Ligand Tuning Research Articles

(Invited) Tuning Chirality of Graphene Quantum Dots to Empower Medical Imaging and Theranostic Applications

Chiral nanostructures from metals and semiconductor, including graphene-based materials, are increasingly recognized for their potential in polarization-sensitive optoelectronics. Particularly, graphene quantum dots (GQDs) modified with L/D amino acids exhibit unique chiral properties due to edge-specific interactions, offering new possibilities in biomedicine. Our study delves into the interaction of these chiral nanomaterials with biological systems, revealing significant implications for their application in biology and medicine. We discovered that attaching L/D amino acid moieties to GQDs induces nanoscale chirality by helical buckling, influenced by the chiral interactions at the graphene edges. The chirality of GQDs affects their interaction at the nanoscale with cells and tissues. Molecular dynamics simulations show that D-GQDs are more likely to accumulate within cellular membranes compared to L-GQDs. Additionally, experiments on chiral GQD permeation through lipid membranes of extracellular vesicles demonstrated that optimizing chirality via ligand tuning and GQD size can significantly enhance their permeation efficiency into lipid bilayers, exceeding 80%. Leveraging this enhanced transmembrane transport, chiral GQDs have been applied in imaging and efficient drug loading for therapeutic extracellular vesicles. Furthermore, we explored how GQD chirality affects transport in tumor-like cellular spheroids. The results indicate that L-GQDs exhibit a 1.7 times higher apparent diffusion coefficient than D-GQDs, enhancing their transport into these spheroids. In summary, our research underscores the importance of controlling and engineering GQD chirality. This approach not only enhances the transport of drug carriers through biological barriers but also opens new avenues for advanced imaging and theranostic applications.

Cerium-based metal-organic-frameworks with ligand tuning of the microstructures for fluoride adsorption: linear and nonlinear kinetic and isotherm adsorption models.

We present the synthesis and characterisation of three Ce-based metal-organic frameworks (Ce-MOFs) using fumaric acid (Fu), terephthalic acid (BDC), and trimesic acid (H3BTC) as linkers. The use of different linkers influenced the size of the MOF particles, surface area, crystallinity, and microporous structure. The successful implementation of Ce-Fu, Ce-BDC, and Ce-H3BTC MOFs for fluoride ion removal from wastewater was carried out, in which Ce-Fu MOFs exhibited a maximum adsorption capacity (AC) of 64.2 mg g-1. The study also reveals that the use of ultrasound as a mediator for adsorption study over conventional method gives rapid adsorption rate, in which 85% of the fluoride uptake took place just in 10 min and achieved maximum AC in 30 min. The kinetics data were most accurately explained by the pseudo-second-order model (PSO). The existence of co-ions such as NO3-, Cl-, HCO3-, SO42-, Br-, CO32-, and PO43- has a substantial effect on fluoride removal. The mechanism between the fluoride ions and the MOF surface took place via the electrostatic force and the ion exchange process, confirmed using X-ray photoelectron spectroscopy (XPS) and delsa nano. The material is sustained its relatively higher F- ions removal efficiency up to the five cycles. This research might help in the development of novel microporous Ce-based MOFs since it possesses a highly stable crystalline structure in water, suggesting a promising role in aqueous applications.

Serine/Threonine Protein Kinases as Attractive Targets for Anti-Cancer Drugs-An Innovative Approach to Ligand Tuning Using Combined Quantum Chemical Calculations, Molecular Docking, Molecular Dynamic Simulations, and Network-like Similarity Graphs.

Serine/threonine protein kinases (CK2, PIM-1, RIO1) are constitutively active, highly conserved, pleiotropic, and multifunctional kinases, which control several signaling pathways and regulate many cellular functions, such as cell activity, survival, proliferation, and apoptosis. Over the past decades, they have gained increasing attention as potential therapeutic targets, ranging from various cancers and neurological, inflammation, and autoimmune disorders to viral diseases, including COVID-19. Despite the accumulation of a vast amount of experimental data, there is still no "recipe" that would facilitate the search for new effective kinase inhibitors. The aim of our study was to develop an effective screening method that would be useful for this purpose. A combination of Density Functional Theory calculations and molecular docking, supplemented with newly developed quantitative methods for the comparison of the binding modes, provided deep insight into the set of desirable properties responsible for their inhibition. The mathematical metrics helped assess the distance between the binding modes, while heatmaps revealed the locations in the ligand that should be modified according to binding site requirements. The Structure-Binding Affinity Index and Structural-Binding Affinity Landscape proposed in this paper helped to measure the extent to which binding affinity is gained or lost in response to a relatively small change in the ligand's structure. The combination of the physico-chemical profile with the aforementioned factors enabled the identification of both "dead" and "promising" search directions. Tests carried out on experimental data have validated and demonstrated the high efficiency of the proposed innovative approach. Our method for quantifying differences between the ligands and their binding capabilities holds promise for guiding future research on new anti-cancer agents.

