Active Small Molecules Research Articles

Unveiling the Unique Reactivity of Anionic Mn(I) Complexes via Metal-Ligand Cooperation: Nucleophilic Attack on C(sp3)-X Bonds.

Metal-ligand cooperation (MLC) has emerged as a pivotal strategy for the catalytic activation of small molecules within both synthetic and biological arenas. Leveraging this approach, a suite of potent catalytic reactions─encompassing hydrogenation, hydroelementation, and dehydrogenative processes─have been realized, with notable advances in manganese catalysis in recent years. However, the activation of alkyl halides by Mn complexes, which typically requires strong reductants to form Mn(-I) complexes that are incompatible with standard cross-coupling conditions, remains a significant challenge. This limitation underscores the urgent need to investigate alternative methods for activating C(sp3)-X bonds using higher valence state Mn complexes. In response to this challenge, we present the synthesis, characterization, and reactivity of a new anionic Mn(I) complex featuring a redox-active dianionic ligand that induces multiple MLC functionalities. We have discovered an innovative mechanism of MLC, characterized by a single ligand transferring two electrons to the metal center. This novel process facilitates an orbital-symmetry-allowed nucleophilic attack on C(sp3)-X bonds, preserving manganese's oxidative state at +1. To the best of our knowledge, this is the first instance where the MLC strategy via a two-electron transfer process has been utilized to execute an SN2 nucleophilic attack at a C(sp3)-X bond by a relatively electron-deficient metal center like Mn(I). Additionally, the dianionic ligand of the anionic Mn(I) complex exhibits ambident nucleophilicity by reacting with different electrophiles, further highlighting its versatile reactivity.

Mechanistic and dynamic insight into novel IL7 receptor activators as immunotherapy for the treatment of tuberculosis

The bacterium that causes tuberculosis (TB), Mycobacterium tuberculosis, is still a significant global public health problem due to its contagious nature and the emergence of drug-resistant variants. This study leverages network pharmacology and computational drug discovery to identify genes linked to TB using the GSE54992 and GSE62525 datasets. In active tuberculosis patients, it identifies 162 DEGs that are not present in healthy people. The research includes an investigation of gene ontology (GO) and protein–protein interaction (PPI) networks to provide a comprehensive understanding of these DEGs. Crucially, it identifies ten hub genes: IL7R, CCR7, CXCR5, CCR6, CCR9, S1PR1, BACH2, CXCL5, SPIB, and EBF. The research suggests IL7R as a potential therapeutic target because of its essential role in FoxO signalling pathways and cytokine-cytokine receptor interaction. IL7 and its receptor (IL7R) are vital for T cell functionality and essential in combating TB. The study explores novel small-molecule activators for IL7R (IL7Rα), aiming to boost the immune response against TB. The following four compounds were found using molecular dynamics simulation, virtual screening, computational pharmacophore modelling, and MM/GBSA analytical techniques: ZINC02131028, ZINC02135418, ZINC46007405, and ZINC59273354. These activators may enhance the IL7 signalling pathway, potentially strengthening the immune fight against M. tuberculosis. Among these ZINC02131028 showed the best results to activate IL7 by binding to its active site, stabilizing its active conformation and enhancing its interaction with the IL7 receptor (IL7R). The findings encourage experimental validation of these IL7 activators, marking a significant step towards innovative TB treatment strategies.

Data-driven discovery of potent small molecule ice recrystallisation inhibitors

Controlling the formation and growth of ice is essential to successfully cryopreserve cells, tissues and biologics. Current efforts to identify materials capable of modulating ice growth are guided by iterative changes and human intuition, with a major focus on proteins and polymers. With limited data, the discovery pipeline is constrained by a poor understanding of the mechanisms and the underlying structure-activity relationships. In this work, this barrier is overcome by constructing machine learning models capable of predicting the ice recrystallisation inhibition activity of small molecules. We generate a new dataset via experimental measurements of ice growth, then harness predictive models combining state-of-the-art descriptors with domain-specific features derived from molecular simulations. The models accurately identify potent small molecule ice recrystallisation inhibitors within a commercial compound library. Identified hits can also mitigate cellular damage during transient warming events in cryopreserved red blood cells, demonstrating how data-driven approaches can be used to discover innovative cryoprotectants and enable next-generation cryopreservation solutions for the cold chain.

