ACS Central Science最新文献

Inspired by biological rebound processes, radical ligand transfer (RLT) has emerged as a powerful and versatile strategy for the selective functionalization of alkyl radicals. RLT enables direct C–X bond formation through homolytic substitution at a metal-bound ligand (M–X) and demonstrates broad functional group tolerance and high potential for catalysis. Despite growing interest and mechanistic understanding, including recent insights into asynchronous concerted ion–electron transfer (cIET), the broader application of RLT strategies remains underdeveloped. In parallel, the closely related S_H2 (bimolecular homolytic substitution) mechanism has gained increasing utility in C–C bond formation, where low-valent metals capture transient radicals and facilitate selective coupling with persistent radical partners─a process referred to as radical sorting. Herein, we present a comprehensive perspective of the evolving landscape of RLT and S_H2 chemistry, emphasizing recent advances. We highlight key bioinspired and computationally guided approaches that have enhanced mechanistic understanding and broadened the substrate scope, including landmark contributions by Kochi, Groves, Shaik, MacMillan, and others. To complement these studies and encourage further development, we also report DFT-based thermodynamic analyses of radical ligand transfer across first-row transition metal complexes bearing porphyrin and BOX ligands. By unifying these mechanistic frameworks, this perspective aims to provide a roadmap for designing novel, selective, and sustainable radical-based transformations.

Radical ligand transfer (RLT) and bimolecular homolytic substitution (S_H2), employed in synergy with other catalytic platforms, enable selective C−X and C−C bond formation through radical strategies.

More drugs are entering aquatic habitats. Scientists are teasing apart how they influence the behavior, reproduction, and biology of organisms that live there.

Covalent ligands contain an electrophilic moiety that reacts with a nucleophilic residue on a target protein, following an initial reversible binding event. Covalent ligand development typically involves efforts to increase on-target selectivity by maximizing the ligand binding affinity and minimizing intrinsic electrophile reactivity. Problematically, this limits labeling kinetics and requires high affinity ligands. The concept of “latency” describes the potential for “turn-on” activation of electrophiles upon target engagement. Here, we investigate the potential intrinsic latency of covalent electrophiles and test the hypothesis that diverse electrophiles can be differentially activated by proximity effects. We develop a kinetic effective molarity (EM_k) approach to quantitatively characterize kinetics associated with diverse electrophilic reaction mechanisms, both with and without binding proximity effects. We observe that different electrophiles are associated with significantly different EM_k parameters, with SuFEx and acrylamide electrophiles associated with the highest intrinsic latency. Eyring transition state analysis revealed that all covalent ligands, independent of electrophile, benefit from significant transition state entropic stabilization. Strikingly, electrophiles associated with the highest latency are associated with greater relative transition state stabilization with different enthalpic and entropic contributions. These findings quantitatively describe electrophile latency and will aid the mechanism-guided development of next-generation covalent ligands associated with “turn-on” reactivity.

A kinetic effective molarity analysis reveals mechanism-dependent differences in proximity-induced reactivity of covalent electrophiles.

Hydrogen-bonded organic frameworks (HOFs) offer atomic-precision platforms for probing water adsorption, yet monotonic building units often fail to meet the multifaceted demands of atmospheric water harvesting (AWH). In this study, a multivariate (MTV) strategy is employed to tune adsorption onset, work capacity, and cycling stability in HOFs. Introducing amino groups in controlled ratios creates a balance between hydrophilic sites and dynamic confinement within ordered frameworks. Specifically, the parent HOF, PFC-76, was constructed from the organic linker [1,1′:4′,1″-terphenyl]-3,3″,5,5″-tetracarboxylic acid (TPTCA), which assembles into 2D honeycomb networks via carboxylic acid dimer synthons. Functionalizing TPTCA with amino groups modulates the framework’s packing and dynamic behavior. Single-crystal X-ray crystallography revealed sliding dynamics in PFC-76-NH₂ during water adsorption, along with ordered water arrangements within the dynamic confinement spaces. Systematic variation of amino content (50%, 67%, and 80%) generated an atactic distribution of functional groups while maintaining crystallinity and porosity. This compositional tuning enhanced H₂O uptake, optimized the adsorption inflection point, and delivered an outstanding cycling stability. The strategy demonstrates how precise control over functional group incorporation and framework dynamics can yield programmable performance in soft porous crystals for practical applications.

Multivariate HOFs with functional tunable groups balance pore space and adsorption sites, enabling PFC-76-NH₂-67% to achieve high uptake, low energy cost, and excellent cycling in water harvesting.

