JACS Au最新文献

[This corrects the article DOI: 10.1021/jacsau.5c00422.].

Boraindanes, composed of aromatic two-dimensional (2D) benzene and saturated three-dimensional (3D) boracycle moieties, are considered promising candidates for bioactive compounds/probes, agents for boron neutron capture therapy, and functional materials, as they combine the photophysical properties of the 2D aromatic and the high molecular recognition ability of the 3D boracycle. However, 2-boraindanes are difficult to access due to the difficulty of constructing two unstable C-(sp³)-B bonds. Herein, we present a straightforward synthesis of highly borylated, phenanthrene-fused 2-boraindane derivatives from biphenyl-linked terminal diacetylides through a B-B bond activation strategy. This methodology provides convenient access to a range of 2-boraindanes simply by changing the starting diyne. Spectroscopic measurements and computational analyses disclosed that the obtained highly borylated 2-boraindanes possess altered photophysical properties compared to the original 2D phenanthrene. The 2D/3D cyclic organoboron framework was utilized to construct a highly selective fluorescent probe for glucose.

Lysosome-targeting chimera technology has been utilized to degrade proteins of interest via the endosome-lysosome pathway mediated by endogenous ligands that engage cell-surface transmembrane proteins. Despite their promising potential, current approaches remain limited by the tissue-specific expression of surface receptors required for endocytosis. Prostate-specific membrane antigen (PSMA) is highly and specifically expressed in prostate cancer, driving significant progress in PSMA-targeted therapies, particularly radioligand therapy and antibody-drug conjugates, through PSMA-mediated internalization. Leveraging this phenomenon, we developed PSMA-targeting chimeras (PATACs), a novel and readily accessible class of heterobispecific small molecules designed for membrane protein degradation. PATACs facilitate the cointernalization of a target protein of interest, directing it into the lysosomal degradation pathway. As a proof of concept, A4, a representative PATAC, induced rapid and dose-dependent degradation of programmed cell death ligand 1 (PD-L1), with significant reduction observed within 4 h at concentrations up to 100 nM. Consequently, this degradation potently enhanced T-cell-mediated killing of LNCaP cells in a coculture system. Molecular dynamics simulations revealed that PATAC A4, featuring a short and rigid linker, exhibits enhanced conformational stability within the PSMA-A4-PD-L1 ternary complexes. These findings reveal PATACs as a promising new class of bifunctional small-molecule modalities for the precise manipulation of membrane proteins and targeted therapy in prostate cancer.

Rubbers are polymer networks that are used in many everyday applications ranging from tires to apparel. Unfortunately, the cross-links that give these materials their desirable properties also make them difficult to recycle. Covalent adaptable networks (CANs) are a promising class of cross-linked polymers that rearrange their cross-links in response to a stimulus like heat, making them more recyclable than conventional thermosets. Herein we present a method of incorporating dithioalkylidenes, a catalyst-free associative dynamic bond, into polybutadiene rubbers using olefin metathesis. The modified polymers are cross-linked with a multiarmed thiol, and the resulting networks are chemically and mechanically recycled. Evolution of the network microstructure during recycling results in up to a 7-fold increase in toughness over three cycles of recycling. We incorporate common fillers like carbon fiber and silica into CANs to provide reinforced composites and recover these fillers through chemical recycling. Finally, we modify devulcanized rubber crumb derived from rubber waste, enabling the preparation of mechanically recyclable composites with 90% upcycled content. This work presents a new method of upcycling waste rubber to access materials with multiple lifecycles.

Light-mediated intermolecular dehydro-Diels-Alder (DDA) reactions have emerged as a powerful strategy for constructing multisubstituted naphthalenesprivileged scaffolds found in natural products, pharmaceuticals, and functional materials. However, developing a general [4 + 2] cycloaddition system that accommodates electron-deficient dienes with both electron-rich and electron-deficient alkynes has remained challenging. Herein, we report a catalyst-free DDA reaction between sulfonyl-substituted aryl maleimides, serving as electron-deficient dienes, and alkynes under visible-light irradiation. By proceeding via a triplet intermediate manifold that bypasses conventional single-electron-transfer pathways and their redox matching constraints, this protocol enables efficient and regioselective access to diverse multisubstituted naphthalenes and exhibits broad compatibility with alkynes of varying electronic nature. Mechanistic studies reveal the essential dual role of the sulfonyl group in promoting the [4 + 2] cycloaddition with high chemoselectivity and facilitating the final aromatization step.