Machine learning-augmented molecular dynamics simulations (MD) reveal insights into the disconnect between affinity and activation of ZTP riboswitch ligands.

The challenge of targeting RNA with small molecules necessitates a better understanding of RNA-ligand interaction mechanisms. However, the dynamic nature of nucleic acids, their ligand-induced stabilization, and how conformational changes influence gene expression pose significant difficulties for experimental investigation. This work employs a combination of computational and experimental methods to address these challenges. By integrating structure-informed design, crystallography, and machine learning-augmented all-atom molecular dynamics simulations (MD) we synthesized, biophysically and biochemically characterized, and studied the dissociation of a library of small molecule activators of the ZTP riboswitch, a ligand-binding RNA motif that regulates bacterial gene expression. We uncovered key interaction mechanisms, revealing valuable insights into the role of ligand binding kinetics on riboswitch activation. Further, we established that ligand on-rates determine activation potency as opposed to binding affinity and elucidated RNA structural differences, which provide mechanistic insights into the interplay of RNA structure on riboswitch activation.

Restoration of LAMP2A expression in old mice leads to changes in the T cell compartment that support improved immune function

Chaperone-mediated autophagy (CMA) is a selective form of autophagy that contributes to the maintenance of cellular homeostasis. CMA activity declines with age in most tissues and systems, including the immune system, due to a reduction in levels of lysosome-associated membrane protein type 2A (LAMP2A), an essential CMA component. In this study, we show that overexpressing a copy of hLAMP2A within T cells since middle-age can prevent some of their age-associated loss of function. Our data support the idea that preserving LAMP2A expression with age through genetic means leads to enhanced proliferative responses, decreased number of regulatory T cell populations, and down-regulated expression of inhibitory receptors by T cells. During aging, elevated numbers of these immunosuppressive T cell populations significantly contribute to the age-associated downregulation of T cell responses. Using comparative proteomics, we confirm that preservation of CMA activity in old mice prevents age-related changes in both the resting and the activated T cell proteome. We also explore the effect of using first-in-class small molecule activators of CMA and demonstrate improved T cell response upon their administration to old mice. We conclude that sustaining CMA activity constitutes a potentially viable therapeutic approach to improving T cell function with age.

N-Glycosylation-Induced Pathologic Protein Conformations as a Tool to Guide the Selection of Biologically Active Small Molecules.

Post-translational modifications such as protein N-glycosylation, significantly influence cellular processes. Dysregulated N-glycosylation, exemplified in Grp94, a member of the Hsp90 family, leads to structural changes and the formation of epichaperomes, contributing to pathologies. Targeting N-glycosylation-induced conformations offers opportunities for developing selective chemical tools and drugs for these pathologic forms of chaperones. We here demonstrate how a specific Grp94 conformation induced by N-glycosylation, identified previously via molecular dynamics simulations, rationalizes the distinct behavior of similar ligands. Integrating dynamic ligand unbinding information with SAR development, we differentiate ligands productively engaging the pathologic Grp94 conformers from those that are not. Additionally, analyzing binding site stereoelectronic properties and QSAR models using cytotoxicity data unveils relationships between chemical, conformational properties, and biological activities. These findings facilitate the design of ligands targeting specific Grp94 conformations induced by abnormal glycosylation, selectively disrupting pathogenic protein networks while sparing normal mechanisms.

Synthesis of C-N bonds by nicotinamide-dependent oxidoreductase: an overview.

Compounds containing chiral C-N bonds play a vital role in the composition of biologically active natural products and small pharmaceutical molecules. Therefore, the development of efficient and convenient methods for synthesizing compounds containing chiral C-N bonds is a crucial area of research. Nicotinamide-dependent oxidoreductases (NDOs) emerge as promising biocatalysts for asymmetric synthesis of chiral C-N bonds due to their mild reaction conditions, exceptional stereoselectivity, high atom economy, and environmentally friendly nature. This review aims to present the structural characteristics and catalytic mechanisms of various NDOs, including imine reductases/ketimine reductases, reductive aminases, EneIRED, and amino acid dehydrogenases. Additionally, the review highlights protein engineering strategies employed to modify the stereoselectivity, substrate specificity, and cofactor preference of NDOs. Furthermore, the applications of NDOs in synthesizing essential medicinal chemicals, such as noncanonical amino acids and chiral amine compounds, are extensively examined. Finally, the review outlines future perspectives by addressing challenges and discussing the potential of utilizing NDOs to establish efficient biosynthesis platforms for C-N bond synthesis. In conclusion, NDOs provide an economical, efficient, and environmentally friendly toolbox for asymmetric synthesis of C-N bonds, thus contributing significantly to the field of pharmaceutical chemical development.

