Class Of Ligands Research Articles

The role of cell exhaustion in lepromatous leprosy.

Leprosy is a neglected chronic infectious disease caused by Mycobacterium leprae or M. lepromatosis, representing a public health concern in several low-income countries. In Brazil, most patients develop lepromatous leprosy, a clinical form characterized by poor bacillary control due to T helper 2 cells, M2 macrophages, and accentuated humoral immunity. Despite extensive studies, the complete mechanism of the disease is not fully understood. The evasion mechanisms used by the pathogen likely involve cellular exhaustion, which can arise from chronic antigen stimulation, leading to dysfunction at immune checkpoints, a progressive loss of T lymphocyte effector function, and low production of proinflammatory cytokines. Our study investigated the contribution of cellular exhaustion to the hyporesponsiveness of lepromatous leprosy patients by evaluating the classical markers PD-1 and LAG-3, their ligands PD-L1 and PD-L2, and the functional activity of cells after PD-1 blockade, using flow cytometry, immunofluorescence, and gene expression analyses in both blood and skin. Our work shows for the first time that LAG-3 is increased in the skin lymphocytes of lepromatous patients, as well as membrane-bound and soluble PD-1. Furthermore, its classical ligands, PD-L1 and PD-L2, are more available for interaction in all monocyte subsets in these patients. We also identified that PD-1 blockade induces an increase in IFN-γ+ and TNF+ T lymphocytes. Taken together, our data suggest that exhaustion markers contribute to the hyporesponsive profile of lepromatous patients, and that PD-1 blockade could contribute to the reestablishment of lymphocyte effector action and potentially become part of multidrug therapy in the future.

A review on biomacromolecular ligand-directed nanoparticles: New era in macrophage targeting.

A review on biomacromolecular ligand-directed nanoparticles: New era in macrophage targeting.

An Experimental and Theoretical Investigation into [2π + 2π] Cycloaddition Reactions Catalyzed by a Cationic Cobalt(I) Complex Containing a Strong-Field PCNHCP Pincer Ligand.

In the past decade, metal-catalyzed [2π + 2π] cycloaddition reactions have gained significant momentum for the synthesis of substituted cyclobutanes and bicyclo[3.2.0]-heptanes. To date, earth-abundant metals that contain redox non-innocent (radical)-type ligands are most commonly used in these cycloaddition reactions, whereby the redox non-innocent ligand plays a crucial role in stabilizing the oxidation and spin-state of the metal center. Classical π-accepting ligands, however, are inactive for these transformations. Here, we report efficient [2π + 2π] cycloaddition reactions that are catalyzed by a cobalt(I) complex containing a traditional π-accepting but redox innocent PCNHCP pincer ligand. Mechanistic and computational investigations revealed a classical Co(I)-Co(III) redox cycle on the singlet spin manifold, where oxidative cyclization is the rate-limiting step. Overall, the herein developed methodology exhibits a wide substrate scope and low catalyst loadings (<1 mol %) and is compatible with a variety of functional groups while occurring under mild conditions (40-60 °C, N2) with short reaction times.

Development of Chiral Bisphosphine Ligands with a Terminal Olefin Enables Asymmetric Orthogonal Auto-Tandem Catalysis.

Auto-tandem catalysis (ATC) leverages the multiple roles of the catalyst, facilitating the direct synthesis of complex molecules from simple starting materials in a highly efficient and step-economical manner. However, in conventional ATC, employing a single catalyst imposes significant limitations on the variety of catalyzed reactions. Herein, we present a novel catalysis strategy termed "orthogonal auto-tandem catalysis (OATC)", which provides the unique opportunity to develop more efficient chemical transformations that cannot be achieved with existing catalytic modes. An unprecedented tandem annulation process involving four different catalytic cycles via asymmetric OATC is demonstrated. The enantiodetermining step is a previously unrealized Pd(0)-catalyzed asymmetric allylic lactonization. The key to the whole success lies in the development of a new class of chiral bisphosphine ligands with a terminal olefin (TOPhos) that addressed not only the racemization issue of allylic ester products in classic π-allylmetal chemistry, but also the inherent compatibility challenges in transition-metal/organo dual catalytic system. Density functional theory (DFT) calculations unveil the vital role of the terminal olefin in TOPhos, enabling the differentiation of competitive enantioselective pathways.

