JACS Au最新文献

Supercritical fluids (SCFs) play a crucial role in various environmental, geological, and celestial processes primarily due to their unique thermodynamic properties and ability to influence chemical reactions. SCFs are generally thought to modulate reactions through their inhomogeneous microscopic behavior. However, how these microscopic behaviors influence reactions within SCFs remains insufficiently clarified. To solve this, metadynamics is employed to describe the reaction events under actual supercritical conditions (800-1000 K). Through the calculations of the free energy surface of probe reactions, we demonstrate that liquid-like atoms and corresponding high-density clusters, specially forming in supercritical fluids, enhance reactant collisions and thermodynamically stabilize the transition state, while this enhancement mechanism shifts near the Widom line, where further crossings of this line result in excess liquid-like atoms and then limited kinetic diffusion. These findings underscore the connection between the fluid microstructure and chemical reactivity, providing a foundation for advancing the industrial applications of SCFs.

Integrating organismal interaction studies with advanced genomic and metabolomic approaches offer great promise for discovering novel natural products and their derivatives, yet this strategy remains relatively unexplored. Here, we illustrate its potential by investigating a newly isolated Xylaria strain from a termite colony environment through combined genome and metabolome analyses, complemented by fungal-bacterial coculture experiments. Genome sequencing of the fungal strain allowed us to pinpoint a cytochalasin-related biosynthetic gene cluster responsible for the production of a portfolio of different bioactive epoxy-cytochalasins. Guided by the hypothesis of biosynthetic promiscuity of the underlying nonribosomal peptide synthetase (NRPS), we demonstrated for the first time that the NRPS can accept unnatural ortho- and meta-halogenated phenylalanine derivatives, leading to the isolation of multiple new chlorinated and brominated cytochalasin analogs. Second, based on the hypothesis that structural diversification can arise from interactions with commensal organisms, cocultivation with a termite-associated Streptomyces strain led to the discovery of a previously undescribed aspartic acid-containing cytochalasan derivative, designated xylachalasin A. Isotope labeling experiments revealed that bacterial catabolic activity is responsible for the modification of the fungal-derived cytochalasin. Isolated cytochalasins were also amiable for semisynthesis modifications, which was exemplified by the synthesis of bifunctional probes. Bioassays of a total of 26 isolated and semisynthesized derivatives demonstrated structure-dependent cytotoxicity in some cases with up to 3-fold log differences in potency and generally good plasma stability. Overall, our integrated approach underscores the vast potential of investigating fungal strains from underexplored ecological niches and their organismal interactions, offering new opportunities to discover novel natural products of potential therapeutic relevance and previously unrecognized biochemical processes.

Being a noble metal, silver is known for its chemical inertness. Molecular nitrogen, due to its extremely strong covalent triple bond, is also typically considered unreactive. It is thus unsurprising that no credible report on the formation of a thermodynamically stable silver and nitrogen compound exists. In this study, we report the synthesis of silver pentazolate (AgN₅), achieved through the direct reaction of elemental silver with molecular nitrogen at a pressure of 118(3) GPa and a temperature of 2000(200) K. The crystal structure of AgN₅ was determined from synchrotron single-crystal X-ray diffraction (SCXRD) data, revealing it to be comprised of cyclo-N₅ ^- anions. Remarkably, this solid's structure does not correspond to any of the silver nitrides previously predicted. Moreover, density functional theory (DFT)-based enthalpy convex hull calculations demonstrate that this AgN₅ compound is the only thermodynamically stable Ag-N solid between 10 and 120 GPa while also providing information on its phonon and electron band structures, including its electronic band gap. Both DFT calculations and SCXRD experimental data yield insights into the stability pressure range of AgN₅ upon decompression. This study provides yet another example of the capability of high pressure and high temperature to facilitate unprecedented chemical reactions between elements often assumed to be inert, in turn enabling the formation of novel nitrogen-rich compounds.