Activation of the heat shock response as a therapeutic strategy for tau toxicity.

Alzheimer's disease is associated with the misfolding and aggregation of two distinct proteins, beta-amyloid and tau. Previously, it has been shown that activation of the cytoprotective heat shock response (HSR) pathway reduces beta-amyloid toxicity. Here, we show that activation of the HSR is also protective against tau toxicity in a cell-autonomous manner. Overexpression of HSF-1, the master regulator of the HSR, ameliorates the motility defect and increases the lifespan of transgenic C. elegans expressing human tau. By contrast, RNA interference of HSF-1 exacerbates the motility defect and shortens lifespan. Targeting regulators of the HSR also affects tau toxicity. Additionally, two small-molecule activators of the HSR, Geranylgeranylacetone (GGA) and Arimoclomol (AC), have substantial beneficial effects. Taken together, this research expands the therapeutic potential of HSR manipulation to tauopathies and reveals that the HSR can impact both beta-amyloid and tau proteotoxicity in Alzheimer's disease.

GNN-DDAS: Drug discovery for identifying anti-schistosome small molecules based on graph neural network.

Schistosomiasis is a tropical disease that poses a significant risk to hundreds of millions of people, yet often goes unnoticed. While praziquantel, a widely used anti-schistosome drug, has a low cost and a high cure rate, it has several drawbacks. These include ineffectiveness against schistosome larvae, reduced efficacy in young children, and emerging drug resistance. Discovering new and active anti-schistosome small molecules is therefore critical, but this process presents the challenge of low accuracy in computer-aided methods. To address this issue, we proposed GNN-DDAS, a novel deep learning framework based on graph neural networks (GNN), designed for drug discovery to identify active anti-schistosome (DDAS)small molecules. Initially, a multi-layer perceptron was used to derive sequence features from various representations of small molecule SMILES. Next, GNN was employed to extract structural features from molecular graphs. Finally, the extracted sequence and structural features were then concatenated and fed into a fully connected network to predict active anti-schistosome small molecules. Experimental results showed that GNN-DDAS exhibited superior performance compared to the benchmark methods on both benchmark and real-world application datasets. Additionally, the use of GNNExplainer model allowed us to analyze the key substructure features of small molecules, providing insight into the effectiveness of GNN-DDAS. Overall, GNN-DDAS provided a promising solution for discovering new and active anti-schistosome small molecules.

Ultrasonic-Induced Surface Disordering Promotes Photocatalytic Hydrogen Evolution of TiO2.

Surface disordering has been considered an effective strategy for tailoring the charge separation and surface chemistry of semiconductor photocatalysts. A simple but reliable method to create surface disordering is, therefore, urgently needed for the development of high-performance semiconductor photocatalysts and their practical applications. Herein, we report that the ultrasonic processing, which is commonly employed in the dispersion of photocatalysts, can induce the surface disordering of TiO2 and significantly promote its performance for photocatalytic hydrogen evolution. A 40 min ultrasonic treatment of TiO2 (Degussa P25) enhances the photocatalytic hydrogen production by 42.7 times, achieving a hydrogen evolution rate of 1425.4 μmol g-1 h-1 without any cocatalyst. Comprehensive structural, spectral, and electrochemical analyses reveal that the ultrasonic treatment induces the surface disordering of TiO2, and consequently reduces the density of deep electron traps, extends the separation of photogenerated charges, and facilitates the hydrogen evolution reaction relative to oxygen reduction. The ultrasonic treatment manifests a more pronounced effect on disordering the surface of anatase than rutile, agreeing well with the enhanced photocatalysis of anatase rather than rutile. This study demonstrates that ultrasonic-induced surface disordering could be an effective strategy for the activation of photocatalysts and might hold significant implications for the applications in photocatalytic hydrogen evolution, small molecule activation, and biomass conversion.

Predicting Activation of Small Molecules Including Dinitrogen via a Carbene with a σ0π2 Electronic Configuration.