Imidazo[1,5-a]pyridines - A Versatile Platform for Structurally Distinct N-Heterocyclic Olefins and π-Extended Heterocycles.

The synthesis of polarized N-heterocyclic olefins (NHOs) based on an imidazo[1,5-a]pyridine scaffold is presented. In contrast to regular NHOs the unique bicyclic heterocyclic core allows the incorporation of various substituents in close proximity to the highly polarized exocyclic C-C bond. The donor properties of the new carbon-based ligand class were quantified and the coordination chemistry explored. Alkenyl or alkynyl groups at the C5-position lead to spontaneous cyclization to yield imidazo[2,1,5-de]quinolizines. The unique cyclization strategy was compatible with a wide range of substitution patterns and yields highly electron-rich π-delocalized heterocycles. The electronic structure of the novel partially antiaromatic heterocycle was thoroughly investigated. One-electron oxidation occurs at low potentials and lead to a stable monomeric radical-cation confirmed by XRD, which showed solution phase fluorescence expanding into the field of open-shell organic materials.

Atomic Layer Restructuring of Gold Surfaces by N-Heterocyclic Carbenes over Large Surface Areas.

Even highly planar, polished metal surfaces display varying levels of roughness that can affect their optical and electronic properties, impacting performance in state-of-the-art microelectronics. Current methods for smoothing rough metallic surfaces require either the removal or addition of substantial amounts of material using complex processes that are incompatible with 3-dimensional nanoscale features needed for state-of-the-art applications. We present a vapor-phase process that results in up to a 60% smoothing of nanometer-scale rough gold surfaces through a single exposure to a class of ligands called N-heterocyclic carbenes. This process does not require removal or addition of metal from the surface and provides smoothing at the Ångström scale. Smoothing occurs in a single deposition, giving quantifiable differences in the adsorption behavior of the resulting surfaces. The process takes place through an adatom-extraction-driven destabilization and restructuring of the surface in a self-limiting manner. This process is achieved without the use of harsh chemical etchants or mechanical intervention, takes only minutes, and can easily be integrated with vapor-phase processing in situ in microfabrication workflows. Our observations demonstrate atomic layer restructuring, a technique that compliments atomic layer deposition and atomic layer etching in the fabrication and processing of high-precision materials.

IPr*diNHC: Sterically Adaptable Dinuclear N-Heterocyclic Carbenes.

N-Heterocyclic carbenes (NHCs) have been established as the predominant ligand class in inorganic and organometallic chemistry. Simultaneously, there has been a major interest in dinuclear ligands, where cooperative effects between the metal centers have been widely exploited across numerous research avenues. Herein, we report the synthesis of dinuclear sterically hindered and adaptable N-heterocyclic ligands based on the modular IPr* framework. These ligands are distinguished by (1) the bridging group between the N-heterocyclic carbene donors and (2) the steric and electronic characteristics of the N-aromatic wingtips. The net effect is a remarkably broadly ranging steric environment around the metal center (%Vbur of 33.9 up to 60.4%) as well as versatile conformation ranging from the perfectly linear (3.2°) to almost fully perpendicular (79.3°) between the carbene donors. The ligands have been evaluated in the gold(I)-catalyzed hydration and carboxylation of alkynes, where they show enhanced catalytic reactivity over mononuclear gold(I) complexes. Considering the importance of dinuclear N-heterocyclic carbenes across different research fields, we expect that this ligand class will be of broad interest in inorganic and organometallic chemistry.

