JACS Au最新文献

Substituent functionalization of unprotected and partially protected carbohydrates with controlled regioselectivity remains challenging due to the difficulty in differentiating hydroxyl groups with similar reactivities. This study presents an efficient protocol for site-specific modification through a "two-stage," regiodivergent polyol tagging and functionalization strategy. To achieve effective tagging, we developed two complementary Ag₂CO₃-ligand-based regimes that enable the regioselective sulfonylation of cis-diol and trans-diol in carbohydrates, controlled by simply toggling the presence of a [Pd] catalyst. Competition experiments and DFT simulations elucidated the underlying dual mechanisms accounting for the regioselectivity. [Pd] catalyst complexes to cis-diol as a bidentate ligand, enhancing the differentiated electrophilicities through stereoelectronic effects and preferentially activating the equatorial C3-OH groups. Conversely, without [Pd], the Ag-(I) complex switches the reaction position, directing sulfonylation to the axial hydroxyl within 1,2-cis-diol, a position that is typically kinetically inert under conventional conditions. And the Ag-(I) complex preferentially coordinates to cis-1,2-substituents on the sugar ring and selectively activates the C2-OH group. The sulfonylated products serve as versatile synthons for the following structural derivations and chemical glycosylations, facilitating efficient access to structurally unique rare sugars, deoxy- and aminosugar analogues, and complex oligosaccharides. This dual-catalytic approach provides a robust platform for precision carbohydrate engineering, advancing the synthesis of biologically relevant oligosaccharides and glycoconjugates.

Microviridins are ribosomally synthesized and post-translationally modified peptides, typically featuring a conserved tricyclic structure formed by two ATP-grasp ligases. However, the diversity and evolution of these enzymes remain incompletely understood. Here, we identify a distinct ATP-grasp ligase subclade (MyxF) that specifically modifies the conserved (KxxE)_n motif, defining a new subclass of microviridins with the (KxxE)_nTxKxPSDx-(D/E)-(D/E) sequence signature. Guided by SSN analysis, we discovered a deep-sea myx biosynthetic gene cluster from 10,000 m sediments and heterologously expressed two pentacyclic microviridin-like peptides, Myxomiditide A and B. Using mass spectrometry and NMR, we fully elucidated their chemical structures, revealing not only the conserved tricyclic core but also two additional N-terminal lactam rings within the KxxEKxxE motif, distinguishing them from known microviridins. Combined in vivo coexpression and in vitro reconstitution uncovered a noncanonical division of labor among four ATP-grasp ligases involved in myxomiditide biosynthesis. MyxF and MyxD1 act as functional isozymes responsible for installation of the N-terminal lactam moieties, whereas MyxD2catalytically inactive on its ownrequires the synergistic presence of both MyxF and MyxD1 to enable formation of the C-terminal lactone rings. The pathway is finalized by MyxC, which catalyzes the terminal lactam macrocyclization, collectively revealing a highly cooperative enzymatic assembly mechanism governing myxomiditide maturation. Furthermore, MyxF exhibited remarkable catalytic plasticity, catalyzing multiple lactam macrocyclizations beyond its native substrate architecture. Notably, Myxomiditide A potently inhibited elastase with nanomolar IC₅₀ values. Collectively, this study expands the enzymatic landscape of ATP-grasp ligases and highlights the deep sea as a rich source of evolutionary innovation in RiPP biosynthesis.

Herein, we unveil an efficient palladium-(II)-catalyzed three-component strategy for the regioselective difunctionalization of unactivated alkenes resulting in γ-selective heteroarylation via cascade cyclization of nucleophile-tethered alkynes. The developed protocol utilizes economically viable aryl, alkenyl, and alkyl halides as electrophilic coupling partners for β-selective incorporation. The reaction is distinguished by its operational simplicity, exhibits broad substrate scope, and retains high catalytic efficiency even in the presence of various pharmacologically relevant motifs. Furthermore, the synthetic approach was expanded to enable cascade borylation under oxidative conditions employing B₂Pin₂ providing access to C-(sp³)-B scaffolds. Notably, this work demonstrates cascade cyclization-driven dicarbofunctionalizations of unactivated alkenes, establishing a valuable synthetic tool for the streamlined assembly of complex heterocyclic molecular frameworks.

A series of tunable morphological nanoaggregates are constructed by hydroxypropyl-β/γ-cyclodextrin (HPβ/γCD) and cucurbit[8]-uril (CB[8]), respectively, encapsulating phenylalanine dipeptide-modified pyrene (PFF) based on host-guest complexation, which not only exhibits a topological transformation from helical nanofibers of PFF to supramolecular nanoparticles, nanotubes, and nanosheets but also induces chiral transmission from phenylalanine dipeptide to pyrene moiety achieving temperature-controlled supramolecular chiral switches. Unlike the encapsulation of HPβCD to PFF at a 1:1 stoichiometric ratio, HPγCD with larger cavity can encapsulate two PFFs, achieving enhanced fluorescence behavior with quantum yield increasing from 1.66% to 32.14% and circular dichroism (CD) with a negative Cotton effect peak at 440 nm with an asymmetric factor (g _abs) of -1.44 × 10^-4. Compared with HPβ/γCD, CB[8] gives a stronger binding affinity of up to 5.99 × 10⁵ M^-1 and a significant positive CD peak at 450 nm. Molecular dynamics and density functional theory calculations reveal that HPγCD and CB[8] could effectively disrupt the symmetric aggregates and restrict the conformations of PFF to realize the efficient chiroptical transmission. Moreover, PFF-HPγCD and PFF-CB[8] supramolecular chiral switches exhibit reversible thermal responsiveness (20-75 °C) and positive circularly polarized luminescence, which are successfully applied to chiral logic gate and polarization-dependent encryption.

