Synthesis and preclinical testing of a selective beta-subtype agonist of thyroid hormone receptor ZTA-261.

BACKGROUND: Thyroid hormones (TH) regulate the basal metabolic rate through their receptors THRα and THRß. TH activates lipid metabolism via THRß, however, an excess amount of TH can lead to tachycardia, bone loss, and muscle wasting through THRα. In recent years, TH analogs that selectively bind to THRß have gained attention as new agents for treating dyslipidemia and obesity, which continue to pose major challenges to public health worldwide. METHODS: We developed a TH analog, ZTA-261, by modifying the existing THRß-selective agonists GC-1 and GC-24. To determine the THRß-selectivity of ZTA-261, an in vitro radiolabeled TH displacement assay was conducted. ZTA-261 was intraperitoneally injected into a mouse model of high-fat diet-induced obesity, and its effectiveness in reducing body weight and visceral fat, and improving lipid metabolism was assessed. In addition, its toxicity in the liver, heart, and bone was evaluated. RESULTS: ZTA-261 is more selective towards THRß than GC-1. Although ZTA-261 is less effective in reducing body weight and visceral fat than GC-1, it is as effective as GC-1 in reducing the levels of serum and liver lipids. These effects are mediated by the same pathway as that of T3, a natural TH, as evidenced by similar changes in the expression of TH-induced and lipid metabolism-related genes. The bone, cardiac, and hepatotoxicity of ZTA-261 are significantly lower than those of GC-1. CONCLUSIONS: ZTA-261, a highly selective and less toxic THRß agonist, has the potential to be used as a drug for treating diseases related to lipid metabolism.

Nearly 10% of the world's population suffers from obesity or is overweight. These conditions are closely related to disorders of lipid metabolism, posing significant challenges to individuals and healthcare systems. Thyroid hormone (TH) activates metabolism by binding to specific protein partners, called TH receptors (THRs). There are two types of THRs, THRα and THRß. THRß activates lipid metabolism; however, THRα negatively affects the heart, bone, and muscle when TH is in excess. This study developed a drug called ZTA-261 that selectively binds to THRß. Its administration to mice with induced obesity from a high-fat diet resulted in reduced body fat without any apparent toxicity. Therefore, ZTA-261 is a promising candidate to improve lipid metabolism and address the obesity epidemic.

Energetics and Redox Kinetics of Pure Ferrocene-Terminated N-Heterocyclic Carbene Self-Assembled Monolayers on Gold.

N-heterocyclic carbene (NHC) self-assembled monolayers (SAMs) on gold have received considerable attention, but little is known about the lateral interactions between neighboring NHC molecules, their stability when subjected to aggressive oxidizing/reducing conditions, and their interactions with solution ions, all of which are essential for their use in a wide range of applications. To address these deficiencies, we present a comprehensive investigation of two different ferrocene (Fc)-terminated NHC SAMs with different chain lengths and linking groups. Pure monolayers of Fc-terminated NHCs display only a single, symmetrical pair of redox peaks, implying the formation of a homogeneous SAM structure with uniformly distributed Fc/Fc+ redox centers. By comparison, pure Fc-alkylthiol SAMs exhibit complex and impractical redox chemistry and require surface dilution in order to achieve reproducible properties. The NHC SAMs examined in this study exhibit very fast Fc redox kinetics and comparable or even superior stability against the application of multiple potential cycles or long-time holding at constant potential compared to alkylthiol SAMs. Furthermore, ion pairing of Fc+ and hydrophobic perchlorate and other hydrophilic anions is observed with Fc-NHC SAMs, highlighting conditions favorable for future applications of these monolayers. This study should therefore shed light on the very promising characteristics of redox-active NHC SAMs as an alternative to traditional Fc-alkylthiol SAMs for multiple practical applications, including in sensors and electrocatalysis.

Enantiospecific cross-coupling of cyclic alkyl sulfones.