Stereochemical Tailoring of Nickel‐based Electrocatalysts for Hydrogen Evolution Reaction

AbstractThe search for alternative non‐noble transition metal catalysts able to evolve hydrogen has been the focus of intense research. Molecular complexes bearing redox‐active ligands have been reported as efficient electrocatalysts for hydrogen evolution reaction (HER). This study showcases a new family of nickel‐thiosemicarbazone complexes displaying significant activity for HER in DMF solvent using trifluoracetic acid as proton source. Following previous works in our group, the ligand was stereochemically tailored, placing methoxy groups at different locations and considering various combinations of positions. Three complexes within the series were shown to outperform the parent catalyst bearing the methoxy group in para position. Overall, the nickel catalyst having the chemical substituent in meta position displays the best catalytic performances while having the lowest overpotential. These results support that ligand stereochemical tailoring in metal complexes improves electrocatalytic HER and suggest that ligand tuning is a promising direction to enhance catalyst performances.

Role of ancillary ligands in S-nitrosothiol and NO generation from nitrite-thiol interactions at mononuclear zinc(ii) sites.

Generation of S-nitrosothiol (RSNO) and nitric oxide (NO) mediated by zinc(ii) coordination motifs is of prime importance for understanding the role of zinc(ii)-based cofactors in redox-signalling pathways. This study uniquely employs a set of mononuclear [L2ZnII]2+ cores (where L = Me4PzPz/Me2PzPy/Me2PzQu) for introducing subtle alterations of the primary coordination sphere and investigates the role of ligand tuning in the transformation of NO2 - in the presence of thiols. Single crystal X-ray diffraction (SCXRD) analyses on [L2ZnII-X](X) (where X = perchlorate/triflate) illustrate consistent changes in the bond distances, thereby showing variations of the metal-ligand interactions depending on the nature of the heterocyclic donor arms (pyrazole/pyridine/quinoline). Moreover, such tuning of the ligands affects the Lewis-acidity of the [L2ZnII]2+ cores as evaluated by 31P NMR and SCXRD studies on the 1 : 1 acid-base adducts [L2ZnII(OPEt3)]2+. Crystallographic and 15N NMR spectroscopic analyses on the nitrite complexes [L2ZnII(κ2-nitrite)](ClO4) reveal that the chemical environments of the nitrite anions in these complexes are nearly identical, despite the dissimilarity in the Lewis-acidity of the [L2ZnII]2+ cores. Interestingly, RSNO and NO generation from the reactions of [L2ZnII(κ2-nitrite)](ClO4) with 4-tert-butylbenzylthiol ( t BuBnSH) exhibits that the [(Me2PzQu)2ZnII]2+ core is the most efficient in promoting nitrite-thiol interactions due to the ease of available hemilabile coordination sites at the Lewis acidic [ZnII]. Detailed UV-vis studies in tandem with computational investigation, for the first time, provide an unambiguous demonstration of the nitrous acid (HNO2) intermediate generated through an intramolecular proton-transfer from thiol to nitrite at zinc(ii).

Investigating cyclization selectivity by ligand tuning based on MHAT/RPC mechanism

In this study, we investigated the metal-catalyzed hydrogen atom transfer (MHAT)/radical polar crossover (RPC) reaction, focusing on the influence of ligands on the cyclization selectivity by employing substrates containing two nucleophiles along with an alkene. We provide new insights into the importance of ligand optimization in the MHAT/RPC mechanism, particularly in hydroarylation reactions.

