Carbon dioxide (CO) fixation and subsequent activation represent grand challenges in materials science and chemical catalysis, with the aim of mitigating the worst impacts of global warming and associated climate change....Carbon dioxide (CO) fixation and subsequent activation represent grand challenges in materials science and chemical catalysis, with the aim of mitigating the worst impacts of global warming and associated climate change. Vibrational spectroscopy can provide essential structural insights into the binding and activation of CO on potential reduction catalysts. The nature of carbon dioxide adsorption on rhodium cluster anions, Rh ( = 3-12), has been investigated using a combination of infrared free-electron laser spectroscopy and quantum chemical calculations. A clear cluster-size dependence to the nature of the binding is observed. On the smallest clusters, Rh ( ≤ 4), CO is dissociatively adsorbed, as indicated by a carbonyl stretch at 1880 cm. By contrast, larger clusters, Rh ( ≥ 7), exhibit highly activated molecular binding, but both motifs are observed on intermediate cluster sizes ( = 5, 6). The extent of chemical activation is clearly discernible spectroscopically and arises from the propensity of CO to attach across Rh-Rh bridge sites, coupled with significant electron transfer from the metal cluster.
Polyketide synthase (PKS) is an ingenious core machine that produces structurally diverse polyketides. Here, we report an unusual iterative type I PKS encoded in the biosynthetic gene cluster of the uridine-derived lipo...Polyketide synthase (PKS) is an ingenious core machine that produces structurally diverse polyketides. Here, we report an unusual iterative type I PKS encoded in the biosynthetic gene cluster of the uridine-derived liponucleoside antibiotic A-94964. While sequence analysis classifies this system as a type I PKS, its domain architecture diverges from that of canonical systems with the individual domains dispersed across four separate proteins. Functional assignments of individual domains were established by heterologous coexpression and in vitro reconstitution. These analyses revealed that this PKS iteratively catalyzes multiple reactions to construct the complex acyl side chain of A-94964, which remains tethered to the ACP domain. The ACP-bound acyl side chain is subsequently transferred to the nucleoside core by an atypical -acetyltransferase, Anb3, which, in complex with Anb9, recognizes ACP-tethered acyl intermediates rather than free acyl-CoA substrates. Phylogenetic analysis suggests that AnbPKSs are related to noncanonical PKS systems such as polyunsaturated fatty acid (PUFA) synthases and enediyne synthases. Based on the distinctive domain architecture and reaction features, we describe this system as a "discrete iterative type I PKS system", thereby expanding the architectural and mechanistic diversity of type I PKSs.
Yamashita A, Mizuno R, Ochi M
… +13 more, Kojima T, Saito H, Nakajima T, Nakao A, Kimata M, Kondo M, Tokunaga M, Kida T, Hagiwara M, Nishi M, Murakawa H, Hanasaki N, Sakai H
Square-net compounds with the HfCuSi-type framework have been a promising platform for realizing topological electronic states and their interplay with quantum many-body phenomena. In these materials, the transition-meta...Square-net compounds with the HfCuSi-type framework have been a promising platform for realizing topological electronic states and their interplay with quantum many-body phenomena. In these materials, the transition-metal tetrahedral layer sandwiched between square-net layers plays a crucial role in determining the correlated physical properties, yet their structural variety has been limited to the single-layer type. Here, we report the discovery of CeAuGeBi, a new square-net compound that represents the bilayer member of a homologous series bridging the HfCuSi-type CeAuBi (112 phase) and ThCrSi-type CeAuGe (122 phase). The bilayer structure of CeAuGeBi is formed by combining two tetrahedral layers of the 112 phase through the insertion of a 122-like block, resulting in two mixed-anion antifluorite-type layers. Intriguingly, both the magnetic and electronic structures are substantially modified relative to the 112 phase. Single-crystal neutron diffraction reveals that the triple Ce layers coordinated by the tetrahedral bilayer exhibit a ferrimagnetic (up-down-up) order, which can be viewed as a combination of the antiferromagnetic orders in the 112 and 122 phases. First-principles calculations demonstrate that hybridization between Ce 5-orbital in the spacer layer and Bi 6-orbital in the square-net layer reshapes the band dispersion into a type-II Dirac-like band. Consistently, magnetotransport measurements show pronounced quantum oscillations with multiple frequencies and extremely light effective masses. These results establish CeAuGeBi as a prototype of a new homologous family of square-net-based topological magnets, where both magnetic order and Dirac-like band can be tuned by controlling the number of spacer layers. This tunable structural framework offers a strategy for the rational design of square-net materials with tailored functionalities.