Methods to form carbon-carbon bonds efficiently and with control of stereochemistry are critical for the construction of complex molecules. Cross-coupling reactions are among the most efficient and widely used reactions to construct molecules, with reactions enabling the retention or installation of chirality as recent additions to this powerful toolbox. Sulfones are robust, accessible organic electrophiles that have many attractive features as cross-coupling partners; however, since the first example of their use in 1979, there have been no examples of their use in enantioselective, enantiospecific or entantioconvergent cross-couplings. The high acidity of sulfones makes it unclear whether this transformation is even possible outside tertiary systems. Here we report the enantiospecific cross-coupling of cyclic sulfones and Grignard reagents. Up to 99% chirality transfer is observed despite the strong basicity of the Grignard components. In situ monitoring reveals that the cross-coupling is kinetically competitive with competing deprotonation, resulting in a highly enantioselective transformation.

If the Crown Fits: Sterically Demanding N-Heterocyclic Carbene Promotes the Formation of Au8Pt Nanoclusters.

While N-heterocyclic carbenes (NHCs) have recently been shown to be effective ligands for gold nanoclusters, very few examples of heterometallic clusters incorporating nongroup 11 metals are known. We present herein an Au-Pt NHC cluster featuring a crown-shaped [Au8Pt(NHC)8]2+ core, produced in high yield without the need for chromatographic purification. The method was largely independent of the substitution pattern of the NHC backbone; however, bulky wingtip groups were needed for clean conversion to the Au8Pt cluster. Clusters were characterized using single crystal X-ray diffraction, multinuclear nuclear magnetic resonance, electrospray ionization mass spectroscopy, and ultraviolet-visible spectroscopy, and electrochemical features of the cluster are also presented. A detailed analysis of the in-progress reaction mixture by ESI-MS supports the direct involvement of Au-H species as intermediates in cluster formation. These studies further demonstrate that NHC wingtip sterics play a key part in determining the nature of the initial cluster species, providing critical information for the generation of new NHC-stabilized nanoclusters.

Visible-light-induced direct C-H alkylation of polycyclic aromatic hydrocarbons with alkylsulfones.

Polycyclic aromatic hydrocarbons (PAHs) are fragments of graphene that have attracted considerable attention as a new class of carbon-based materials. The functionalization of edge positions in PAHs is important to enable the modulation of physical and chemical properties essential for various applications. However, straightforward methods that combine functional group tolerance and regioselectivity remain sought after. Here we report a photochemical approach for the direct alkylation of carbon-hydrogen bonds in PAHs that takes place in a regiospecific manner, an outcome that has never been achieved in related thermal reactions. A reaction mechanism involving a single electron transfer process from photo-excited PAHs to sulfones, and a rationale for the origin of regioselectivity are proposed on the basis of spectroscopic analyses and theoretical calculations.

N-Heterocyclic Carbene-Stabilized Atomically Precise Metal Nanoclusters.

This perspective highlights advances in the preparation and understanding of metal nanoclusters stabilized by organic ligands with a focus on N-heterocyclic carbenes (NHCs). We demonstrate the need for a clear understanding of the relationship between NHC properties and their resulting metal nanocluster structure and properties. We emphasize the importance of balancing nanocluster stability with the introduction of reactive sites for catalytic applications and the importance of a better understanding of how these clusters interact with their environments for effective use in biological applications. The impact of atom-scale simulations, development of atomic interaction potentials suitable for large-scale molecular dynamics simulations, and a deeper understanding of the mechanisms behind synthetic methods and physical properties (e.g., the bright fluorescence displayed by many clusters) are emphasized.

Mesoionic carbene-based self-assembled monolayers on gold.

N-Heterocyclic carbenes (NHC) have been widely studied as ligands for surface chemistry, and have shown advantages compared to existing ligands (e.g. thiols). Herein, we introduce mesoionic carbenes (MICs) as a new type of surface ligand. MICs exhibit higher σ-donor ability compared to typical NHCs, yet they have received little attention in the area of surface chemistry. The synthesis of MICs derived from imidazo[1,2-a]pyridine was established and fully characterized by spectroscopic methods. The self-assembly of these MICs on gold was analyzed by X-ray photoelectron spectroscopy (XPS). Additionally, XPS was used to compare bonding ability in MICs compared to the typical NHCs. These results show that MIC overlayers on gold are robust, resistant to replacement by NHCs, and may be superior to NHCs for applications that require even greater levels of robustness.