A gold-based inhibitor of oxidative phosphorylation is effective against triple negative breast cancer

Triple-negative breast cancer (TNBC) is associated with metabolic heterogeneity and poor prognosis with limited treatment options. New treatment paradigms for TNBC remains an unmet need. Thus, therapeutics that target metabolism are particularly attractive approaches. We previously designed organometallic Au(III) compounds capable of modulating mitochondrial respiration by ligand tuning with high anticancer potency in vitro and in vivo. Here, we show that an efficacious Au(III) dithiocarbamate (AuDTC) compound induce mitochondrial dysfunction and oxidative damage in cancer cells. Efficacy of AuDTC in TNBC mouse models harboring mitochondrial oxidative phosphorylation (OXPHOS) dependence and metabolic heterogeneity establishes its therapeutic potential following systemic delivery. This provides evidence that AuDTC is an effective modulator of mitochondrial respiration worthy of clinical development in the context of TNBC. One sentence summaryMetabolic-targeting of triple-negative breast cancer by gold anticancer agent may provide efficacious therapy.

Ligand Tuning in Cu(pyalk)2 Water Oxidation Electrocatalysis

Molecular copper water oxidation electrocatalysts have been extensively studied in recent years for their potential use in artificial photosynthetic systems for solar energy conversion. Although ligand modification and its ability to influence catalytic properties is a key advantage of molecular systems, there are, as yet, few examples of systematic studies of these effects. Our oxidatively resistant pyalk (2-pyridyl-2-propanoate) ligand forms a complex with copper(II) that catalyzes water oxidation and provides an attractive scaffold for systematic ligand tuning. Here, we report a series of analogous copper complexes with electron-donating (methoxy-) and -withdrawing (methoxycarbonyl-) groups at the para-position of the pyalk ligand. Trends in the pKa and redox potential align with first-principles predictions for the electron-withdrawing and electron-donating groups. While the modified complexes show good activity for water oxidation, lowered faradaic efficiency in comparison to the parent complex highlights the importance of stability considerations for catalyst tuning.

Betainic and ionic tungsten (VI) imido alkylidene N-heterocyclic olefin complexes

A series of betainic and ionic tungsten (VI) imido alkylidene N-heterocyclic olefin (NHO) complexes W2 – W7 of the general formulae [W(N-2,6-iPr2-C6H3)(CHCMe2Ph)(X)n(NHO)m] and [W(N-2,6-iPr2-C6H3)(CHCMe2Ph)(X)n(NHO)m (B(ArF)4)x] (NHO = 2-methylene-1,3,4,5-tetramethyl-4,5-dihydro-1H-imidazol-3-ium, 2-methylene-1,3-dimethyl-1H-benzo[d]imidazolium; X = CF3SO3, OCMe(CF3)2, n, m = 1, 2; x = 0,1) have been prepared. By adapting the number and type of NHO ligands, catalysts W2 and W7 show an improved activity in ring-closing metathesis compared to a previous system. In particular, the ionic and tetra-coordinated W7, which is ligated by only one NHO ligand, displays promising catalytic behavior. The results indicate that the overall still moderate performance can be further optimized by ligand tuning, suggesting less basic NHOs as promising candidates for further investigations.

Modulating the electronic properties of divalent lanthanoid complexes with subtle ligand tuning.

Five new compounds of formula [LnII(Mentpa)2](BPh4)2 (Ln = Eu, n = 0 (1-Eu), n = 2 (2-Eu) and n = 3 (3-Eu); Ln = Yb, n = 0 (1-Yb) and n = 2 (2-Yb); tpa = tris(2-pyridylmethyl)amine, n = 0-3 corresponds to successive methylation of the 6-position of the pyridine rings of Mentpa) have been synthesized and their structural, photophysical and electrochemical properties investigated. The LnII ions in the five complexes possess cubic coordination geometry and exhibit only small structural differences, due to the lengthening of the Ln-N bonds to accommodate the additional steric bulk associated with increasing methylation of the Mentpa ligands. Photophysical studies indicate moderate shifts in absorbance, emission and excitation bands associated with the 4f7 ↔ 4f65d1 (EuII) and 4f14 ↔ 4f135d1 (YbII) transitions, while electrochemistry reveals modulation of the redox potential of the LnII to LnIII oxidation. There is a strong correlation between Ln-N bond lengths and both the photophysical transition energies and metal redox-potentials, revealing how subtle ligand changes and ligand field effects can be used to modulate the electronic properties of complexes of divalent lanthanoid ions. Utilization of these insights may ultimately afford design and property tuning strategies for future functional molecular complexes based on divalent lanthanoid metals.