Herein, by integrating benzo[1,2-:4,5-']bis([1,2,5]thiadiazole) with strong electron-withdrawing capacity and 4,4'-azanediyldibenzoic acid with strong electron-donating capacity into one donor-acceptor-donor type organic...Herein, by integrating benzo[1,2-:4,5-']bis([1,2,5]thiadiazole) with strong electron-withdrawing capacity and 4,4'-azanediyldibenzoic acid with strong electron-donating capacity into one donor-acceptor-donor type organic linker, a near-infrared-II (NIR-II) emissive zirconium-tetracarboxylate framework, HIAM-4030, was reported. HIAM-4030 possesses an topology and shows a maximum emission peak at 1052 nm. The HIAM-4030-based nanocomposite exhibits targeted delivery, anti-inflammatory efficacy, and real-time, noninvasive visualization of inflammatory bowel disease via NIR-II fluorescence imaging. This work sheds light on the rational design and construction of luminescent metal-organic frameworks with NIR-II emission behaviors for biomedical applications.
Toward the development of new separation strategies for rare earth elements (REs; La-Lu, Y, Sc), the discovery of divergent reactivity for RE complexes is an essential first step. We report the synthesis, photophysical c...Toward the development of new separation strategies for rare earth elements (REs; La-Lu, Y, Sc), the discovery of divergent reactivity for RE complexes is an essential first step. We report the synthesis, photophysical characterization, and photodimerization reactivity of a series of kinetically inert rare earth coordination compounds encapsulated by a 1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid (DO3A) ligand appended with a triazole-bridged anthracene arm, RE(DO3A-anthracene), (RE = La-Pr, Sm-Lu, Y). Ultraviolet (UV) light irradiation of all compounds produces the respective photodimers, . The reaction kinetics are studied using UV-vis spectroscopy and are found to have no correlation with the size of the RE cation, a rare outcome in rare earth chemistry. A dichotomy is found between diamagnetic, fast-reacting congeners and paramagnetic, slow-reacting congeners, with , , and as notable paramagnetic, fast-reacting exceptions. We hypothesize that photodimerization can occur for this system by a singlet and/or triplet pathway, the latter of which can be suppressed by the addition of a triplet quencher (cyclooctatetraene, COT), which promotes the singlet-only pathway. The reaction rates of the singlet-only pathway correlate well with the fluorescence lifetimes of . The findings presented here are discussed in the context of a previously reported solid-state photodimerization of a series of anthracene-based rare earth compounds, wherein differences are attributed to the intermediacy of an excimer in the solid-state reaction; no such intermediacy is observed in the present solution studies. This study lays key groundwork for a selective rare earth separation system based on anthracene photodimerization, where kinetic selectivity is achieved through excited-state quenching.
Recognition-encoded melamine oligomers (REMO) equipped with complementary 4-nitrophenol () and phosphine oxide () side chains show sequence-dependent folding properties that resemble the folding of single-stranded nuclei...Recognition-encoded melamine oligomers (REMO) equipped with complementary 4-nitrophenol () and phosphine oxide () side chains show sequence-dependent folding properties that resemble the folding of single-stranded nucleic acids. Automated solid phase synthesis was used to obtain a series of REMO with an at one end of the chain and a at the other. The two complementary recognition units were separated by 0-8 blanks (, triazines equipped with alkyl side chains). UV-vis absorption denaturation experiments with perfluoro--butanol in dichloromethane solution were used to quantify intramolecular 4-nitrophenol·phosphine oxide base-pairing in these oligomers. 1,2-Folding was not detected, but the other oligomers populate 50-90% of the folded state depending on sequence. Another series of oligomers with two complementary recognition units at each end of the chain was used to investigate folding of hairpin loop and helical structures. In these systems, the folded single strand makes two base-pairing interactions, so folding is governed by the effective molarities for the two intramolecular H-bonds, EM, and a cooperativity parameter, α. At least four looped-out bases are required to form a stable hairpin: two hairpin sequences, and , showed strong positive allosteric cooperativity (α > 10) with 96% population of the folded state. The helical sequence, , which showed strong positive cooperativity is consistent with a hexagonal grid model for the conformation of the backbone. These sequence-structure relationships show that favorable folding motifs arise when the positions of complementary recognition sites align with the conformational preferences of the triazine-piperazine backbone.
