JACS Au最新文献

Free radicals, with their high reactivity, offer a promising strategy for tumor treatment by effectively circumventing drug resistance. Free-radical-based cancer therapies include radiotherapy, chemotherapy, and emerging approaches such as chemodynamic therapy (CDT) and photodynamic therapy (PDT). Conventional PDT, widely used in cancer treatment, relies on excited photosensitizers generating reactive oxygen species (ROS) via electron or energy transfer to kill cancer cells. However, the generation of both Type I and Type II ROS critically depends on microoxic and normoxic conditions, and the hypoxic tumor microenvironment severely limits therapeutic efficacy. Enhancing the cancer-cell-killing effect of PDT remains challenging. Herein, we constructed an S-rhodamine photosensitizer activated upon photoirradiation and NADH induction, generating a sulfur-bridged xanthene-based triarylmethyl radical (TAM^•) in an oxygen-independent manner. Acting as a broad-spectrum hydrogen atom abstractor, this radical attacks biomolecules within cancer cells more effectively than ROS by extracting hydrogen atoms from endogenous biological substrates, depleting intracellular NADH and glutathione (GSH), and causing critical DNA damage. These actions induce severe DNA damage and disrupt intracellular homeostasis, ultimately eradicating cancer cells through a combination of ferroptosis and apoptosis. It exhibited potent antitumor activity in the 4T-1 tumor-bearing mouse model. This design strategy for modulating the stability of photogenerated carbon radicals holds significant promise for the development of novel anticancer agents.

We report the palladium-catalyzed one-pot synthesis of enantiopure 20-, 30-, and 40-membered cyclophanes shaped by axially twisted allene units. Under Cs⁺-template, the two smaller macrocycles (2 and 3) are favored over the largest (4). X-ray studies reveal that rac-2 assembles into homochiral helices that pack to form channels, while rac-3 forms racemic dimers. These shape-persistent hosts, with unique chiral 3D cavities, undergo guest-induced conformational switching and (enantio)-selectively bind diols and ammonium cations, including hydroxycarboxylic acids and α-hydroxyammoniums, as evidenced by diagnostic ECD shifts.

We report a novel, metal-free, and biocompatible method for tyrosine-specific functionalization using kinetically persistent iminium intermediates in aqueous media. By employing weakly coordinating anion-based ion-pair catalysts, this approach overcomes the inherent instability of iminium species in water, enabling efficient conjugation with phenolic compounds. The method showcases broad applicability, including the functionalization of pharmaceuticals, phenol-containing natural products, and tyrosine residues in biopolymers, all under mild and environmentally friendly conditions. Importantly, the approach preserves stereochemical integrity during biomolecule modifications and achieves high chemo- and regioselectivity. This work offers a versatile platform for biofunctionalization, with potential applications in drug discovery, therapeutic innovation, and biomolecular engineering.

Sulfur, particularly SO₂, remains one of the primary poisons in catalytic systems for treating exhaust gases. Currently, the elimination of CO is still challenging in the presence of SO₂ at low temperatures (<150 °C). Herein, we introduce a strategyshunt catalysisto development of sulfur-tolerant catalysts for CO oxidation. Shunt Pt/FeO _x -Al₂O₃ catalysts were constructed for CO oxidation in the presence of SO₂, in which tiny Pt nanoparticles with sizes of 3-4 nm were uniformly incorporated onto binary nanohybrids composed of amorphous FeO _x and γ-Al₂O₃. By deliberately adjusting the Fe-to-Al ratio to be about 1:10 at the surface region of the FeO _x -Al₂O₃ nanohybrids, the resulting 2 wt % Pt/FeO _x -Al₂O₃ catalysts possessed high and persistent activity to catalyze CO oxidation (1 vol % CO) in the presence of 30 ppm of SO₂ over a wide temperature range from 30 to 140 °C. This was as a result of the Pt/FeO _x -Al₂O₃ catalysts being able to preferentially shunt CO to the Pt/FeO _x interfaces and SO₂ and its oxidation productSO₃to the Pt/Al₂O₃ interfaces, which bestowed outstanding SO₂ tolerance to the Pt/FeO _x interfaces for effective catalysis of CO oxidation. This work presents a practical solution to the deactivation of CO oxidation catalysts under the SO₂ atmosphere at room and industrial temperature. The key is that this shunt path can effectively alleviate the poisoning of catalytic sites caused by impurities or byproducts, thus ensuring the activity and durability of the catalyst. This is method realizes the cross-fusion of multiple catalytic sites and bionic engineering approaches.

