Active Substrate Research Articles

Enhanced Cancer Cell Specificity Through Combined Blue Light Therapy and Starvation Strategies.

In this study, the effectiveness of combining short-term starvation (STS or fasting) is investigated with blue light illumination therapy in delaying the progression of various types of cancer, including osteosarcoma, cervical, breast, liver carcinoma, and melanoma cancer in animal models. Moreover, the comparative analysis between cancerous (including HeLa, 143B, MDA-MB-231, and HepG2) and normal cell lines (including NCM460, HEKa, and L-O2), highlights the selectivity of the treatment's cytotoxic effects, favoring cancer cells while largely sparing normal cells. In HeLa cancer cells, treatment with the STS and blue light illumination combination resulted in increased phosphorylation of JNK and p38, which led to the activation of downstream signalling substrates, such as p53 and H2AX. This activation induced mitochondrial and nuclear damage, ultimately leading to tumor cell death. The combination treatment also caused metabolic disorders in tumor cells, which interfered with biomolecule availability and selectively induced lethal effects in tumor cells. Therefore, the combination treatment can be an effective strategy for eliminating cancer.

Synergistic regulation of dual thresholds: Hydroxyl occupancy and carbon species in the targeted catalytic hydrocracking of lignite

The preparation of carbon-based catalyst supports from low-grade lignite, followed by its self-catalytic hydrocracking to produce lignite-derived aromatic compounds, is crucial for achieving efficient lignite utilization and expanding aromatic compound sources. During lignite catalytic hydrocracking, the uncontrolled diffusive migration of active hydrogen (H*) and insufficient protection of aromatic rings reduce the yield of aromatic compounds. Using Heishan lignite as the raw material, we employed a relay process of thermal-induced self-assembly and oxidation-mediated carbon distortion for fabricating the Co3O4/AC&GC-S-600 composite material, which features an optimal hydroxyl occupancy ratio and a balanced combination of amorphous carbon/graphite carbon (AC/GC) types. The optimal hydroxyl occupancy threshold balances Co3O4 dispersion and hydrophilicity, facilitating the efficient formation and directional migration of H* through synergistic interaction between Co3O4 and H2O. The adequate threshold of AC/GC ratio regulates substrate adsorption, activation, and inhibition of aromatic hydrogenation, enhancing selective C–O bridge bond cleavage and preserving the unsaturation of aromatic rings. The synergistic regulation of dual thresholds promotes the rapid formation and the directional migration of H*, enabling efficient conversion of Heishan lignite to aromatic compounds (45.8% conversion, 80.8% selectivity) under mild conditions. Characterization techniques, experimental analyses, kinetic studies, and density functional theory calculations confirm that thermally induced self-assembly and oxidation-mediated carbon distortion are crucial for redistributing the carbon framework of the Heishan lignite matrix and regulating the optimal dual thresholds of hydroxyl occupancy and AC/GC types, which are essential for the catalytic hydrocracking of Heishan lignite to aromatic compounds. This strategy provides a scientific basis for selective catalytic production of lignite-based aromatic compounds, thereby supporting its clean and efficient utilization.

Innovative synthesis and practical application of graphitic carbon nitride/α-zirconium phosphate in visible light-activated Knoevenagel condensation

To advance the development of efficient photocatalysts activated by visible light for environmental applications. We employed a simple approach to synthesize g-C3N4/α-ZrP composite in different mass ratios, followed by comprehensive characterization through several techniques such as X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), scanning electron microscope coupled with energy dispersive X-ray spectroscopy (SEM/EDS), and UV–Visible diffuse reflectance spectra (DRS). Furthermore, the g-C3N4/α-ZrP with mass ratio 6:1 was demonstrated high performance catalytic activity in Knoevenagel condensation (Yield 88 %–96 %) in a short reaction time (5–20 min) under visible light irradiation. The use of g-C3N4/α-ZrP has transformed the traditional synthesis of carbon–carbon double bonds, offering improved reaction rates and reduced by-products. These next-generation photocatalysts also exhibit remarkable properties that facilitate the activation of substrates under milder conditions, opening up new possibilities for green and sustainable synthesis. This advancement contributes to the development of environmentally friendly and efficient synthetic methodologies.