In the framework of developing artificial metalloenzyme (ArM) prodrug therapies, two main factors need to be considered; the cancer targeting capabilities of the ArM biocatalyst and the bioorthogonal prodrug activation mechanism. In this study, both these aspects were investigated to develop an example of an anticancer ArM prodrug strategy. To address targeting, the concept of multivalent lectin-directed artificial metalloenzymes was established using a Halotag-PduU-ACG lectin fusion protein (HtPA) functionalized with a gold catalyst. Acting through multivalent binding of hexameric lectin complexes (caused by PduU oligomerization), selective binding to sialic acid-rich cancer cells was proven. To address prodrug activation, the propargylbenzoxime (PBO) group was developed to undergo gold-catalyzed hydroamination, followed by spontaneous N-O bond cleavage to release carbonyl functional groups under mild and physiological conditions. Further adaptation of the PBO group was also explored so that carbonyl release could elicit the synthesis of indole-containing molecules. HtPA-based artificial metalloenzymes were then subsequently applied in cell assays for the activation of a PBO-based prodrug to highlight this alternative approach of an ArM prodrug therapy.

DNA methylation and histone modifications are critical epigenetic regulators that orchestrate gene expression and modulate various physiological and pathological processes. However, existing methodologies for simultaneous profiling of these epigenetic marks often require high cell input and suffer from data loss due to bisulfite conversion. In this study, we present advanced multimodal chromatin profiling methods, MethylTag and Multi-MethylTag, that address these challenges by integrating Tn5 transposase with methylated adaptors and optimizing postbisulfite library preparation. These methods enable high-resolution, multidimensional chromatin profiling with reduced cell input and improved data integrity. We validated these techniques in various human and mouse cell lines, revealing complex interactions between DNA methylation and histone modifications. Our findings highlight the utility of these approaches in enhancing epigenetic research and deepening our understanding of the regulatory mechanisms underlying gene expression.

The most fundamental abstraction underlying all modern computers is the Turing Machine, that is, if any modern computer can simulate a Turing Machine, an equivalence which is called "Turing completeness", it is theoretically possible to achieve any task that can be algorithmically described by executing a series of discrete unit operations. In chemistry, the ability to program chemical processes and ensure unit operations are understood at a high level of abstraction and then reduced to practice is extremely challenging. Herein, we exploit the concept of Turing completeness applied to robotic chemical platforms that execute unit operations to synthesize complex molecules using a chemically aware programming language, XDL. We leverage the concept of computability by computers to synthesizability of chemical compounds by automated synthesis machines. The results of an interactive demonstration of Turing completeness using the color gamut and conditional logic are presented to serve as a proxy for conceptual, chemical space exploration. This formal description establishes a formal framework in future chemical programming languages to ensure complex logic operations are expressed and executed correctly, with the possibility of error correction, in the autonomous pursuit of increasingly complex molecules.

The COVID-19 pandemic spurred the rapid development of nirmatrelvir, a main protease (M^pro) inhibitor now widely prescribed as part of Paxlovid (nirmatrelvir plus ritonavir). However, increasing use has raised concerns about drug resistance. Resistance selection studies have identified multiple M^pro mutations, with E166V emerging as a particularly resistant variant. Sequencing data from COVID-19 patients confirms E166V as a clinically relevant mutation, and importantly, this substitution also confers cross-resistance to several next-generation M^pro inhibitors under development. In response, this study reports the rational design of inhibitors active against nirmatrelvir-resistant E166V/A mutants. The lead candidate, Jun13698, shows potent inhibition of both wild-type M^pro and the E166V/A mutants. Structural studies and molecular dynamics simulations reveal that Jun13698 forms stable complexes with wild-type and mutant proteases, consistent with its potent enzymatic and antiviral activity. Together, these findings position Jun13698 as a promising next-generation M^pro inhibitor capable of overcoming clinically relevant nirmatrelvir resistance.

Csp ³-Cl bonds are essential as diversification handles in organic synthesis and are found in many natural products and bioactive molecules. In this work, we introduce a general protocol for the selective chlorination of aryl cyclopropanes, olefins, and activated C-H bonds using direct photoexcitation of Willgerodt-type reagents to generate chlorine radicals. Preliminary results for an iodine-(I/III) catalytic process starting from abundant chloride salts are also presented. Furthermore, a one-pot protocol has been developed for the telescoped functionalization of benzylic chlorides with C-, N-, O-, and S-nucleophiles. Especially, this approach provides a platform to access 1,1-diaryl motifs, which are important building blocks for the synthesis of pharmacophores.