Distinct oligomeric assemblies of STING induced by non-nucleotide agonists

STING plays essential roles coordinating innate immune responses to processes that range from pathogenic infection to genomic instability. Its adaptor function is activated by cyclic dinucleotide (CDN) secondary messengers originating from self (2’3’-cGAMP) or bacterial sources (3’3’-CDNs). Different classes of CDNs possess distinct binding modes, stabilizing STING’s ligand-binding domain (LBD) in either a closed or open conformation. The closed conformation, induced by the endogenous ligand 2’3’-cGAMP, has been extensively studied using cryo-EM. However, significant questions remain regarding the structural basis of STING activation by open conformation-inducing ligands. Using cryo-EM, we investigate potential differences in conformational changes and oligomeric assemblies of STING for closed and open conformation-inducing synthetic agonists. While we observe a characteristic 180° rotation for both classes, the open-LBD inducing agonist diABZI-3 uniquely induces a quaternary structure reminiscent but distinct from the reported autoinhibited state of apo-STING. Additionally, we observe slower rates of activation for this ligand class in functional assays, which collectively suggests the existence of a potential additional regulatory mechanism for open conformation-inducing ligands that involves head-to-head interactions and restriction of curved oligomer formation. These observations have potential implications in the selection of an optimal class of STING agonist in the context of a defined therapeutic application.

Surface engineering of Pt nanocatalysts with transition metal oleates for selective catalysis: a case study on the hydrogenation of α,β-unsaturated aldehydes.

Selective and active catalysts enable effective use of feedstocks, reduced energy consumption and waste generation. Tuning the electronic structure of heterogeneous metal nanocatalysts via their surface modifications is a promising strategy to design highly selective and active catalysts for the synthesis of harder to make and more cost-efficient products. We introduce transition metal oleates as a new class of ligands to engineer the catalytically active and very selective surface in organic solvents. Using citral hydrogenation and 5 nm Pt NPs as a model reaction and model catalytic system, respectively, we show that surface engineering of Pt nanocatalysts with metal oleates allows synthesis of desired partially hydrogenated product (geraniol) with ∼90% conversion with selectivity over 93%. We demonstrate that the selective synthesis of the unsaturated alcohols catalyzed by Pt NPs modified by adsorption of the transition metal salts cannot be explained by the widely accepted mechanism of preferred coordination of CO groups by Lewis acids (e.g. partially oxidized transition surface metals). Our results indicate that CO groups prefer to bind to negatively charged surfaces. We propose the explanation on how the adsorption of transition metal oleates can result in the increased electron density at the surface of Pt nanoparticles. Our study not only provides reliable solutions to selective hydrogenation but opens a new possibility of using metal oleates for the electronic ligand effect.

Multiple Atropo Selectivity by κ2‐N,O‐Oxazoline Urea Ligands in Cobaltaelectro‐Catalyzed C─H Activations: Decoding Selectivity with Data Science Integration

Enantioselective catalysis is one of the most prominent strategies in organic synthesis to access chiral bioactive compounds and advanced organic materials. Particularly, the development of chiral ligands has significantly advanced the efficiency and selectivity of transition metal‐catalyzed enantioselective transformations. Over recent decades, numerous chiral ligand classes with distinct geometrical and electronic properties have been established. Despite these advances, the demand for novel, tunable, and highly effective chiral ligands persists, driven by the need for structurally diverse chiral molecules and the pursuit of greener, more sustainable catalytic processes. Herein, a novel class of chiral oxazoline ureas is introduced and their potential as κ2‐N,O‐preligands in enantioselective transition metal catalysis is demonstrated. The chiral oxazoline urea ligands are featurized and compared with amide and enol derivatives using the physical organic descriptors. A multivariate linear regression model is constructed to quantitatively describe the effect of the quinoline fragment from the substrate and the ligand on enantioselectivity. Moreover, the model is effectively applied to atropo‐enantioselective cobaltaelectro‐catalyzed C─H annulations of 1‐alkynyl indoles.

Enhanced Pyridine-Oxazoline Ligand-Enabled Pd(II)-Catalyzed Aminoacetoxylation of Alkenes for the Asymmetric Synthesis of Biaryl-Bridged 7-Membered N-Heterocycles and Atropisomers.