Correlating enzymatic reactivity for different substrates using transferable data-driven collective variables

Machine learning (ML) is transforming the investigation of complex biological processes. In enzymatic catalysis, one significant challenge is identifying the reactive conformations (RC) of the enzyme:substrate complex where the substrate assumes a precise arrangement in the active site necessary to initiate a reaction. Traditional methods are hindered by the complexity of the multidimensional free energy landscape involved in the transition from nonreactive to reactive conformations. Here, we applied ML techniques to address this challenge, focusing on human pancreatic α-amylase, a crucial enzyme in type-II diabetes treatment. Using ML-based collective variables (CVs), we correlated the probability of being in a RC with the experimental catalytic activity of several malto-oligosaccharide substrates. Our findings demonstrate a remarkable transferability of these CVs across various compounds, significantly streamlining the modeling process and reducing both computational demand and manual intervention in setting up simulations for new substrates. This approach not only advances our understanding of enzymatic processes but also holds substantial potential for accelerating drug discovery by enabling rapid and accurate evaluation of drug efficacy across different generations of inhibitors.

Enantioselective Three-Component α-Allylic Alkylation of α-Amino Esters by Synergistic Photoinduced Pd/Carbonyl Catalysis.

Photoinduced excited-state Pd catalysis has emerged as an intriguing strategy for unlocking new reactivity potential of simple substrates. However, the related transformations are still limited and the enantiocontrol remains challenging. Organocatalysis displays unique capability in substrate activation and stereocontrol. Combination of organocatalysis and photoinduced excited-state Pd catalysis may provide opportunities to develop new enantioselective reactions from simple substrates. By applying cooperative triple catalysis including excited-state Pd catalysis, ground-state Pd catalysis, and carbonyl catalysis, we have successfully realized enantioselective α-allylic alkylation of α-amino esters with simple styrene and alkyl halide starting materials. The reaction allows rapid modular assembly of the three reaction partners into a variety of chiral quaternary α-amino esters in good yields with 90-99 % ee, without protecting group manipulations at the active NH2 group. The cooperation of the chiral pyridoxal catalyst and the chiral phosphine ligand accounts for the excellent chirality induction.

Reassessing the Neural Correlates of Social Exclusion: A Replication Study of the Cyberball Paradigm Using Arterial Spin Labeling.

The cyberball paradigm has been used in numerous neuroimaging studies to elicit activation in neural substrates of social exclusion, which have been interpreted in terms of activity associated with "social pain". The objectives of the study were to assess not only the replicability but also the specificity of the areas activated by this paradigm. Functional imaging with arterial spin labeling, an approach to image longer mental states. We replicated findings of previous meta-analyses of this paradigm in the inferior frontal gyrus and ventral cingular cortex. However, these areas were also active in a watch condition (in which participants were not excluded), although less so. These findings relativize a simple and specific interpretation of these areas as the neural substrates of social exclusion and social pain, as in previous studies. In a broader experimental context, similar activations have been reported by neuroimaging studies when semantic disambiguation and evaluation of action goals are required, an interpretation that may also apply to the effects elicited by this paradigm.

Rhodium-Catalyzed Meta-C-H Arylation of Arenes with Varied Linker Lengths: Bridging Catalytic Selectivity with Structural Diversity.