Although the main group species in the s and p blocks have begun to gain prominence in the field of dinitrogen (N2) activation in recent years, reports of carbene-mediated N2 activation remain particularly rare, especially for carbenes with a σ0π2 electronic configuration. Herein, we demonstrate examples of N2 activation initiated by a carbene with a σ0π2 electronic configuration and consequent N2 hydroboration reaction (with a reaction barrier as low as 19.9 kcal/mol) via density functional theory calculations. Meanwhile, the "push-pull" electronic effect upon introduction of a hydroborenium complex facilitates the generation of a thermodynamically and kinetically more stable product. In addition, such a σ0π2 carbene can also activate a series of H-X (X = H, CH3, or Bpin) bonds through an oxidative addition process with activation energies ranging from 6.0 to 18.0 kcal/mol. Our findings highlight the importance of σ0π2 carbenes in the field of small molecule activation, especially N2 activation.

Old and New Biologics and Small Molecules in Inflammatory Bowel Disease: Anti Integrins

Recently, novel biologics or small molecular drugs have been introduced for overcoming the unmet needs associated with anti-tumor necrosis factor α agents for inflammtory bowel disease (IBD) treatment. Among these novel drugs, anti integrin agents block leukocyte trafficking to the intestine by blocking the interaction between integrin and cell adhesion molecules. Vedolizumab (anti-α4β7) is most widely used anti-integrin approved in both ulcerative colitis and Crohn's disease .It has been shown to be effective in both induction and maintenance therapy with a favorable safety profile due to gut selectivity. Several models incorporating clinical, genetic, immune and gut microbial markers to predict response to vedolizumab in IBD have been developed. Etrolizumab (anti-β7) blocks leukocyte trafficking via α4β7 and cell adhesion via αEβ7 integrins. In addition, the introduction of subcutaneous vedolizumab showed similar efficacy and safety with improved patients' convenience. Other investigational anti-integrin therapies include abrilumab (anti-α4β7 IgG2), PN-943 (orally administered and gut-restricted α4β7 antagonist peptide), AJM300 (orally active small molecule inhibitor of α4), and ontamalimab (anti-MAdCAM-1 IgG).

Comprehensive characterization of a novel small-molecule activator for the nuclear receptor Nur77: Chemical, molecular, and biological insights

The nuclear receptor Nur77 is a transcription factor belonging to the NR4A subfamily. Upon activation, it regulates a wide array of biological and pathophysiological processes by modulating the expression of its target genes. Previous findings have classified Nur77 as an orphan receptor because of the discovery of a structurally atypical ligand-binding domain and the lack of identification of an endogenous ligand. Nevertheless, recent studies have uncovered several endogenous, natural, and small synthetic molecules that can bind to and activate Nur77. However, developing selective and potent Nur77 activators remains a significant challenge. The discovery of novel and potential small synthetic molecules that modulate Nur77 activity will facilitate therapeutic interventions of Nur77 against several human diseases. In this study, we have reported the development of a novel and effective Nur77 ligand. Our data show that (1E,4E)-1,5-di(pyrazin-2-yl)penta-1,4-dien-3-one (PB) induces Nur77 transcriptional activity by interacting with a putative Nur77 ligand binding site by forming solid hydrogen bonding. Calculated chemical parameters denote that PB has sophisticated chemical features that will enhance its interaction with the Nur77 ligand-binding domain. Molecular docking simulations showed that PB fits in the Nur77 putative ligand binding site with solid hydrogen bonding, and molecular dynamics simulations indicate that PB binding would stabilize the Nur77 ligand binding domain. Further, in vitro studies revealed that PB increases Nur77 nuclear expression and activity, inhibits cigarette smoke-induced inflammatory phenotype of airway epithelial cells, and protects against apoptosis. These findings provide insights into developing an effective Nur77 small-molecule activator which could be developed into a therapeutic agent against inflammatory diseases.

Inhibition of glycolytic reprogramming suppresses innate immune-mediated inflammation in experimental amyotrophic lateral sclerosis.