Dynamic molecular crystals capable of undergoing cooperative structural transformations offer exciting prospects for next-generation actuators, sensors, and stimuli-responsive materials. However, realizing large-scale de...Dynamic molecular crystals capable of undergoing cooperative structural transformations offer exciting prospects for next-generation actuators, sensors, and stimuli-responsive materials. However, realizing large-scale deformation in the solid state─particularly through torsional mechanisms─remains rare. Here, we examine a cyanostilbene derivative, αDDDCS, that exhibits solid-state twist elasticity enabled by cooperative conformational torsion and packing motif conversion. This system features three enantiotropic polymorphs that interconvert through thermoelastic and mechanosalient phase transitions, reflecting a competition between thermodynamic stability and kinetic accessibility, including a Y → C thermoelastic transformation involving a 27% lattice elongation─among the largest reported to date. Single-crystal X-ray diffraction, variable-temperature characterization, and quantum chemical calculations reveal that the transformation proceeds through a π-stacking-to-μ-herringbone transition, governed by a distinct torsional barrier and polymorph-specific free energy landscape. Remarkably, this is the first demonstration of twist elasticity accessed via mechanosalient actuation. Our findings establish conformational twist as a viable molecular design element for achieving high-strain responsiveness in dynamic crystals.
Ribosomally synthesized and post-translationally modified peptides (RiPPs) continue to provide a rich source of structurally diverse and bioactive natural products, yet radical -adenosylmethionine (rSAM)-catalyzed C-C bo...Ribosomally synthesized and post-translationally modified peptides (RiPPs) continue to provide a rich source of structurally diverse and bioactive natural products, yet radical -adenosylmethionine (rSAM)-catalyzed C-C bond formation remains unexplored in lanthipeptide biosynthesis. Here, we report the discovery of azepinopeptide A, a new class of lanthipeptides featuring an unprecedented tetrahydropyrrolo[1',2':1,2]azepino[3,4-]indole scaffold formed through rSAM-catalyzed cross-linking of adjacent Trp1 and Pro2 residues. This unusual sp-sp C-C bond formation, which has not been observed in any previously characterized rSAM enzyme-catalyzed RiPP, is mediated by a distinct subclass of lanthipeptide rSAM enzymes. Biochemical reconstitution and mutational analyses demonstrate that these enzymes exclusively recognize the mature, leader-free lanthipeptide substrate and lack both the RiPP recognition element and the auxiliary iron-sulfur cluster that are essential in other RiPP rSAM systems. Computational structural analysis, supported by co-expression studies, reveals a specialized binding pocket capable of accommodating the lanthipeptide substrate and positioning the catalytic [4Fe-4S] cluster deep within the pocket. This arrangement provides a basis for the observed regioselectivity and strict requirement for leader peptide removal. Azepinopeptides A and B exhibit potent neuroprotective activity at low concentrations comparable to that of the positive control, 3--butylphthalide. Bioinformatic analyses further uncover hundreds of related biosynthetic gene clusters, highlighting the prevalence of this biosynthetic strategy. Together, these findings expand the catalytic repertoire of rSAM enzymes and introduce a new platform for the biosynthetic generation of medium-sized ring peptide architectures with therapeutic potential.
Extended solids that combine unpaired electron spin and structural chirality can host unconventional magnetic behaviors with potential for electronic technologies. A versatile strategy for creating chiral solids is incor...Extended solids that combine unpaired electron spin and structural chirality can host unconventional magnetic behaviors with potential for electronic technologies. A versatile strategy for creating chiral solids is incorporation of chiral organic molecules into inorganic crystals. However, such hybrid organic-inorganic materials have so far been examined through the lens of absolute chirality, leaving enantiomeric excess () underexplored as a tuning parameter. Here, we report two-dimensional (2D) intercalation compounds with controllable produced by cation exchange of MnPS with chiral organic molecules. We show that these materials' magnetism is determined by intercalant rather than absolute chirality. Moreover, low- materials display thermally activated dynamic magnetism absent from enantiopure analogs. These -dependent magnetic behaviors are explained by local ordering of Mn vacancies, directed by correlated vacancy-intercalant electrostatics and confined molecular packing. Together, these results demonstrate a distinctive tuning strategy for molecule-material hybrids and establish design principles for 2D chiral and magnetically dynamic materials.