Chemical tools have allowed the interrogation of molecular events in biological systems through the realization of additive-free labeling approaches such as strain-promoted chemistry. Although design and synthesis of strained compounds remain challenging tasks, efforts to identify an alternative chemical strategy to achieve such additive-free labeling are lacking. Serendipitously, we found that a trifluoroborate unit can act as an auxiliary group to enable the additive-free Friedel-Crafts alkylation reaction at room temperature in the potentially protein-compatible solvent hexafluoroisopropanol (HFIP) without any additional catalysts such as a Lewis acidic metal and a Brønsted acid. The structure-reactivity relationship of a set of thiophene electrophiles for the dehydrative alkylation of tryptophan revealed the inability of various functional groups to cause such an additive-free labeling process, while all of the synthesized trifluoroborate variants displayed substantially enhanced reactivity even in the absence of additives. As the boron moiety serving as an auxiliary group remains on the thiophene unit after the tryptophan bioconjugation, facile secondary functionalization of alkylated tryptophan through boron-based chemistry proved to be possible at a protein level. Because strain-promoted chemistry has shown great promise for diverse applications beyond small-molecule studies by eliminating the need for additives/catalysts, the boron auxiliary approach may be a promising chemical strategy in a wide variety of contexts.

Cadmium chalcogenide quantum dots (CdX QDs, X = S, Se, Te) are among the most extensively studied semiconductor nanocrystals due to their size-tunable optical properties and wide potential applications in optoelectronics, bioimaging, and sensing. While early syntheses relied on high-temperature organometallic routes in organic solvents, the demand for safer, greener, and more biocompatible approaches has driven increasing interest in aqueous-based methods. These two strategies differ substantially in terms of precursor chemistry, surface passivation, and control over nanocrystal quality. In parallel, continuous flow technology has brought transformative assets to the field, offering precise reaction control, scalability, and reproducibility, which are essential for both fundamental studies and industrial translation. This review summarizes the evolution of CdX QDs synthesis, contrasting organic and aqueous batch approaches, and focuses on recent advances in aqueous continuous flow strategies. Finally, we highlight perspectives on the integration of automated machine learning and artificial intelligence approaches with continuous flow, which may accelerate the discovery, optimization, and scalable production of high-quality QDs for next-generation technologies.

The proteoform profile of antibody Fc domains determines antibody effector functions, not only for biopharmaceuticals but also for endogenous antibodies. Endogenous immunoglobulin G (IgG) Fc-proteoforms have been well characterized by using different MS-based approaches, comprising bottom-up and intact Fc domain workflows. However, assessment of IgA1 and IgM Fc domains is still challenging, due to the more complex structure, and analyses have been limited to the peptide level only. In this work, a light-chain affinity capturing workflow combined with isotype-specific hinge-region digestion and subsequent intact Fc domain nanoRP-LC-MS analysis has been developed. The novel approach shows very good sensitivity and precision, enabling simultaneous capturing of antibody isotypes with sequential release and analysis of IgG, IgA1 and IgM Fcs from 10 μL of plasma. Single donor human samples were successfully analyzed, providing a comprehensive overview on Fc proteoforms but also on associated Fc-components such as the joining (J) chain of IgA and IgM and CD5L.

Cubane-type iron-sulfur clusters (Fe₄S₄) are some of the most versatile metallocofactors and, as such, among multiple functions, primarily responsible for mediating challenging electron transfers (ETs). Their efficient ET chemistry is enabled by a conflated interplay of cofactor-protein interactions, which can be categorized into the covalent first (1°) sphere ones and the noncovalent second (2°) sphere ones. The latter have remained particularly elusive, as they are difficult to observe and assess directly and independently. Accordingly, our understanding of these effects is hampered by their entangled nature. To address this, we herein leverage a systematic series of synthetic Fe₄S₄ complexes, which allows spectroscopically investigating 2° sphere electrostatic interactions and covalent 1° sphere interactions separately from one another. We expand the study of 1° sphere interactions with a histidine-type ligand in [Fe₄S₄]¹⁺ complexes to the [Fe₄S₄]²⁺ and [Fe₄S₄]³⁺ oxidation states, supporting the notion that 1° sphere interactions "fine-tune" the electronic/magnetic structure of these systems in a manner that persists at ambient temperatures. In contrast, scrutinizing the 2° sphere electric dipolar interactions in [Fe₄S₄]^1+,2+,3+ complexes revealed that although similar effects are observable at extremely low temperatures, no significant alteration of the clusters' gross electronic/magnetic structure persists at the temperatures relevant to enzyme function. These results thus not only systematically catalogue the influence of 1° sphere covalent and 2° sphere electrostatic interactions on the observables and properties of Fe₄S₄ complexes, but also establish a clear energetic distinction between the two. As such, they will facilitate identifying the elusive 2° sphere interactions in biological systems, while also strengthening our biophysical understanding of structure-function relationships in Fe₄S₄ cofactors.