The directing group (DG)-assisted approach has so far been the major route to achieve selective C-H activation at both proximal and distal positions. While rhodium catalysts are highly effective in DG-assisted ortho-C-H arylation, meta-C-H arylation with rhodium has not yet been reported. In this study, we present the first example of Rh-catalyzed meta-C-H arylation of arenes. We found that the 2-cyanophenyl-based directing group, in conjunction with aryl boronic acids, selectively promotes meta-arylation with complete mono-selectivity. Despite significant advancements in meta-C-H activation for substrates with shorter linkers, such as hydrocinnamic acids, benzyl alcohols/amines, etc., meta-C-H activation of substrates with longer alkyl chains remains challenging with limited literature examples. We demonstrated that arenes with varying chain lengths, including conformationally flexible and less rigid ones such as 4-phenylbutanoic acid, 5-phenyl valeric acid, 6-phenylcaproic acid, 3-phenylpropanol, and 4-phenylbutanol underwent meta-arylation with high levels of regiocontrol. From a synthetic perspective, this approach could be valuable as it allows for the production of biaryl derivatives of flexible arenes with native functional groups at the meta-position. The synthetic utility of this strategy is demonstrated through the total synthesis of CNBCA, a bioactive compound possessing promising potency against the SHP2 enzyme activity in vitro.

Rhodium‐Catalyzed Meta‐C‐H Arylation of Arenes with Varied Linker Lengths: Bridging Catalytic Selectivity with Structural Diversity

The directing group (DG)‐assisted approach has so far been the major route to achieve selective C‐H activation at both proximal and distal positions. While rhodium catalysts are highly effective in DG‐assisted ortho‐C‐H arylation, meta‐C‐H arylation with rhodium has not yet been reported. In this study, we present the first example of Rh‐catalyzed meta‐C‐H arylation of arenes. We found that the 2‐cyanophenyl‐based directing group, in conjunction with aryl boronic acids, selectively promotes meta‐arylation with complete mono‐selectivity. Despite significant advancements in meta‐C‐H activation for substrates with shorter linkers, such as hydrocinnamic acids, benzyl alcohols/amines, etc., meta‐C‐H activation of substrates with longer alkyl chains remains challenging with limited literature examples. We demonstrated that arenes with varying chain lengths, including conformationally flexible and less rigid ones such as 4‐phenylbutanoic acid, 5‐phenyl valeric acid, 6‐phenylcaproic acid, 3‐phenylpropanol, and 4‐phenylbutanol underwent meta‐arylation with high levels of regiocontrol. From a synthetic perspective, this approach could be valuable as it allows for the production of biaryl derivatives of flexible arenes with native functional groups at the meta‐position. The synthetic utility of this strategy is demonstrated through the total synthesis of CNBCA, a bioactive compound possessing promising potency against the SHP2 enzyme activity in vitro.

Enantioselective Three‐Component α‐Allylic Alkylation of α‐Amino Esters by Synergistic Photoinduced Pd/Carbonyl Catalysis

Photoinduced excited‐state Pd catalysis has emerged as an intriguing strategy for unlocking new reactivity potential of simple substrates. However, the related transformations are still limited and the enantiocontrol remains challenging. Organocatalysis displays unique capability in substrate activation and stereocontrol. Combination of organocatalysis and photoinduced excited‐state Pd catalysis may provide opportunities to develop new enantioselective reactions from simple substrates. By applying cooperative triple catalysis including excited‐state Pd catalysis, ground‐state Pd catalysis, and carbonyl catalysis, we have successfully realized enantioselective α‐allylic alkylation of α‐amino esters with simple styrene and alkyl halide starting materials. The reaction allows rapid modular assembly of the three reaction partners into a variety of chiral quaternary α‐amino esters in good yields with 90‐99% ee, without protecting group manipulations at the active NH2 group. The cooperation of the chiral pyridoxal catalyst and the chiral phosphine ligand accounts for the excellent chirality induction.

Recent Insights into the Reaction Mechanisms of Non-Heme Diiron Enzymes Containing Oxoiron(IV) Complexes.

Oxoiron(IV) complexes are key intermediates in the catalytic reactions of some non-heme diiron enzymes. These enzymes, across various subfamilies, activate dioxygen to generate high-valent diiron-oxo species, which, in turn, drive the activation of substrates and mediate a variety of challenging oxidative transformations. In this review, we summarize the structures, formation mechanisms, and functions of high-valent diiron-oxo intermediates in eight representative diiron enzymes (sMMO, RNR, ToMO, MIOX, PhnZ, SCD1, AlkB, and SznF) spanning five subfamilies. We also categorize and analyze the structural and mechanistic differences among these enzymes.