[NiFe] hydrogenases catalyze reversible oxidation of molecular hydrogen (H) through four redox states (Ni-SI, Ni-L, Ni-C, Ni-R), yet the spectroscopic heterogeneity of the Ni-L and Ni-R intermediates has long obscured th...[NiFe] hydrogenases catalyze reversible oxidation of molecular hydrogen (H) through four redox states (Ni-SI, Ni-L, Ni-C, Ni-R), yet the spectroscopic heterogeneity of the Ni-L and Ni-R intermediates has long obscured their mechanistic roles. Using multiscale quantum mechanics/molecular mechanics (QM/MM) calculations, long-time scale molecular dynamics (MD), quantum cluster models, and electron paramagnetic resonance (EPR) and infrared spectroscopy (IR) spectroscopy simulations, we resolve the structural and electronic origins of this heterogeneity. We show that the spectroscopic heterogeneity of Ni-L and Ni-R arises from Cys546-protonated and Glu34-protonated configurations (residue numbering based on Miyazaki F, referred as MF hereafter) along the proton-transfer coordinate, thermodynamically favoring the Glu34-protonated form. A conserved Cys546-Glu34 proton-sharing motif is stabilized by conformationally flexible second-sphere residues Thr18 and Arg479, which strongly modulate catalytic-state energetics and govern proton localization in both Ni-L and Ni-R. Only Glu34-protonated models quantitatively reproduce experimental EPR -tensors and hyperfine couplings constants (HFC), while Cys546 deprotonation yields characteristic CO/CN red shifts. These results, established for the O-sensitive MF and further supported by analogous protonation energetics in the O-tolerant Hyd-1, suggest that the Cys-Glu proton-sharing motif and its second-sphere gating mechanism may be broadly conserved within Group 1 [NiFe] hydrogenases. These findings reconcile long-standing models of Ni-L/Ni-R heterogeneity and reveal how second-sphere dynamics gate proton transfer in [NiFe] hydrogenase, offering design principles for next-generation bioinspired hydrogen-evolution catalysts.
Aryl C-glycosides represent a valuable class of carbohydrates with broad biological activity in drug discovery, yet their rapid and stereoselective synthesis from unprotected native saccharides remains a significant chal...Aryl C-glycosides represent a valuable class of carbohydrates with broad biological activity in drug discovery, yet their rapid and stereoselective synthesis from unprotected native saccharides remains a significant challenge. Here we report a nickel-catalyzed, ligand-promoted stereoselective C1-arylation of unprotected saccharides with aryl bromides, enabled by glycosyl sulfonylhydrazide donors that are accessible in one step from native sugars. Notably, a series of -disulfonylpyridinedicarboxamidine tridentate ligands was developed and found to be critical for achieving both high reactivity and anomeric selectivity. The present method accommodates a broad range of aryl and heteroaryl bromides and is applicable to diverse mono- and oligosaccharides. To showcase the synthetic utility of this approach, we constructed a Taxol-sugar conjugate library. anticancer activity studies revealed that most conjugates retained significant antiproliferative activity against the tested cancer cell lines, while compound was identified as selectively targeting glucose-dependent cancer cells with markedly improved water solubility compared with Taxol, emerging as a promising lead compound for cancer therapy.
J Am Chem Soc
· 2026 Jun · PMID 42381376
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We report an anion photoelectron spectroscopic study of the photodetachment of uranium hexafluoride anion (UF) to neutral UF, the primary species involved in uranium isotopic enrichment. The adiabatic electron affinity (...We report an anion photoelectron spectroscopic study of the photodetachment of uranium hexafluoride anion (UF) to neutral UF, the primary species involved in uranium isotopic enrichment. The adiabatic electron affinity (AEA) of UF and the vertical detachment energy (VDE) of UF, both predicted using high-level relativistic coupled-cluster calculations, provided unequivocal support for the assignment of the observed spectral features in the anion photoelectron spectrum of UF. The experimental AEA value of UF and the VDE value of UF were determined to be 5.05 ± 0.10 eV and 5.66 ± 0.10 eV, respectively. This work provides the first direct, spectroscopic determination of the electron affinity of UF.