A new class of binaphthyl unit-enhanced pyridine-oxazoline ligands was developed to promote the Pd-catalyzed enantioselective intramolecular 7-exo aminoacetoxylation of unactivated biaryl alkenes. Biaryl-bridged 7-membered N-heterocycles bearing a chiral center were obtained in good yields with excellent enantioselectivities (up to 99:1 er). Computational investigations on a series of biaryl-bridged 7-membered rings provided insights into the rotational barrier of the potentially chiral biaryl unit by the substituent effect including the heteroatom, the protecting group, and the chiral center. The kinetic resolution of racemic axially chiral biaryls via intramolecular enantioselective aminoacetoxylation of alkenes has also been achieved, affording previously inaccessible biaryl-bridged 7-membered N-heterocycles bearing both a chiral center and a chiral axis, as well as axially chiral biaryl amino alcohols.

Probing the E3 Ligase Adapter Cereblon with Chemical Biology.

ConspectusThe E3 ligase substrate adapter cereblon (CRBN) has garnered widespread interest from the research laboratory to the clinic. CRBN was first discovered for its association with neurological development and subsequently identified as the target of thalidomide and lenalidomide, therapeutic agents used in the treatment of hematopoietic malignancies. Both thalidomide and lenalidomide have been repurposed as ligands for targeted protein degradation therapeutic modalities. These agents were proposed to mimic a naturally occurring ligand, although the native substrate recognition mechanism of CRBN remained elusive. Chemical biology, which involves the use of chemical tools to modulate and probe biological systems, can provide unique insights into the molecular mechanisms and interactions of proteins with their cognate ligands. Here we describe our use of chemical biology approaches, including photoaffinity labeling, chemical proteomics, and targeted protein degradation, to interrogate the biological activities of CRBN in the presence or absence of its ligands. Our development of a photoaffinity labeling probe derived from lenalidomide, termed photolenalidomide, enabled mapping of the binding site on CRBN and identification of a new target recruited to CRBN by lenalidomide through chemical proteomics. Further derivatization of the lenalidomide scaffold afforded DEG-77, a potent degrader with therapeutic efficacy against acute myeloid leukemia. Our parallel development of chemically defined probes that are inspired by heterobifunctional targeted protein degradation agents and functionally engage CRBN in cells revealed that thalidomide is a peptidomimetic of an underappreciated protein modification termed the C-terminal cyclic imide, which arises from intramolecular cyclization of asparagine or glutamine residues and represents a degron endogenously recognized by CRBN. Protein engineering and proteomic efforts validated the CRBN-dependent regulation of proteins bearing the C-terminal cyclic imide modification in vitro and in cells and the prevalence of the C-terminal cyclic imide in the biological system. Application of C-terminal cyclic imides as a class of cyclimid ligands for targeted protein degradation led to the development of a variety of heterobifunctional degraders with distinct efficacy and target selectivity, whereas examination of the occurrence of C-terminal cyclic imides as a form of protein damage uncovered the intrinsic and extrinsic factors that predispose peptides and proteins to C-terminal cyclic imide formation and the role of CRBN in mitigating the accumulation of damaged proteins with a propensity for aggregation. Future investigation of C-terminal cyclic imides, synthetic ligands, and their relationship to CRBN biology will illuminate regulatory mechanisms that are controlled by CRBN and drive the pursuit of additional functional chemistries on proteins and the biological pathways that intercept them.

Computational Evaluation of Redox Potentials of Metal Complexes for Aqueous Flow Batteries.

Flow batteries are a promising option for large-scale stationary energy storage, but better redox active materials are required. Computational density functional theory (DFT) approach to materials screening can identify the most promising avenues and accelerate the development of the technology. In this work, metal complexes with functionalized organic ligands are focused on. The right redox potential, good chemical stability, and high solubility are the main characters in designing a high-performance aqueous electrolyte. Here, Fe, Ti, Mn, and Ni are studied as central metals of the complexes with two ligand classes containing N- and O- groups. The accuracy of the DFT redox potentials is compared to experiments whenever available. In addition, some cyclic voltammetry measurements are performed for Fe-bipyridine, phenanthroline, and terpyridine complexes. The computational redox potentials for ≈180 different metal-ligand combinations are evaluated. Overall, this work presents a new insight into the design of new electrolytes for aqueous flow batteries.