N-heterocyclic carbene adsorption states on Pt(111) and Ru(0001).

N-heterocyclic carbene ligands (NHCs) are increasingly used to tune the properties of metal surfaces. The generally greater chemical and thermal robustness of NHCs on gold, as compared to thiolate surface ligands, underscores their potential for a range of applications. While much is now known about the adsorption geometry, overlayer structure, dynamics, and stability of NHCs on coinage elements, especially gold and copper, much less is known about their interaction with the surfaces of Pt-group metals, despite the importance of such metals in catalysis and electrochemistry. In this study, reflection absorption infrared spectroscopy (RAIRS) is used to probe the structure of benzimidazolylidene NHC ligands on Pt(111) and Ru(0001). The experiments exploit the intense absorption peaks of a CF3 substituent on the phenyl ring of the NHC backbone to provide unprecedented insight into adsorption geometry and chemical stability. The results also permit comparison with literature data for NHC ligands on Au(111) and to DFT predictions for NHCs on Pt(111) and Ru(0001), thereby greatly extending the known surface chemistry of NHCs and providing much needed molecular information for the design of metal-organic hybrid materials involving strongly reactive metals.

Insights into the synthesis of NHC-stabilized Au nanoclusters through real-time reaction monitoring.

Atomically precise gold nanoclusters (AuNCs) are interesting nanomaterials with potential applications in catalysis, bioimaging and optoelectronics. Their compositions and properties are commonly evaluated by various analytical techniques, including UV-vis spectroscopy, NMR spectroscopy, ESI mass spectrometry, and single-crystal X-ray diffraction. While these techniques have provided detailed insights into the structure and properties of nanoclusters, synthetic methods still suffer from a lack of in situ and real-time reaction monitoring methodologies. This limits insight into the mechanism of formation of AuNCs and hinders attempts at optimization. We have demonstrated the utility of HPLC-MS as a monitoring methodology in the synthesis of two NHC-protected gold nanoclusters: [Au13(NHC)9Cl3]2+ and [Au24(NHC)14Cl2H3]3+. Herein we show that HPLC coupled with mass spectrometry and 13C NMR spectroscopy of labelled derivatives enables new insight into critical reaction dynamics of AuNCs synthesis and rapid reaction optimization.

Functionalized N-Heterocyclic Carbene Monolayers on Gold for Surface-Initiated Polymerizations.

Although N-heterocyclic carbenes (NHCs) are superior to thiol adsorbates in that they form remarkably stable bonds with gold, the generation of NHC-based self-assembled monolayers (SAMs) typically requires a strong base and an inert atmosphere, which limits the utility of such films in many applications. Herein, we report the development and use of bench-stable NHC adsorbates, benzimidazolium methanesulfonates, for the direct formation of NHC films on gold surfaces under an ambient atmosphere at room temperature without the need for extraordinary precautions. The generated NHC SAMs were fully characterized using ellipsometry, X-ray photoelectron spectroscopy (XPS), polarization modulation infrared reflection-absorption spectroscopy (PM-IRRAS), and contact angle measurements, and they were compared to analogous SAMs generated from an NHC bicarbonate adsorbate. Based on these findings, a unique radical initiator α,ω-bidentate azo-terminated NHC adsorbate, NHC15AZO[OMs], was designed and synthesized for the preparation of SAMs on gold surfaces with both NHC headgroups bound to the surface. The adsorbate molecules in NHC15AZO SAMs can exist in a hairpin or a linear conformation depending on the concentration of the adsorbate solution used to prepare the SAM. These conformations were studied by a combination of ellipsometry, XPS, PM-IRRAS, and scanning electron microscopy using gold nanoparticles (AuNPs) as a tag material. Moreover, the potential utility of these unique radical-initiating NHC films as surface-initiated polymerization platforms was demonstrated by controlling the thickness of polystyrene brush films grown from azo-terminated NHC monolayer surfaces simply by adjusting the reaction time of the photoinitiated radical polymer growth process.