Innate immune activation has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, metabolic pathways that govern this bioenergetically demanding process in ALS remains elusive. Here we investigated whether and how immunometabolic transformation of innate immune cells contributes to disease progression in an experimental model of this neurodegenerative disease. We utilized multidimensional flow cytometry and integrative metabolomics to characterize the immunometabolic phenotype of circulating and spinal cord innate immune cells in the B6SJL-Tg(SOD1*G93A)1Gur/J model of ALS (SOD1-G93A) at various disease stages (before vs. after the onset of motor dysfunction). Behavioral and survival analyses were also conducted to determine the impact of an energy-regulating compound on innate immune cell metabolism, inflammation, and disease development. Temporally coordinated accumulation of circulating inflammatory Ly6C + monocytes and spinal cord F4/80 + CD45hi infiltrates precedes the onset of motor dysfunction in SOD1-G93A mice. Subsequent metabolomic analysis reveals that this phenomenon is accompanied by glycolytic reprogramming of spinal cord inflammatory CD11b + cells, comprising both resident F4/80 + CD45low microglia and F4/80 + CD45hi infiltrates. Furthermore, pharmacologic inhibition of glycolysis by ZLN005, a small molecule activator of Ppargc1a, restrains inflammatory glycolytic activation of spinal cord CD11b + cells, enhances motor function, and prolongs survival in SOD1-G93A mice. These observations suggest that modulation of inflammatory glycolytic reprogramming of innate immune cells may represent a promising therapeutic approach in ALS.

Rescue of Familial Lecithin:Cholesterol Acyltranferase Deficiency Mutations with an Allosteric Activator.

Lecithin:cholesterol acyltransferase (LCAT) deficiencies represent severe disorders characterized by aberrant cholesterol esterification in plasma, leading to life-threatening conditions. This study investigates the efficacy of Compound 2, a piperidinyl pyrazolopyridine allosteric activator that binds the membrane-binding domain of LCAT, in rescuing the activity of LCAT variants associated with disease. The variants K218N, N228K, and G230R, all located in the cap and lid domains of LCAT, demonstrated notable activity restoration in response to Compound 2. Molecular dynamics simulations and structural modeling indicate that these mutations disrupt the lid and membrane binding domain, with Compound 2 potentially dampening these structural alterations. Conversely, variants such as M252K and F382V in the cap and α/β-hydrolase domain, respectively, exhibited limited or no rescue by Compound 2. Future research should prioritize in vivo investigations that would validate the therapeutic potential of Compound 2 and related activators in familial LCAT deficiency patients with mutations in the cap and lid of the enzyme. SIGNIFICANCE STATEMENT: Lecithin:cholesterol acyltranferase (LCAT) catalyzes the first step of reverse cholesterol transport, namely the esterification of cholesterol in high density lipoprotein particles. Somatic mutations in LCAT lead to excess cholesterol in blood plasma and, in severe cases, kidney failure. In this study, we show that recently discovered small molecule activators can rescue function in LCAT-deficient variants when the mutations occur in the lid and cap domains of the enzyme.

Predicting Small Molecule Activations Including Dinitrogen Based on an Inorganic Benzene B4N2 Framework.

Although main group species have emerged in the field of dinitrogen activation in recent years, the reported examples are particularly rare in comparison with transition metal complexes due to their significant challenges. Herein, we demonstrate a [4 + 2] cycloaddition reaction of N2 (with an activation energy as low as 12.5 kcal mol-1) initiated by an inorganic benzene via density functional theory calculations. Such N2 activation is supported by the elongated nitrogen-nitrogen bond distance (dNN), decreased vibration frequency (νNN), and weakened Wiberg bond index (WBINN). Subsequently, the "push-pull" electronic effect, formed by introducing a Lewis acid, HB(C6F5)2, facilitates the generation of thermodynamically more stable products. In addition, this inorganic benzene could also be used to activate a series of small molecules, including carbon dioxide, acetylene, ethylene, and acetonitrile with reaction barriers ranging from 4.7 to 11.6 kcal mol-1. Our findings provide an alternative approach to N2 activation and functionalization, theoretically validating the feasibility of the dual Lewis acid strategy for dinitrogen activation.

3D-printed multifunctional biomass hydrogel device for controlled photothermal distribution and molecular release