A Machine Learning-Guided Approach to Navigate the Substrate Activity Scope of Galactose Oxidase: Application in the Conversion of Pharmaceutically Relevant Bulky Secondary Alcohols

A Machine Learning-Guided Approach to Navigate the Substrate Activity Scope of Galactose Oxidase: Application in the Conversion of Pharmaceutically Relevant Bulky Secondary Alcohols

Breaking the limitations of activity and stability in powdered materials for oxygen evolution reaction: The critical role of catalyst-inducing seeds

Powdered catalysts are extensively employed in industrial-scale energy conversion devices but struggle with weak powder-substrate adhesion and inherent instability in gas-evolving and highly oxidative oxygen evolution reactions (OER). This work introduces an innovative strategy in which powdered materials serve a critical role as catalyst-inducing seeds to break these limitations. Specifically, powdered Ti2CTx MXene with anchored cobalt single atoms (Co-SAs) shows negligible catalytic activity on its own but serves as catalyst-inducing seeds, significantly enhancing the catalytic activity of the conductive FeNi substrate. Mechanistic studies demonstrate that Co-SAs accelerate the oxidation rate of Ti2CTx, leading to the micro-battery corrosion behavior between oxidized Co/Ti2CTx and FeNi alloy, which generates highly OER-active corrosion products tightly bonded to FeNi alloy, thereby enhancing catalytic activity and ensuring stability. The prepared porous electrode shows a low overpotential of 303 mV to deliver an ultra-high current density of 1000 mA cm−2 and maintains activity for 1200 hours under high current density conditions, rivaling advanced self-supporting electrodes. Moreover, replacing Co in Co/Ti2CTx with metals like Fe, Ni or Mn, yields comparable effects, suggesting the scalability of catalyst-inducing seeds. This approach breaks traditional limitations of powdered materials in OER, offering an effective pathway to engineer advanced catalytic electrodes.

Electrochemical Deconstructive Methoxylation of Arylalcohols-A Synthetic and Mechanistic Investigation.

Herein, we report a mechanistic investigation of a recently developed electrochemical method for the deconstructive methoxylation of arylalcohols. A combination of synthetic, electroanalytical, and computational experiments have been performed to gain a deeper understanding of the reaction mechanism and the structural requirements for fragmentation to occur. It was found that 2-arylalcohols undergo anodic oxidation to form the corresponding aromatic radical cations, which fragment to form oxocarbenium ions and benzylic radical intermediates via mesolytic cleavage, with further anodic oxidation and trapping of the benzylic carbocation with methanol to generate the observed methyl ether products. It was also found that the electrochemical fragmentation of 2-arylalkanols is promoted by structural features that stabilize the oxocarbenium ions and/or benzylic radical intermediates formed upon mesolytic cleavage of the aromatic radical cations. With an enhanced understanding of the reaction mechanism and the structural features that promote fragmentation, it is anticipated that alternative electrosynthetic transformations will be developed that utilize this powerful, yet underdeveloped, mode of substrate activation.

Nicotinamide Riboside and CD38: Covalent Inhibition and Live-Cell Labeling.