Mutations in GBA1, the gene encoding the lysosomal hydrolase glucocerebrosidase (GCase), are the strongest common genetic risk factor for Parkinson’s Disease (PD). However, these mutations are incompletely penetrant, which suggests that there are likely genetic modifiers of GCase function. To identify such genes, we implemented a live cell GCase activity-based CRISPR-platform to enable genome-wide screening for novel regulators of lysosomal GCase activity. Among the screening hits, we find significant enrichment of genes linked to development and progression of PD through genome-wide association studies (GWAS). Moreover, we identify two lysosomal lipid transporter genes, including those encoding the lysosphospholipid transporter SPNS1 and the cholesterol transporter NPC1, and find an allele of SPNS1 that is associated with increased risk of PD. We show that disruption of SPNS1 does not affect GCase protein levels but impairs its lysosomal function. Collectively, these data suggest that dysfunction of many PD-associated genes converge to impact lysosomal GCase activity and thereby contribute to disease pathogenesis. A better understanding of the impacts of these and the other GCase modulators identified here should help unravel the important, yet complex, relationship between GBA1 and PD.

A fluorogenic substrate of GCase enables genome-wide screening for genes that influence its activity and reveals candidate risk factors for PD, showcasing the power of activity-based screening.

Pancreatic ductal adenocarcinoma (PDAC) remains refractory to current immune checkpoint blockade (ICB) therapies, necessitating innovative therapeutic strategies. Emerging evidence implicates aberrant sialoglycan upregulation as a key mediator of immune evasion in PDAC. Herein, we report Y-320, a highly potent oral sialylation inhibitor discovered through high-throughput screening. Y-320 suppresses α-2,3/2,6-sialylation in PDAC cells (IC₅₀ ≈ 200 nM) with >300-fold higher activity than the known pan-inhibitor P-3F_ax-Neu5Ac. Structural analyses reveal competitive occupation of multiple sialyltransferases’ substrate-binding pockets as Y-320’s action mechanism. In vivo, Y-320 significantly inhibits tumor growth and remodels the tumor immune microenvironment. Mechanistic studies establish that the therapeutic efficacy of Y-320 depends on the coordinated engagement between CD8⁺ T cell and macrophage. Importantly, Y-320 synergizes with anti-PD-1 therapy to overcome ICB resistance in PDAC, demonstrating superior tumor suppression compared to monotherapies. Our findings demonstrate that Y-320 shows promise for use as a therapeutic agent for cancer and validates sialylation inhibition as a novel glycoimmune checkpoint strategy for PDAC and other immunotherapy-resistant malignancies.

Y-320, an oral sialylation inhibitor identified through high-throughput screening, reduces tumor sialoglycans to block the sialic acid-Siglec immunosuppressive axis and enhance antitumor immunity.

Bioluminescence-assisted photoproximity labeling enables spatial proteome mapping in deep tissues.

The glycosylation of proteins endows them with distinct biophysical properties and allows them to play fundamental roles in cellular communication. Much of our understanding of glycoproteins has derived from the ability to enzymatically manipulate glycan structures. In particular, selective cleavage of glycans from proteins simplifies the analysis of glycoproteins and the determination of structure–activity relationships. However, limited enzymatic tools are available for the study of mucin-type O-glycans. To address this, we carried out the directed evolution of a glycoside hydrolase to increase its ability to cleave the sialyl T-antigen, a ubiquitous O-glycan structure in humans. We employed ultrahigh-throughput droplet-based microfluidics to rapidly screen vast libraries of variants in pL-sized droplets, thus minimizing the quantities of complex substrate required. Furthermore, by use of fluorescent protein-fusion and ratiometric gating during droplet sorting we could account for varying expression levels and identify highly active hits that could have been overlooked due to lower expression levels. Within just two rounds of screening, we uncovered variants with 840-fold enhancements in activity and new specificities compared to those of the WT enzyme. This campaign highlights the versatility of glycoside hydrolases and provides a broadly applicable strategy to engineer enzymatic tools for glycomics through microfluidic screening.

Combining a protein expression reporter with ultrahigh-throughput droplet-based microfluidics enabled us to drastically remodel the active site of a glycoside hydrolase and engineer new activities.

Allylboronic esters are highly versatile intermediates in organic synthesis. In this work, we report a general and scalable strategy for the regioselective deoxygenative borylation of allylic alcohols, enals, enones, and acrylates, upgrading these abundant functional groups in feedstock chemicals and natural products into value-added borylated synthetic handles. This method achieves efficient C–O bond activation under mild electroreductive conditions, and the effective control of regioselectivity was made possible by optimizing the borylating agent and supporting electrolyte. The utility of this approach was further demonstrated in a series of telescoped synthetic sequences, enabling alcohol and carbonyl transposition, formal cross-coupling of alcohols and aldehydes, allylic amination, and vinylogous homologation. This electrosynthetic protocol offers a broadly applicable, modular route to complex allylboron compounds from simple and readily available starting materials, including terpenoid natural products.

Regioselective electrochemical borylation of allylic alcohols, enones, enals, and acrylates is reported, which enables diverse synthetic strategies to upgrade abundant feedstocks and natural products.