Methionine oxidation is a key hallmark of cellular oxidative stress, which is reversed by methionine sulfoxide reductases (Msrs) as part of cellular defense mechanisms. Current tools for studying methionine oxidation and Msr function rely on sulfoxide reduction or transcriptional analysis, which are inadequate for monitoring enzyme activity under persistent oxidative stress. Moreover, no activity-based protein profiling (ABPP) tools have been reported for investigating the functional state of Msrs in cells. Here, we present SO-acetylene, a methionine sulfoxide-inspired, cysteine-reactive probe for profiling Msrs and other proteins involved in oxidative stress responses. This substrate-inspired probe preferentially labels catalytic cysteines of Msrs, serving as an activity-based probe. The application of SO-acetylene to Escherichia coli under hypochlorite stress resulted in the labeling of multiple oxidative stress-related proteins, revealing distinct activity patterns among Msrs that diverge from transcriptional regulation. Furthermore, comparative labeling experiments with the conventional probe iodoacetamide revealed that SO-acetylene provides complementary coverage of cysteine reactivity, efficiently capturing the active-site cysteine of a DJ-1 superfamily glyoxalase, which is poorly labeled by iodoacetamide-alkyne.

Continuous manufacturing offers a sustainable and flexible approach for fine chemical production, yet its application to complex agrochemicals like tetraconazole remains largely unexplored. Herein, we report the first continuous-flow synthesis of the fungicide tetraconazole, addressing the challenging catalytic synthesis of α-aryl acrylates. We demonstrate that a packed-bed flow reactor, equipped with a newly designed heterogeneous base catalyst, achieves unprecedented selectivity in the dehydrative aldol condensationa transformation that previously suffered from poor conversion and yielded different major products under batch conditions. This key reaction proceeds with high efficiency and selectivity for the first time in a continuous-flow system, resulting in the desired acrylate product (7). Kinetic analysis, supported by in situ monitoring using a high-temperature superconductor (HTS) portable 200 MHz ¹H NMR spectrometer with an in-line cell, reveals that this flow-induced selectivity is not merely due to enhanced mixing but stems from an accelerated interconversion equilibrium between crucial intermediates, effectively enabling a direct elimination pathway that bypasses the typically slow dehydration step. This robust catalytic strategy was successfully integrated into a three-step sequential and continuous-flow process for the synthesis of the tetraconazole precursor, combining the catalytic dehydrative aldol condensation, the catalytic 1,4-addition of triazoles, and a flow ester reduction using LiBH₄. Crucially, the integration of the water-containing upstream process with the moisture-sensitive reduction was achieved via an efficient in-line liquid-liquid extraction module. This work provides an impactful example of applying sophisticated reactor engineering and mechanistic insight into transform a historically nonselective batch reaction into a high-yielding (up to 74% overall) and fully integrated continuous manufacturing method for a complex pesticide.

The human macrophage galactose-type lectin (MGL) recognizes exposed GalNAc residues abundantly found in tumor O-glycans. Herein, we have used an integrative chemical, structural, and functional approach to unravel the intricate specificity and molecular determinants that underlie the recognition of Thomsen-nouveau (Tn), the sialylated variant (STn), and Thomsen-Friedenreich (TF) O-glycans by the carbohydrate recognition domain of the MGL (MGL-CRD) at the molecular and cellular levels. The MGL-CRD prefers binding to Tn > STn ≫ TF O-glycans. In this molecular context, NMR, isothermal titration calorimetry, and molecular dynamics simulations revealed quantitative key structural and dynamic differences in binding, depending on the O-glycan. Interestingly, the density of Tn epitopes was critical for engaging multiple MGL-CRDs to MUC1 Tn-glycopeptides; however, the enthalpy-entropy balance strongly influenced the affinity, and a higher Tn density did not improve the binding. Cell-based mucin arrays recapitulated the MGL-CRD binding preference (Tn > STn ≫TF), but no preference for a specific O-glycan pattern in mucins was observed. The MGL-CRD also selectively recognizes glycoengineered gastric cancer cells expressing Tn/STn. Conversely, in the cellular context, employing CHO cells expressing the full-length MGL (CHO^+MGL) allowed analysis of the MGL binding properties in its native presentation toward tagged isolated mucin reporters. Specificity for short tumor-associated O-glycans without any preference for a specific mucin was confirmed. Stunningly, the CHO^+MGL cells revealed that the MGL shows similar binding to the STn and TF mucin reporters, suggesting that its natural oligomeric state displays promiscuous binding to simple O-glycans. Conceptually, the key role of glycan and lectin presentations for binding is thus highlighted. Moreover, this suggests the compelling scenario that the MGL serves as a universal receptor for truncated cancer-associated O-glycans.