Nicotinamide adenine dinucleotide (NAD+) is required for a myriad of metabolic, signaling, and post-translational events in cells. Its levels in tissues and organs are closely associated with health conditions. The homeostasis of NAD+ is regulated by biosynthetic pathways and consuming enzymes. As a membrane-bound protein with robust NAD+ hydrolase activity, cluster of differentiation 38 (CD38) is a major degrader of NAD+. Deficiency or inhibition of CD38 enhances NAD+ levels in vivo, resulting in various therapeutic benefits. As a metabolic precursor of NAD+, nicotinamide mononucleotide can be rapidly hydrolyzed by CD38, whereas nicotinamide riboside (NR) lacks CD38 substrate activity. Given their structural similarities, we explored the inhibition potential of NR. To our surprise, NR exhibits marked inhibitory activity against CD38 by forming a stable ribosyl-ester bond with the glutamate residue 226 at the active site. Inspired by this discovery, we designed and synthesized a clickable NR featuring an azido substitution at the 5'-OH position. This cell-permeable NR analogue enables covalent labeling and imaging of both extracellular and intracellular CD38 in live cells. Our work discovers an unrecognized molecular function of NR and generates a covalent probe for health-related CD38. These findings offer new insights into the role of NR in modulating NAD+ metabolism and CD38-mediated signaling as well as an innovative tool for in-depth studies of CD38 in physiology and pathophysiology.

CO2 Reduction by Transition‐Metal Complex Systems: Effect of Hydrogen Bonding on the Second Coordination Sphere

AbstractHomogeneous electrocatalysts typified by transition‐metal complex show transcendent potency in efficient energy catalysis through molecular design. For example, metal complexes with elaborate design performed wonderful activity and selectivity for electrocatalytic CO2 reduction. Primary coordination sphere of metal complexes plays a key role in regulating its intrinsic redox properties and catalytic activity. However, the overall reduction efficiency of CO2 is also bound up with the substrate activation process. Transition‐metal complexes are hoped to exhibit reasonable redox potential, reactive activity, and stability, while binding and activating CO2 molecules to achieve efficient CO2 reduction. Construction of second coordination sphere, especially hydrogen‐bonding network of transition‐metal complexes, is reported to be the “kill two birds with one stone” strategy to realize efficient CO2 reduction catalysis via systematic catalyst properties modulation and substrate activation. Herein, we present recent progress on the construction of hydrogen‐bonding network in the second coordination sphere of metal complexes by ligand modification or the introduction of exogenous organic ligand, and the resulted productive enhancement of the catalytic performance of metal complexes by the improvement of adsorption capacity and activation of CO2, proton transfer rate, and stability of reaction intermediates, and so forth.

6‐Hydroxy Picolinohydrazides Promoted Cu(I)‐Catalyzed Hydroxylation Reaction in Water: Machine‐Learning Accelerated Ligands Design and Reaction Optimization

AbstractHydroxylated (hetero)arenes are privileged motifs in natural products, materials, small‐molecule pharmaceuticals and serve as versatile intermediates in synthetic organic chemistry. Herein, we report an efficient Cu(I)/6‐hydroxy picolinohydrazide‐catalyzed hydroxylation reaction of (hetero)aryl halides (Br, Cl) in water. By establishing machine learning (ML) models, the design of ligands and optimization of reaction conditions were effectively accelerated. The N‐(1,3‐dimethyl‐9H‐ carbazol‐9‐yl)‐6‐hydroxypicolinamide (L32, 6‐HPA‐DMCA) demonstrated high efficiency for (hetero)aryl bromides, promoting hydroxylation reactions with a minimal catalyst loading of 0.01 mol % (100 ppm) at 80 °C to reach 10000 TON; for substrates containing sensitive functional groups, the catalyst loading needs to be increased to 3.0 mol % under near‐room temperature conditions. N‐(2,7‐Di‐tert‐butyl‐9H‐carbazol‐9‐yl)‐6‐hydroxypicolinamide (L42, 6‐HPA‐DTBCA) displayed superior reaction activity for chloride substrates, enabling hydroxylation reactions at 100 °C with 2–3 mol % catalyst loading. These represent the state of art for both lowest catalyst loading and temperature in the copper‐catalyzed hydroxylation reactions. Furthermore, this method features a sustainable and environmentally friendly solvent system, accommodates a wide range of substrates, and shows potential for developing robust and scalable synthesis processes for key pharmaceutical intermediates.

6-Hydroxy Picolinohydrazides Promoted Cu(I)-Catalyzed Hydroxylation Reaction in Water: Machine-Learning Accelerated Ligands Design and Reaction Optimization.