Simultaneous Construction of Axial and Central Stereogenicity by Cobalt-Catalyzed Stereoconvergent Reductive Coupling of Heterobiaryl Triflates and Aldehydes.

Catalytic stereoconvergent coupling of racemic heterobiaryl triflates and aldehydes promoted by a readily available chiral cobalt complex is presented. Such processes represent an unprecedented reaction pathway for cobalt catalysis that enable simultaneous construction of axial and central stereogenicity through diastereo- and enantioselective dynamic kinetic transformations and introduction of a chiral fragment onto the heterobiaryl cores without the requirement of preforming stoichiometric amounts of organometallic reagents, affording densely functionalized secondary alcohols in up to 96 % yield, >98 : 2 dr and >99.5:0.5 er. Preliminary investigations on the application of the products demonstrate their potential for serving as a new class of chiral catalysts and ligands. Mechanistic studies suggest that a dynamic kinetic stereoselective process induced by chiral cobalt catalysis is involved.

A Platform Approach for Designing Sustainable Indole Thiosemicarbazone Corrosion Inhibitors with Enhanced Adsorption Properties.

With an estimated global cost of $2.5 trillion per year, metal corrosion represents a major challenge across all industrial sectors. Numerous inorganic and organic corrosion inhibitors have been developed, but there are growing concerns about their toxicity and impact on the environment. Here, superior organic corrosion inhibitors based on indole-3-carboxaldehyde, a compound commonly found in the digestive system, and thiosemicarbazones, a safe class of ligands, were designed and studied for mild steel in pH 1 sulfuric acid solutions. Electroanalytical techniques and gravimetric tests revealed inhibition efficiencies as high as 98.9% at 30 °C. Models using Langmuir isotherms gave adsorption equilibrium constants Kads of 2 to 9 × 104 M-1 and corresponding Gibbs free energies of adsorption (ΔGads) as high as -41.44 kJ mol-1, indicating their chemisorption. SEM images confirmed the efficacy of these corrosion inhibitors, as surface features showed limited to no changes after tests. Surface analysis by XPS and LC-MS revealed inhibitor concentrations on the order of 0.7 to 1.8 μg cm-2 for the best compounds, further underlining their performance at low concentrations. Mapping of the surface by MALDI-MS further confirmed the homogeneous coating of the steel surface, with no visible fluctuations in concentrations. As all inhibitors shared the same indole thiosemicarbazone platform, unique structure-performance relationships were drawn from theoretical calculations. Notably, DFT and AIMD explained the differences in performance, highlighting the role of side groups in the distribution of the molecular orbitals and the role of water molecules in enhancing the electronic properties of the organic corrosion inhibitors and promoting their chemisorption.

Homogeneous catalyst graph neural network: A human-interpretable graph neural network tool for ligand optimization in asymmetric catalysis.

Homogeneous catalyst graph neural network: A human-interpretable graph neural network tool for ligand optimization in asymmetric catalysis.

The Distribution of Dissolved Copper and Natural Organic Ligands in Tropical Coastal Waters Under Seasonal Variation

The bioavailability of dissolved copper (Cu) in seawater is influenced by the presence of natural organic matter. Changes in physicochemical conditions, such as pH, temperature, and salinity, can significantly affect the solubility and speciation of copper, thereby impacting the complexation of Cu(II)-binding organic ligands. The concentration of dissolved Cu in the coastal water of Mersing, Malaysia, was detected by anodic stripping voltammetry (ASV). The natural organic copper(II)-binding ligands (CuL) and their conditional stability constants (log K′) were determined by using the competitive ligand exchange–adsorptive cathodic stripping voltammetry method (CLE–AdCSV) in our samples. The in situ parameters, such as pH, temperature, salinity, and dissolved oxygen (DO), were found to be significantly different between sampling periods and indicated the different physical chemical conditions between the sampling periods. However, we found a consistent concentration of dissolved Cu throughout the water column between sampling periods. This suggests that the presence of a strong class of natural organic ligands (L1) in Mersing’s coastal water maintains the dissolved Cu(II) ions in the water column and prevents the scavenging and precipitation processes under the seasonal variations.