Molecular assembly is a fundamental organizational principle in both living organisms and the fabrication of functional materials. However, artificial self-assembly systems lag far behind biological systems in terms of efficiency, controllability, complexity, and functionality. Here, inspired by catalysis in chemical reactions, we propose a novel strategy, termed as molecular catassembly, that employs catassemblers to dynamically manipulate cooperative multisite noncovalent interactions, thereby directing the pathway and accelerating assembly processes. By translating catalytic and biological principles into the catassembly, we summarize the distinctive features and multifaceted roles of catassemblers in manipulating cooperative multisite noncovalent interactions, facilitating mass transfer in crowded environments, and mediating energy transduction and feedback that endow systems with information-processing capabilities. Furthermore, we emphasize the pivotal role of catassemblers in multistep reaction-assembly cascades for the fabrication of hierarchical functional materials and the regulation of the cellular signaling pathway. We further elucidate how the integration of artificial intelligence technologies offers transformative potential to redefine the research paradigm of molecular (cat-)-assembly. Nevertheless, the research of catassembly remains in its infancy and demands the integration of advanced concepts and methodologies from multiple disciplines. Such interdisciplinary efforts will be crucial for unraveling the complexity and functionality of molecular assembly, ultimately offering new perspectives and methodologies for both life sciences and soft matter research.

⁶⁸Ga-labeled macrocyclic ligands have been extensively studied and used for positron emission tomography (PET) imaging. Compared with 12-membered DOTA derivatives, NOTA-based chelators with 9-membered macrocyclic rings exhibit more advantageous coordination stability for Ga³⁺ ions. However, studies of the 10-membered DETA macrocycle are still quite limited. Here, we present the synthesis of four different-sized chiral macrocyclic ligands L1-L4, followed by radiolabeling and stability studies to reveal the influence of ring size and chiral substituents on Ga³⁺ chelation. In the ⁶⁸Ga radiolabeling experiments, chiral NOTA L1 exhibits the highest radiochemical yield of 99% at 25 °C. While for the chiral DETA L2/L3 and the chiral DOTA L4, their radiolabeling efficiencies are inferior at room temperature, but remarkable improvements were observed at higher temperatures. L1-L4 all exhibit superior Ga³⁺ coordination stability than their achiral counterparts, while the chiral DETA L2 with an α-methyl group shows a slightly better performance than its β-analogue L3. Serum stability tests and kinetic studies under acid and alkaline conditions were conducted, highlighting the favorable kinetic inertness of these chiral ligands for potential ⁶⁸Ga-labeled PET imaging applications.

Efficient generation of singlet oxygen (1O2) underpins critical applications in photodynamic therapy, selective oxidation, and environmental remediation. Single-atom catalysts (SACs), particularly transition-metal-nitrogen-carbon single-atom catalysts (TM-N-C SACs) featuring TMN4 motifs embedded in carbon matrices, have shown promise in catalyzing this spin-forbidden transformation of ground-state triplet oxygen (3O2) to 1O2. However, the underlying catalytic mechanisms and governing electronic factors remain elusive due to challenges in both experimental characterization and computational approaches. In this work, we integrate density functional embedding theory (DFET) with second-order N-electron valence state perturbation theory (NEVPT2) to resolve the electronic structure and reactivity of CoN4-graphene (Gr). Embedded NEVPT2 accurately identifies the Co center's electronic configuration as (d xy 2d yz 2d xz 2dz2 1dx2‑y2 0) and predicts a weak, polarized Co-O2 interaction with an adsorption energy of -0.37 eV, consistent with experimental trends. Furthermore, we reveal a stepwise, photoinduced electron-transfer mechanism for 1O2 generation on CoN4-Gr, fundamentally distinct from the energy-transfer pathway operative in photosensitized systems. This work demonstrates the effectiveness and efficiency of combining DFET with high-level wave function methods for accurately describing complex correlated catalytic systems. The insights obtained not only deepen our understanding of SAC-mediated 1O2 generation but also establish a transferable theoretical framework for the rational design of efficient, photosensitizer-free catalysts for reactive oxygen species production.