Hydroxylated (hetero)arenes are privileged motifs in natural products, materials, small-molecule pharmaceuticals and serve as versatile intermediates in synthetic organic chemistry. Herein, we report an efficient Cu(I)/6-hydroxy picolinohydrazide-catalyzed hydroxylation reaction of (hetero)aryl halides (Br, Cl) in water. By establishing machine learning (ML) models, the design of ligands and optimization of reaction conditions were effectively accelerated. The N-(1,3-dimethyl-9H- carbazol-9-yl)-6-hydroxypicolinamide (L32, 6-HPA-DMCA) demonstrated high efficiency for (hetero)aryl bromides, promoting hydroxylation reactions with a minimal catalyst loading of 0.01 mol % (100 ppm) at 80 °C to reach 10000 TON; for substrates containing sensitive functional groups, the catalyst loading needs to be increased to 3.0 mol % under near-room temperature conditions. N-(2,7-Di-tert-butyl-9H-carbazol-9-yl)-6-hydroxypicolinamide (L42, 6-HPA-DTBCA) displayed superior reaction activity for chloride substrates, enabling hydroxylation reactions at 100 °C with 2-3 mol % catalyst loading. These represent the state of art for both lowest catalyst loading and temperature in the copper-catalyzed hydroxylation reactions. Furthermore, this method features a sustainable and environmentally friendly solvent system, accommodates a wide range of substrates, and shows potential for developing robust and scalable synthesis processes for key pharmaceutical intermediates.

Asymmetric Synthesis of Benzofuranones with a C3 Quaternary Center via an Addition/Cyclization Cascade Using Noncovalent N-Heterocyclic Carbene Catalysis.

An asymmetric addition/cyclization cascade of amidoesters and iminoquinones is developed using noncovalent N-heterocyclic carbene (NHC) catalysis. The process enables access to various functionalized benzofuranones with an all-carbon quaternary stereocenter with high yields and ee values. The reaction displays a broad substrate scope. Via product modifications, enantioenriched synthesis of biologically relevant spirocyclic lactones and lactams is achieved. Substrate activation via noncovalent interaction with NHC is suggested for the process.

The iron-catalysed Suzuki coupling of aryl chlorides

The very widely exploited Suzuki biaryl coupling reaction typically requires catalysts based on palladium, but there is an increasing desire to replace this metal with a more sustainable, less expensive alternative, with catalysts based on iron being a particularly attractive target. Here we show that a simple iron-based catalyst with an N-heterocyclic carbene ligand can be used to excellent effect in the Suzuki biaryl coupling of aryl chloride substrates with aryl boronic esters activated by an organolithium reagent. Mechanistic studies suggest the possible involvement of Fe(I) as the lowest oxidation state on the catalytic manifold and show that the challenging step is not activation of the aryl chloride substrate, but rather the transmetallation step. These findings are likely to lead to a renaissance of iron-catalysed carbon–carbon bond-forming transformations with soft nucleophilic coupling partners.

Brain Metabolism in Health and Neurodegeneration: The Interplay Among Neurons and Astrocytes.

The regulation of energy in the brain has garnered substantial attention in recent years due to its significant implications in various disorders and aging. The brain's energy metabolism is a dynamic and tightly regulated network that balances energy demand and supply by engaging complementary molecular pathways. The crosstalk among these pathways enables the system to switch its preferred fuel source based on substrate availability, activity levels, and cell state-related factors such as redox balance. Brain energy production relies on multi-cellular cooperation and is continuously supplied by fuel from the blood due to limited internal energy stores. Astrocytes, which interface with neurons and blood vessels, play a crucial role in coordinating the brain's metabolic activity, and their dysfunction can have detrimental effects on brain health. This review characterizes the major energy substrates (glucose, lactate, glycogen, ketones and lipids) in astrocyte metabolism and their role in brain health, focusing on recent developments in the field.