Effects of ligand tuning and core doping of atomically precise copper nanoclusters on CO2 electroreduction selectivity

Atomically precise nanoclusters (NCs) provide opportunities for correlating the structure and electrocatalytic properties at atomic level. Herein, we report the single-atom doping effect and ligand effect on CO2 electroreduction (eCO2RR) by comparing monogold-doped Au1Cu24 and homocopper Cu25 NCs protected by triphenylphosphine or/and tris(4-fluorophenyl)phosphine. Catalytic results revealed that the electronic distribution of Cu25 NCs is enormously contracted by doping Au atoms, entitling it to exhibit the unique inhibition of hydrogen evolution reaction. And the inductive effect of ligand strongly favors the formation of formate in eCO2RR. Overall, this work will provide guidance for the rational design of the copper-based catalysts in the eCO2RR.

Ligand Tuning of Localized Surface Plasmon Resonances in Antimony-Doped Tin Oxide Nanocrystals.

Aliovalent-doped metal oxide nanocrystals exhibiting localized surface plasmons (LSPRs) are applied in systems that require reflection/scattering/absorption in infrared and optical transparency in visible. Indium tin oxide (ITO) is currently leading the field, but indium resources are known to be very restricted. Antimony-doped tin oxide (ATO) is a cheap candidate to substitute the ITO, but it exhibits less advantageous electronic properties and limited control of the LSPRs. To date, LSPR tuning in ATO NCs has been achieved electrochemically and by aliovalent doping, with a significant decrease in doping efficiency with an increasing doping level. Here, we synthesize plasmonic ATO nanocrystals (NCs) via a solvothermal route and demonstrate ligand exchange to tune the LSPR energies. Attachment of ligands acting as Lewis acids and bases results in LSPR peak shifts with a doping efficiency overcoming those by aliovalent doping. Thus, this strategy is of potential interest for plasmon implementations, which are of potential interest for infrared upconversion, smart glazing, heat absorbers, or thermal barriers.

Finely Tuning Tridentate Carboxylic Acids for the Construction of Rod Scandium Metal-Organic Frameworks with High Chemical Stability and Selective Gas Adsorption.

By systematic ligand tuning for control of the secondary building units, the use of tridentate carboxylic acid to construct the rod scandium metal-organic framework NTUniv-55 (NTUniv = Nantong University) with high chemical stability and interesting selective gas adsorption was reported.

Gram-scale synthesis of carboxylic acids via catalytic acceptorless dehydrogenative coupling of alcohols and hydroxides at an ultralow Ru loading

Acceptorless dehydrogenative coupling (ADC) of alcohols and water/hydroxides is an emergent and graceful approach to produce carboxylic acids. Therefore, it is of high demand to develop active and practical catalysts/catalytic systems for this attractive transformation. Herein, we designed and fabricated a series of cyclometallated N-heterocyclic carbene-Ru (NHC-Ru) complexes via ligand tuning of [Ru-1], the superior complex in our previous work. Gratifyingly, gram-scale synthesis of carboxylic acids was efficiently enabled at an ultralow Ru loading (62.5 ppm) in open air. Moreover, effects of distinct ancillary NHC ligands and other parameters on this catalytic process were thoroughly studied, while further systematic studies were carried out to provide rationales for the activity trend of [Ru-1]-[Ru-7]. Finally, determination of quantitative green metrics illustrated that the present work exhibited superiority over representative literature reports. Hopefully, this study could provide valuable input for researchers who are engaging in metal-catalyzed ADC reactions.