For peptide-drug conjugate (PDC) development, high-quality peptide ligands with easy functionalization are essential. Combinatorial chemical peptide libraries are key for discovering high-affinity non-natural ligands, yet their utility has long been hindered by low-purity libraries that cause false positives. To address this, we developed an N-terminal cysteine-based dynamic catch-and-release (CbDCR) platform, leveraging its unique 1,2-aminothiol motif as a privileged handle for site-selective orthogonal conjugation, enabling efficient library purification while retaining a universal anchor for downstream functionalization. A recyclable 2-formylphenylboronic acid resin (2FPBA resin) was designed to catch and release N-terminal cysteine-containing peptides in a pH-responsive manner, eliminating the need for complex tags and providing simplicity, scalability, and high purification efficiency through optimized workflows. The platform effectively purifies SPPS-synthesized peptides, enriches N-terminal cysteine-containing peptides from protein lysates, supports high-purity split-and-pool library preparation, and integrates with microplate-based high-throughput workflows. Using a highly pure "RGD"-focused nonstandard library, high-affinity integrin αvβ6-targeting peptides were identified, and three peptide-radionuclide conjugates with potential diagnostic value for pancreatic cancer were constructed via N-terminal cysteine. Overall, CbDCR streamlines library purification, affinity screening, and conjugate construction, accelerating the development of high-value peptide ligands and PDCs.

Glycopeptides and glycoproteins with structural precision are valuable for functional studies and applications. Conventional couplings of glycosyl amino acids are slow, wasteful, and impractical for broad use. To address the fundamental synthetic challenges, the current work presents a new paradigm for glycopeptide synthesis, featuring a key component (thioester-functionalized glycosyl amino acid) and a comprehensive reaction system (AgSbF₆ for activation, Oxyma as an additive, DIPEA as a base, under microwave irradiation). The reaction offers rapid and clean on-resin conversion (10 min), economical reagent use (1 equiv), broad effectiveness across varied glycan structures and multiple peptide coupling sites (27 examples), and readiness to automation. Moreover, it seamlessly integrates with enzymatic glycan elaboration and protein ligation strategies, furnishing glycopeptides and glycoproteins with an increased structural complexity. Taken together, this robust and versatile platform broadens access to complex glycopeptides and glycoproteins, thereby offering a powerful entry point for functional glycoscience and biomedical discovery.

Amyloid fibrils formed by the protein α-synuclein are implicated in the pathogenesis of synucleinopathies. In addition to their rigid cross-β core, these fibrils have intrinsically disordered regions on their surface, which are important for interactions with other cellular components, such as chaperones. Chaperones play a vital role in preventing and reversing amyloid formation in neurodegenerative diseases. How they recognize misfolded proteins is an active field of research. DNAJB1 is a cochaperone that recognizes fibrils and recruits other chaperones such as Hsp70 and Apg2, which collectively disaggregate fibrils formed by α-synuclein, tau, and huntingtin. Because DNAJB1 was reported to bind the C-terminus of α-synuclein and S129 in this C-terminus is predominantly phosphorylated in patient-derived fibrils, we wanted to determine the effect of this post-translational modification on DNAJB1 binding. Using electron micrographs, NMR spectroscopy, and binding assays, we show that phosphorylation at S129 reduces the dynamics of the intrinsically disordered C-terminus of α-synuclein fibrils and increases the binding of DNAJB1 to this very C-terminus. MD simulations further suggest that the reduced dynamics is due to increased interaction of the phosphorylated C-terminus with the fibril core. DNAJB1 binds the exact same region at the C-terminus, indicating the phosphorylation at S129 might have a dual effect of reducing fibril surface dynamics and increasing chaperone recognition.