Wang JH, Lee LC, Yip AM
… +4 more, Shum J, Cheng QH, Mak EC, Lo KK
J Am Chem Soc
· 2026 Jun · PMID 42381286
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Photodynamic therapy (PDT) is effective for localized cancers, but its reliance on external light limits treatment depth and uniformity. Herein, we report a programmable supramolecular chemiluminescence (CL)-induced PDT...Photodynamic therapy (PDT) is effective for localized cancers, but its reliance on external light limits treatment depth and uniformity. Herein, we report a programmable supramolecular chemiluminescence (CL)-induced PDT platform that generates reactive oxygen species (ROS) in the absence of light irradiation and displays intrinsic cancer selectivity. This platform is constructed through the supramolecular interaction between enzyme-responsive chemiluminescent spiroadamantyl phenoxy-1,2-dioxetane probes (, , and ) and luminescent iridium(III) complexes bearing a trimethyl-β-cyclodextrin (TMCD) host [Ir(NC)(bpy-TMCD)](Cl) (HNC = 2-phenylpyridine (Hppy) (), 2-phenylquinoline (Hpq) (), and 2-(1-naphthyl)benzothiazole (Hbsn) ()). The chemiluminescent probes exhibited CL upon reaction with alkaline phosphatase (ALP), porcine liver esterase (PLE), and β-galactosidase (β-gal); while the iridium(III) complexes showed intense phosphorescence with efficient singlet oxygen production, distinct intracellular localization, and tunable (photo)cytotoxicity. In aqueous solutions, mixing the chemiluminescent probes with TMCD-tagged iridium(III) complexes afforded supramolecular adducts that, upon enzyme activation, underwent chemiluminescence resonance energy transfer (CRET) from the dioxetane donors to the iridium(III) acceptors. Remarkably, the ALP-responsive conjugate formed from probe and complex (adduct ) selectively generated ROS and elicited potent cytotoxicity in cancerous HeLa cells and spheroids under light-free conditions, with apoptosis as the predominant cell death pathway, while remaining noncytotoxic in normal HEK293 cells. This modular platform couples supramolecular host-guest assembly, enzyme-specific activation, and CRET-induced ROS generation to overcome the limitations of conventional PDT, enabling cancer-selective, light-free therapy.
Zhang X, Tao Y, Yang C
… +19 more, Zhou Q, Luo L, Wang B, Ding J, Chen T, Yang C, Wang J, Wang Y, Hu H, Bo S, Feng X, Zhao J, Liu Q, Zheng K, Sun H, Liu L, Su C, Zhang T, Liu B
J Am Chem Soc
· 2026 Jun · PMID 42381227
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Photocatalytic HO synthesis via the two-electron O reduction reaction (2e ORR) is attractive, yet the interplay between active-site-mediated excited-state electron behavior and O activation at the atomic scale remains u...Photocatalytic HO synthesis via the two-electron O reduction reaction (2e ORR) is attractive, yet the interplay between active-site-mediated excited-state electron behavior and O activation at the atomic scale remains unclear. Herein, we establish a mechanism-guided integrated strategy combining theoretical screening, experimental construction, and characterization to identify Ta single-atom sites as the optimal 5d metal centers on carbon nitride for HO photosynthesis. The resulting catalyst combines favorable excited-state charge localization with thermodynamic advantages for the 2e ORR, achieving an apparent quantum yield of 14.53% at 420 nm and a solar-to-chemical conversion efficiency of 1.12% in pure water. Multidimensional spectroscopy measurements and theoretical calculations demonstrate that Ta single-atom sites act as dynamically adaptive catalytic centers through flexible valence-state evolution (+4.16 → +4.37 → +3.14), facilitating initial O adsorption and then accumulating and transferring excited-state electrons to drive end-on O activation through Ta 5d-O 2p orbital coupling, thereby accelerating *OOH-mediated selective HO formation. This work establishes a framework for understanding dynamic single-atom photocatalysis and guiding the design of adaptive active sites for artificial HO photosynthesis.
J Am Chem Soc
· 2026 Jun · PMID 42380088
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We developed a photoredox strategy for the highly regioselective oxygenation of tertiary allylic and propargylic C-H bonds with alcohols or water nucleophiles. The reaction proceeds via a redox-gated radical-polar-crosso...We developed a photoredox strategy for the highly regioselective oxygenation of tertiary allylic and propargylic C-H bonds with alcohols or water nucleophiles. The reaction proceeds via a redox-gated radical-polar-crossover pathway, in which intermolecular hydrogen atom transfer generates allylic radicals that are selectively oxidized to carbocations only at tertiary sites, enabling a subsequent C-O bond formation by trapping with oxygen nucleophiles. This approach overrides the inherent preference for less hindered positions in classical metal-catalyzed π-allyl chemistry. The method accommodates internal alkenes, alkynes, and diverse alcohol nucleophiles, including complex bioactive substrates, and enables both intermolecular and intramolecular modes of oxygenation.