High-performance lanthanum-based metal–organic framework with ligand tuning of the microstructures for removal of fluoride from water

Excess fluoride in water poses a threat to ecology and human health, which has attracted global attention. In this study, a series of lanthanum-based metal–organic frameworks (La-MOFs) were synthesized by varying the organic ligands (i.e., terephthalic acid (BDC), trimesic acid (BTC), biphenyl-4,4-dicarboxylic acid (BPDC), 2,5-dihydroxyterephthalic acid (BHTA), and 1,2,4,5-benzenetetracarboxylic acid (PMA)) to control the microscopic structure of the MOFs and subsequently apply them for the removal of fluoride in water. The maximum capture capacities of La-BTC, La-BPDC, La-BHTA, La-PMA, and La-BDC at 298 K are 105.2, 125.9, 145.5, 158.9, and 171.7 mg g−1, respectively. The adsorption capacity is greater than most reported adsorbents. The adsorption isotherms of La-MOFs for fluoride are well fit to the Langmuir isotherm model. In addition, the adsorption kinetics of La-BTC, La-BPDC, La-BHTA, La-PMA, and La-BDC follows the pseudo-second-order kinetic model, and the kinetic rate-limiting step of adsorption is chemical adsorption. Thermodynamics revealed that temperature is favorable for the adsorption of fluoride. Meanwhile, La-BTC, La-BPDC, La-BHTA, La-PMA, and La-BDC are suitable for the removal of fluoride in a relatively wide pH range (4.0–9.0). Simultaneously, from X-ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR) analysis, electrostatic attraction and ligand exchange are identified as the main action mechanisms for the adsorption of fluoride of La-MOFs. The prepared La-MOFs are used as efficient adsorbents for removal of fluoride in actual water, indicating that they have great potential in removing fluoride in real and complex environmental water. This work provides a new strategy for designing adsorbents with adjustable microstructure and expected function to effectively recover fluorosis in water.

Ligand Ratio Plays a Critical Role in the Design of Optimal Multifunctional Gold Nanoclusters for Targeted Gastric Cancer Therapy.

Nanodrug delivery systems (NDDSs) based on water-soluble and atomically precise gold nanoclusters (AuNCs) are under the spotlight due to their great potential in cancer theranostics. Gastric cancer (GC) is one of the most aggressive cancers with a low early diagnosis rate, with drug therapy being the primary means to overcome its increasing incidence. In this work, we designed and characterized a set of 28 targeted nanosystems based on Au144(p-MBA)60 (p-MBA = para-mercaptobenzoic acid) nanocluster to be potentially employed as combination therapy in GC treatment. The proposed multifunctional AuNCs are functionalized with cytotoxic drugs (5-fluorouracil and epirubicin) or inhibitors of different signaling pathways (phosphatidylinositol 3-kinases (PI3K)/protein kinase B (Akt)/mammalian target of the rapamycin (mTOR), vascular endothelial growth factor (VEGF), and hypoxia-inducible factor (HIF)) and RGD peptides as targeting ligands, and we studied the role of ligand ratio in their optimal structural conformation using peptide-protein docking and all-atom molecular dynamics (MD) simulations. The results reveal that the peptide/drug ratio is a crucial factor influencing the potential targeting ability of the nanosystem. The most convenient features were observed when the peptide amount was favored over the drug in most cases; however, we demonstrated that the system composition and the intermolecular interactions on the ligand shell are crucial for achieving the desired effect. This approach helps guide the experimental stage, providing essential information on the size and composition of the nanosystem at the atomic level for ligand tuning in order to increase the desired properties.

Precise Ligand Tuning Emission of Mn-Doped CsPbCl3 Nanocrystals by the Amount of Sulfonates.

Using Mn-doped CsPbCl3 nanocrystals (Mn:CsPbCl3 NCs) to improve perovskite's properties is becoming an important strategy. Here, we demonstrate a modified supersaturated recrystallization route to synthesize high-quality Mn:CsPbCl3 NCs at room temperature. Unprecedentedly, sulfonate ligands with various concentrations are shown to successfully tune the dual-color emission of Mn:CsPbCl3 NCs. Ultrafast transient absorption studies reveal that the host-to-dopant internal energy-transfer process involves the mediated traps. Interestingly, the dual-color emission is tuned via stabilizing mediated traps with a small amount of ligand (band edge (BE) emission reduces and Mn2+ emission increases), passivating the deep traps with a large amount of ligand (Mn2+ emission increases), and destroying Mn:CsPbCl3 NCs with too much ligand (both BE and Mn2+ emission is quenched). Furthermore, the ligand tuning Mn2+ emission exhibits quenching for Cu2+ with high sensitivity and selectivity. Our work provides a new strategy to tune the optical properties of Mn:CsPbCl3 NCs and presents its potential application in an optical detector.