Photothermal therapy based on photothermal conversion has received increasing attention due to its non-invasiveness and low side effects. In this study, a 3D-printed biomass photothermal therapy device was prepared for accurate control of photothermal conversion and molecular release. The prepared black phosphorus nanosheets (BPNSs) showed excellent photothermal performance and antibacterial activity. A temperature-regulated sol-gel reversible system was prepared with konjac glucomannan (KGM), tara gum (TG), BPNSs, and manganese dioxide (MnO2) nanoparticles. The sol-gel transition was attributed to the change of interactions of hydrogen bond, and molecular entanglement. Photothermal conversion films with accurate multi-layer and array structures were prepared by 3D printing using the biomass sol-gel conversion system. The photothermal conversion efficiency was regulated by the concentration of BPNSs and MnO2. Under infrared radiation (808 nm, 1 W/cm2) for 5 min, the temperatures of hydrogel films with a MnO2 concentration of 0, 0.5, and 1 % were raised from 25 to 29.3, 61.8, and 90.8 °C, respectively. The accurate temperature distribution induced the controlled release of small active molecules such as epigallocatechin gallate (EGCG) loaded in hydrogels, which was resulted from the changes in the hydrogel structure and the decrease in adsorption energy between polysaccharide and EGCG at high temperatures. This study provides a biomass 3D-printed multifunctional photothermal therapy device and more understanding of the molecular release during photothermal conversion.

Development of Brain Penetrant Pyridazine Pantothenate Kinase Activators.

Conversion of pantothenate to phosphopantothenate in humans is the first dedicated step in the coenzyme A (CoA) biosynthesis pathway and is mediated by four isoforms of pantothenate kinase. These enzymes are allosterically regulated by acyl-CoA levels, which control the rate of CoA biosynthesis. Small molecule activators of the PANK enzymes that overcome feedback suppression increase CoA levels in cultured cells and animals and have shown great potential for the treatment of pantothenate kinase-associated neurodegeneration and propionic acidemias. In this study, we detail the further optimization of PANK pyridazine activators using structure-guided design and focus on the cellular CoA activation potential, metabolic stability, and solubility as the primary drivers of the structure-activity relationship. These studies led to the prioritization of three late-stage preclinical lead PANK modulators with improved pharmacokinetic profiles and the ability to substantially increase brain CoA levels. Compound 22 (BBP-671) eventually advanced into clinical testing for the treatment of PKAN and propionic acidemia.

Novel Lewis Acid-Base Interactions in Polymer-Derived Sodium-Doped Amorphous Si-B-N Ceramic: Towards Main-Group-Mediated Hydrogen Activation.

Interest is growing in transition metal-free compounds for small molecule activation and catalysis. We discuss the opportunities arising from synthesizing sodium-doped amorphous silicon-boron-nitride (Na-doped a-SiBN). Na+ cations and 3-fold coordinated BIII moieties were incorporated into an amorphous silicon nitride network via chemical modification of a polysilazane followed by pyrolysis in ammonia (NH3) at 1000 °C. Emphasis is placed on the mechanisms of hydrogen (H2) activation within Na-doped a-SiBN structure. This material design approach allows the homogeneous distribution of Na+ and BIII moieties surrounded by SiN4 units contributing to the transformation of the BIII moieties into 4-fold coordinated geometry upon encountering H2, potentially serving as frustrated Lewis acid (FLA) sites. Exposure to H2 induced formation of frustrated Lewis base (FLB) N-= sites with Na+ as a charge-compensating cation, resulting in the in situ formation of a frustrated Lewis pair (FLP) motif (≡BFLA⋅⋅⋅Hδ-⋅⋅⋅Hδ+⋅⋅⋅:N-(Na+)=). Reversible H2 adsorption-desorption behavior with high activation energy for H2 desorption (124 kJ mol-1) suggested the H2 chemisorption on Na-doped a-SiBN. These findings highlight a future landscape full of possibilities within our reach, where we anticipate main-group-mediated small molecule activation will have an important impact on the design of more efficient catalytic processes and the discovery of new catalytic transformations.

Recent progress in transition metal complexes featuring silylene as ligands.

Silylenes, divalent silicon(II) compounds, once considered highly reactive and transient species, are now widely employed as stable synthons in main-group and coordination chemistry for myriad applications. The synthesis of stable silylenes represents a major breakthrough, which led to extensive exploration of silylenes in stabilizing low-valent main-group elements and as versatile ligands in coordination chemistry and catalysis. In recent years, the exploration of transition metal complexes stabilized with silylene ligands has captivated significant research attention. This is due to their robust σ-donor characteristics and capacity to stabilize transition metals in low valent states. It has also been demonstrated that the transition metal complexes of silylenes are effective catalysts for hydroboration, hydrosilylation, hydrogenation, hydrogen isotope exchange reactions, and small molecule activation chemistry. This review article focuses on the recent progress in the synthesis and catalytic application of transition metal complexes of silylenes.