as a practical and versatile method for the expeditious assembly of complex architectures from readily available chemical resources, is a complementary approach for the expeditious assembly of all-carbon quaternary centers.

Dual N-Heterocyclic Carbene/Transition Metal 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.

Air and Water Stable Bicyclic (alkyl)(amino)Carbene Stabilized Phosphenium Cation: Reactivity and Selective Fluoride Ion Affinity.

The synthesis and reactivity of an air and water stable Bicyclic (alkyl)(amino)carbene (BICAAC) stabilized phosphenium cation (1) is reported. Air and water stable phosphenium cation are rare in the literature. Compound 1 is obtained by reaction of BICAAC with Ph2PCl in THF followed by anion exchange with LiOTf. The reduction and oxidation of 1 yielded corresponding α-radical phosphine species (2) and BICAAC stabilized phosphenium oxide (3) respectively. All compounds are well characterized by single crystal X-ray diffraction studies. The Lewis acidity of compounds 1 and 3 are determined by conducting fluoride ion affinity experiments using UV-Vis spectrophotometry and multinuclei NMR spectroscopy. Compounds 1 and 3 exhibited selective binding to fluoride anion but did not interact with other halides (Cl- and Br-). Quantum chemical calculations were performed to understand the structure and nature of bonding interactions in these compounds, as well as to comprehend the specific bonding affinity to fluoride over other halide ions.

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.

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.

Efficient Blue Photo- and Electroluminescence from CF3-Decorated Cu(I) Complexes.

Luminescent organometallic complexes of earth-abundant copper(I) have long been studied in organic light-emitting diodes (OLED). Particularly, Cu(I)-based carbene-metal-amide (CMA) complexes have recently emerged as promising organometallic emitters. However, blue-emitting Cu(I) CMA complexes have been rarely reported. Here we constructed two blue-emitting Cu(I) CMA emitters, MAC*-Cu-CF3Cz and MAC*-Cu-2CF3Cz, by introducing one or two CF3 substitutes into carbazole ligands. Both complexes exhibited high thermal stability and blue emission colors. Moreover, two complexes exhibited different emission origins rooting from different donor ligands: a distinct thermally activated delayed fluorescence (TADF) from ligand-to-ligand charge transfer excited states for MAC*-Cu-CF3Cz or a dominant phosphorescence nature from local triplet excited state of the carbazole ligand for MAC*-Cu-2CF3Cz. Inspiringly, MAC*-Cu-CF3Cz had high photoluminescence quantum yields of up to 94 % and short emission lifetimes of down to 1.2 µs in doped films, accompanied by relatively high radiative rates in the 105 s-1 order. The resultant vacuum-deposited OLEDs based on MAC*-Cu-CF3Cz delivered pure-blue electroluminescence at 462 nm together with a high external quantum efficiency of 13.0 %.