Kikkawa K, Goswami A, Morishita K
… +3 more, Wang H, Nakamura T, Aida T
J Am Chem Soc
· 2026 Jun · PMID 42378691
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Tough adhesion, combining high levels of both adhesive strength and ductility, is important for a wide range of everyday applications, but achieving it remains challenging because of the strength-ductility trade-off. Cur...Tough adhesion, combining high levels of both adhesive strength and ductility, is important for a wide range of everyday applications, but achieving it remains challenging because of the strength-ductility trade-off. Currently, only a few polymer adhesives provide tough adhesion by addressing this trade-off. In contrast, small-molecule adhesives offer advantages such as easy removability and recyclability; however, none have been reported to achieve tough adhesion because they cannot form entangled networks necessary for the emergence of ductility. Here, we report fluoro-crown ether phosphates such as FP-fmoc as the first small-molecule adhesives that enable highly strong and ductile adhesion to a broad range of materials. Yet, they are readily removable by washing with ethanol. Notably, FP-fmoc exhibits tough adhesion to polytetrafluoroethylene (PTFE), whose surface is highly inert and difficult to bond. By integrating multiple dynamic interactions, including F-F, hydrogen bonding, and π-π stacking interactions, FP-fmoc achieves an unprecedented level of ductility despite being a small molecule. Detailed investigations using solid-state NMR and FT-IR revealed that FP-fmoc forms F-F interactions with the surface of PTFE.
J Am Chem Soc
· 2026 Jun · PMID 42378465
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Developing efficient bifunctional electrocatalysts for the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) is crucial for metal-air batteries and regenerative fuel cells. Among the most promising cand...Developing efficient bifunctional electrocatalysts for the oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) is crucial for metal-air batteries and regenerative fuel cells. Among the most promising candidates, transition-metal single-atom catalysts (SACs) supported on N-doped graphene offer high atomic utilization and tunable coordination environments, but their rational design remains challenging because their molecule-like electronic states often fall outside conventional descriptor frameworks based on linear scaling relations or -band concepts. Here, we show that the bifunctional activity of these SACs is governed by an electron-counting rule defined by the total number of metal and valence electrons, Nds. By combining subgroup discovery, first-principles calculations, projected-density-of-states and COHP analyses, we uncover a three-regime adsorption mechanism in which intermediate binding is controlled by the interplay among metal-adsorbate hybridization, antibonding-state occupation, and shell saturation. As Nds increases, the adsorption strength first increases, then decreases, and finally partially recovers, leading to a nonmonotonic periodic dependence of the binding energies of *OH, *O, and *OOH, and consequently of bifunctional ORR/OER activity. Guided by this mechanism, we develop physics-informed predictive models that enable high-throughput screening of more than 1000 candidate SACs and identify optimal bifunctional systems. Experimental synthesis and electrochemical characterization of Rh-SAC and Co-SAC systems confirm the predicted trends and their benchmark-level bifunctional performance. These results establish electron counting as a unifying physical principle for oxygen electrocatalysis on single-atom catalysts and provide a general route toward mechanism-driven catalyst discovery.