Does Fluorine Make a Difference? How Fluoro Groups Influence the (Structural) Properties of MOFs

AbstractHerein, the influence of fluorine substituents on the structural and physical properties of MOFs with aromatic carboxylate ligands is investigated. To achieve this, the focus is limited to a few widely used ligand classes, e. g. terephthalates or trimesates. It is shown that the torsion angle between the phenyl ring and the carboxylate groups plays a decisive role. This can also be transferred to more complex ligands. These considerations clearly show why there are isostructural variants of some MOFs with perfluorinated ligands known (e. g. MIL‐53), while for others no successful synthesis has been reported up to now (e. g. HKUST‐1). In order to investigate the influence of the fluorination of the linker on the properties of the corresponding MOFs, isostructural systems were analysed more specifically. It was found that the thermal and chemical stability decreases with fluorination, while the absorption of CO2 in particular is enhanced. With regard to the specific surface area (SBET), the results are contradictory.

ActRII or BMPR ligands inhibit skeletal myoblast differentiation, and BMPs promote heterotopic ossification in skeletal muscles in mice

BackgroundPrior studies suggested that canonical Activin Receptor II (ActRII) and BMP receptor (BMPR) ligands can have opposing, distinct effects on skeletal muscle depending in part on differential downstream SMAD activation. It was therefore of interest to test ActRII ligands versus BMP ligands in settings of muscle differentiation and in vivo.Methods and resultsIn human skeletal muscle cells, both ActRII ligands and BMP ligands inhibited myogenic differentiation: ActRII ligands in a SMAD2/3-dependent manner, and BMP ligands via SMAD1/5. Surprisingly, a neutralizing ActRIIA/B antibody mitigated the negative effects of both classes of ligands, indicating that some BMPs act at least partially through the ActRII receptors in skeletal muscle. Gene expression analysis showed that both ActRII and BMP ligands repress muscle differentiation genes in human myoblasts and myotubes. In mice, hepatic BMP9 over-expression induced liver toxicity, caused multi-organ wasting, and promoted a pro-atrophy gene signature despite elevated SMAD1/5 signaling in skeletal muscle. Local overexpression of BMP7 or BMP9, achieved by intramuscular AAV delivery, induced heterotopic ossification. Elevated SMAD1/5 signaling with increased expression of BMP target genes was also observed in sarcopenic muscles of old rats.ConclusionsThe canonical ActRII ligand-SMAD2/3 and BMP ligand-SMAD1/5 axes can both block human myoblast differentiation. Our observations further demonstrate the osteoinductive function of BMP ligands while pointing to a potential relevancy of blocking the BMP-SMAD1/5 axis in the setting of therapeutic anti-ActRIIA/B inhibition.

Frustrated Lewis pairs reactivity across the periodic table: The 2024 Catalysis Award Lecture

This article presents an overview of some of our developments of the chemistry of “frustrated Lewis pairs” (FLPs). We begin with a brief outline of the foundations of this discovery and applications of FLPs in hydrogenations. Recent advances in asymmetric hydrogenations and CO2 reduction are discussed. Early studies of FLPs with alkynes and olefins are introduced and shown to lead to the more recent uncovering of phosphino-phosphination reactions, affording a route to dissymmetric bidentate phosphines, a class of understudied ligands for transition metal catalysis. The concept of FLP is further expanding into alkali metal species, with applications in the chemistry with CO or H2 as well as Fischer–Tropsch chemistry. Efforts to use FLPs to model the reduction of N2 in Haber–Bosch type chemistry are also discussed. The concept of FLPs is applied to xenon difluoride chemistry and the fluorination of electron deficient boranes and borates affording new anions that offer potential applications in catalysis. Finally, the broad scope of chemistry where FLPs are being applied is briefly highlighted, demonstrating the impact of this concept around the world and across the periodic table.