N-Heterocyclic Carbene-Stabilized Hydrido Au24 Nanoclusters: Synthesis, Structure, and Electrocatalytic Reduction of CO2.

Atomically precise hydrido gold nanoclusters are extremely rare but interesting due to their potential applications in catalysis. By optimization of molecular precursors, we have prepared an unprecedented N-heterocyclic carbene-stabilized hydrido gold nanocluster, [Au24(NHC)14Cl2H3]3+. This cluster comprises a dimer of two Au12 kernels, each adopting an icosahedral shape with one missing vertex. The two kernels are joined through triangular faces, which are capped with a total of three hydrides. The hydrides are detected by electrospray ionization mass spectrometry and nuclear magnetic resonance spectroscopy, with density functional theory calculations supporting their position bridging the six uncoordinated gold sites. The reactivity of this Au24H3 cluster in the electrocatalytic reduction of CO2 is demonstrated and benchmarked against related catalysts.

NHC-Stabilized Au10 Nanoclusters and Their Conversion to Au25 Nanoclusters.

Herein, we describe the synthesis of a toroidal Au10 cluster stabilized by N-heterocyclic carbene and halide ligands via reduction of the corresponding NHC-Au-X complexes (X = Cl, Br, I). The significant effect of the halide ligands on the formation, stability, and further conversions of these clusters is presented. While solutions of the chloride derivatives of Au10 show no change even upon heating, the bromide derivative readily undergoes conversion to form a biicosahedral Au25 cluster at room temperature. For the iodide derivative, the formation of a significant amount of Au25 was observed even upon the reduction of NHC-Au-I. The isolated bromide derivative of the Au25 cluster displays a relatively high (ca. 15%) photoluminescence quantum yield, attributed to the high rigidity of the cluster, which is enforced by multiple CH-π interactions within the molecular structure. Density functional theory computations are used to characterize the electronic structure and optical absorption of the Au10 cluster. 13C-Labeling is employed to assist with characterization of the products and to observe their conversions by NMR spectroscopy.

Highly Ordered N-Heterocyclic Carbene Monolayers on Cu(111).

The benzannulated N-heterocyclic carbene, 1,3-dibenzylbenzimidazolylidene (NHCDBZ) forms large, highly ordered domains when adsorbed on Cu(111) under ultrahigh vacuum conditions. A combination of scanning tunnelling microscopy (STM), high-resolution electron energy loss spectroscopy (HREELS), and density functional theory (DFT) calculations reveals that the overlayer consists of vertical benzannulated NHC moieties coordinating to Cu adatoms. Long-range order results from the placement of the two benzyl substituents on opposite sides of the benzimidazole moiety, with their aromatic rings approximately parallel to the surface. The organization of three surface-bound benzyl substituents from three different NHCs into a triangular array controls the formation of a highly ordered Kagome-like surface lattice. By comparison with earlier studies of NHCs on Cu(111), we show that the binding geometry and self-assembly of NHCDBZ are influenced by intermolecular and adsorbate-substrate interactions and facilitated by the flexibility of the methylene linkage between the N-heterocycle and the aromatic wingtip substituents.

Synthesis and Characterization of Enantiopure Chiral Bis NHC-Stabilized Edge-Shared Au10 Nanocluster with Unique Prolate Shape.

Herein we report the first chiral Au10 nanoclusters stabilized by chiral bis N-heterocyclic carbene (bisNHC) ligands. ESI-MS and single-crystal X-ray crystallography confirmed the molecular formula to be [Au10(bisNHC)4Br2](O2CCF3)2. The chiral Au10 nanocluster adopts a linear edge-shared tetrahedral geometry with a prolate shape. DFT calculations provide insight into the electronic structure, optical absorption, and circular dichroism (CD) characteristics of this unique Au10 nanocluster. CD spectra demonstrate chirality transfer from the chiral bisNHC ligand to the inner Au10 nanocluster core. Examination of ESI-MS and UV-vis spectra show that cluster [Au9(bisNHC)4Br]Br2 is formed initially and then transformed into the Au10 nanocluster in solution.