Liu Y, Pieters S, Bineva-Todd G
… +12 more, Sagiroglugil M, Burnap SA, Hoddle F, Cioce A, Ohara A, Schmidt SD, Bruemmer K, Bertozzi CR, Polizzi K, Struwe WB, Rovira C, Schumann B
J Am Chem Soc
· 2026 Jun · PMID 42378460
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Asparagine-linked protein glycosylation is among the most frequent modifications of proteins trafficking through the secretory pathway. These glycans are manufactured in an assembly line process, yielding a common precur...Asparagine-linked protein glycosylation is among the most frequent modifications of proteins trafficking through the secretory pathway. These glycans are manufactured in an assembly line process, yielding a common precursor that is then subjected to individual modifications with different levels of complexity. An important biosynthetic modulator is the incorporation of -acetylglucosamine (GlcNAc) at distinct positions in N-linked glycan biosynthesis, commencing with the activity of the glycosyltransferase MGAT1. While mapping of N-glycans to their corresponding protein attachment sites is generally possible, not much is known about the glycoprotein substrate choice for MGAT1 and related transferases. Analogs of GlcNAc with small bioorthogonal tags can be incorporated into N-glycans. However, due to the promiscuity of some GlcNAc transferases, incorporation is of little specificity toward individual positions. Here, we report an iterative bump-and-hole approach for the design of a bioorthogonal precision tool to study the activity of MGAT1 in mammalian cells. Structure-informed protein engineering abrogated the activity of MGAT1 toward the nucleotide-sugar UDP-GlcNAc while retaining activity toward bumped, azide-modified analogs. Kinetic and computational analyses using a neural network approach informed the synthesis of a tailored UDP-GlcNAc analog with preferential acceptance by the engineered enzyme. Following substrate biosynthesis, the strategy allowed selective incorporation of a chemical tag on MGAT1 substrate proteins in living mammalian cells with little background incorporation by other GlcNAc transferases. Our work expands the toolbox for glycan-based reporter compounds.
Shan C, Chen Q, Sun X
… +7 more, Hu S, Bathini T, Yang Z, Chen K, Mou S, Wang R, Tan W
J Am Chem Soc
· 2026 Jun · PMID 42378337
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Aromatic camptothecins (CPTs) are clinically potent TOP1 inhibitors constrained by an "aromaticity-solubility" paradox, which leads to poor bioavailability and efflux-mediated resistance. Here, we report a modular strate...Aromatic camptothecins (CPTs) are clinically potent TOP1 inhibitors constrained by an "aromaticity-solubility" paradox, which leads to poor bioavailability and efflux-mediated resistance. Here, we report a modular strategy to reprogram the planar CPT scaffold into multifunctional topoisomerase I (TOP1) degraders by integrating hydrophobic tagging (HyT) with supramolecular self-assembly. Adamantane HyT introduces an orthogonal aliphatic module, converting classical inhibitors into proteasome-dependent degraders with enhanced membrane permeability while preserving TOP1-DNA binding affinity. This tag synergistically acts as a supramolecular anchor, enabling host-guest assembly with poly(β-cyclodextrin) to form stable, pH-responsive nanoparticles without pharmacophore modification. Our lead candidate, , demonstrates potent TOP1 degradation and achieves superior tumor regression in xenograft models compared to clinical irinotecan. This synergistic HyT-supramolecular approach rebalances aromaticity for optimized drug-like properties, establishing a paradigm to transform solubility-limited warheads into high-performance degraders with integrated delivery.
Zhao H, Qi S, Zhou Z
… +5 more, Zhu C, Liu JC, Yun Y, Zhen N, Zhang L
J Am Chem Soc
· 2026 Jun · PMID 42378237
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The controllable synthesis of metal-oxo clusters (MOCs) is often limited by competing reaction pathways and strongly coupled variables, which hinder the synthetic efficiency and scalability. Here, we develop a machine-le...The controllable synthesis of metal-oxo clusters (MOCs) is often limited by competing reaction pathways and strongly coupled variables, which hinder the synthetic efficiency and scalability. Here, we develop a machine-learning-assisted reaction-space optimization strategy that defines an effective synthetic window through data-driven modeling and key parameter identification, enabling precise control over complex reaction systems. Within this framework, an unprecedented racemic cluster rapidly formed within several seconds at room temperature, and 266 g of phase-pure crystalline product was obtained within 15 min. Under the structure-directing effect of trimethylolpropane ligands, tin species underwent rapid hydrolysis-condensation, while titanium atoms were incorporated through oxo bridge reconstruction. The system rapidly converged to the thermodynamically favored structure, as supported by mass spectrometry and theoretical calculations, enabling highly selective synthesis within seconds. Through modulating the steric hindrance and electronic properties of terminal ligands, truncated tetrahedral units achieved assembly evolution from isolated clusters to supramolecular two-dimensional (2D) layers and three-dimensional (3D) networks via halogen or hydrogen bonding interactions and eventually homochiral metal-organic frameworks (MOFs). Furthermore, the cluster exhibited interesting lithographic applications to achieve a high-resolution performance with a line width of 9.83 nm. This work establishes a generalizable machine-learning-assisted route toward rapid, scalable synthesis of functional metal-oxo clusters.