"Canopy Catalysts" for Alkyne Metathesis: Molybdenum Alkylidyne Complexes with a Tripodal Ligand Framework.

A new family of structurally well-defined molybdenum alkylidyne catalysts for alkyne metathesis, which is distinguished by a tripodal trisilanolate ligand architecture, is presented. Complexes of type 1 combine the virtues of previous generations of silanolate-based catalysts with a significantly improved functional group tolerance. They are easy to prepare on scale; the modularity of the ligand synthesis allows the steric and electronic properties to be fine-tuned and hence the application profile of the catalysts to be optimized. This opportunity is manifested in the development of catalyst 1f, which is as reactive as the best ancestors but exhibits an unrivaled scope. The new catalysts work well in the presence of unprotected alcohols and various other protic groups. The chelate effect entails even a certain stability toward water, which marks a big leap forward in metal alkylidyne chemistry in general. At the same time, they tolerate many donor sites, including basic nitrogen and numerous heterocycles. This aspect is substantiated by applications to polyfunctional (natural) products. A combined spectroscopic, crystallographic, and computational study provides insights into structure and electronic character of complexes of type 1. Particularly informative are a density functional theory (DFT)-based chemical shift tensor analysis of the alkylidyne carbon atom and 95Mo NMR spectroscopy; this analytical tool had been rarely used in organometallic chemistry before but turns out to be a sensitive probe that deserves more attention. The data show that the podand ligands render a Mo-alkylidyne a priori more electrophilic than analogous monodentate triarylsilanols; proper ligand tuning, however, allows the Lewis acidity as well as the steric demand about the central atom to be adjusted to the point that excellent performance of the catalyst is ensured.

Research Trend of Metal-Organic Frameworks for Magnetic Refrigeration Materials Application

The magnetocaloric effect (MCE), which is the reversible temperature change of magnetic materials due to an applied magnetic field, occurs largely in the vicinity of the magnetic phase transition temperature. This phenomenon can be used to induce magnetic refrigeration, a viable, energy-efficient solid-state cooling technology. Recently, Metal-organic frameworks (MOFs), due to their structural diversity of tunable crystalline pore structure and chemical functionality, have been studied as good candidates for magnetic refrigeration materials in the cryogenic region. In cryogenic cooling applications, MCE using MOF can have great potential, and is even considered comparable to conventional lanthanum alloys and magnetic nanoparticles. Owing to the presence of large internal pores, however, MOF also exhibits the drawback of low magnetic density. To overcome this problem, therefore, recent reports in literature that achieve high magnetic entropy change using a dense structure formation and ligand tuning are introduced.

Cyclometalated Gold(III) Complexes Bearing DACH Ligands.

The synthesis of a novel class of cyclometalated gold(III) complexes supported by benzoylpyridine, benzylpyridine, and (1R,2R)-(+)-1,2-diaminocyclohexane (DACH) ligands, along with their crystal structures, is reported. These compounds provide a new scaffold to investigate biological properties of gold(III) complexes. The six complexes were prepared and characterized, following reactions of (C,N) cyclometalated gold(III) scaffolds, [Au(C^N)Cl2] with DACH, which yielded a new series of cyclometaled gold(III), 3-5, of the type [Au(C^NH)(DACH)2]+ and the nitrogen-substituted cyclometalated Au(III), 6-8, of the type [Au(C^N)(DACH)]2+. Antiproliferative activity of these complexes in a panel of cancer cells showed promising results with IC50 in the micromolar range and selectivity over normal epithelial cells, MRC5. Whereas 8 shows minimal interaction with superhelical DNA except at high gold concentrations of 500 μM, complex 5 does not show interaction even at 1000 μM. The complexes display significant uptake in OVCAR8 cancer cells within 200-1200 pmol/million cells with the exception of complex 4. Differential cellular uptake was observed for the complexes; for example, while 3 and 8 display significant uptake, 4 showed minimal uptake. The compounds proved to be stable under physiological conditions and were minimally affected by either glutathione or sodium ascorbate. Cell cycle studies reveal a G1 arrest induced by representative complexes. The results reveal that enhanced Au(III) stabilization promoted by combined cyclometalated and DACH ligands may offer ligand tuning insights for novel anticancer drug design.