Targeted protein degradation, particularly through molecular glue degraders (MGDs), offers a promising strategy for targeting "undruggable" proteins. However, existing fluorescence-based screening approaches, such as time-resolved fluorescence resonance energy transfer, may be constrained by conformational changes or inefficient labeling of targets, necessitating more efficient screening approaches. Here, we present a MGDs screening approach based on surface plasmon resonance (SPR) coupled with degradomics and interactomics (SPR-DI). This approach leverages the high-throughput and label-free SPR for screening E3 ligands, followed by an unbiased "dual filter" of degradomics and interactomics to identify candidate proteins of interests (POIs). The feasibility of SPR-DI was validated using previously established MGD VH032, which can drive VHL to induce CDO1 degradation. Employing VHL and Keap1 as drivers E3, we then screened a natural product library and successfully identified triptolide and pycropodophyllin as potential MGDs. Subsequent investigations demonstrated that triptolide facilitates VHL-mediated degradation of IMP3, whereas picropodophyllin promotes Keap1-mediated degradation of DDX52 and LDHB. These degradation events were confirmed to depend on the respective E3 and ubiquitin-proteasome system, underscoring the capacity of these compounds to induce ternary complex formation. In conclusion, the establishment of SPR-DI provides a promising tool for the discovery of MGDs and their corresponding POIs, offering instructive insights to advance future MGD screening methodologies.

1,3-Dienyl amines are important and versatile motifs in organic synthesis, and the functionalization of π-components with aldimines has emerged as a powerful strategy for their construction. However, existing methods typically rely on conjugated enynes or dienes and are limited to two-component reactions. Herein, we report a nickel-catalyzed chemoselective three-component alkenylative coupling of aldimines, simple alkynes, and alkenyl boronic acids, which provides stereodefined, multisubstituted 1,3-dienyl amines in good to excellent yields (up to 97% yield). Methanol acts as a sustainable protic solvent, facilitating the ring opening of the aza-nickelacycle intermediate generated via oxidative cyclization of the aldimine and alkyne. Furthermore, employing a P-chiral monophosphine ligand allows the enantioselective variant of this reaction to proceed with excellent stereocontrol (up to 98% yield and 99% ee).

Traditionally, a retrosynthesis aims to disconnect a molecular target into simpler precursors as quickly as possible, prioritizing the early deconstruction of primary contributors to the molecule's overall structural complexity (i.e., primary complexity elements). The complementary approach, which rapidly constructs complexity early in the forward synthesis, is much less common. Herein, we report a 14-step protective group-free total synthesis of the polycyclic sesquiterpenoid alkaloid hispidospermidin, which exploits an early-stage complexity-generating bicycle formation to forge the carbon skeleton, followed by subsequent peripheral functionalizations. Specifically, a key Giese conjugate addition of a bridgehead radical established the quaternary center, and a novel isomerization was discovered, which enabled a one-pot protocol to establish the trans-hydrindane moiety, and application of a C-H desaturation/etherification sequence constructed the tetrahydrofuran moiety at a late stage. Uniquely, our strategy generates the primary complexity element, the bicyclo[3.3.1]-nonane core, in the first step of the synthesis, whereas the three previous syntheses feature mid- to late-stage bicycle construction (total of 23-31 steps). Analysis of the structural complexity landscape of the four syntheses of hispidospermidin suggests that building a molecule from the "Inside-Out", as described here, may be a broadly applicable strategy to expedite the total synthesis of topologically complex molecules.

Herein, we introduce a powerful alkene difunctionalization process where anomeric amides (i.e., N-halogenated-O-activated hydroxylamines) react directly with olefins, without the use of catalysts or additives, to yield the corresponding N-haloalkyl-O-activated hydroxylamines. These multifunctional hydroxylamines (MFHAs), containing both alkyl halide and O-activated hydroxylamine moieties, are convenient building blocks/electrophilic aminating reagents for the synthesis of structurally complex N-unprotected secondary amines and various N-heterocycles (i.e., N-alkyl/N-aryl aziridines, pyrrolidines, oxazolidinones and tetrahydroquinolines). Both activated and unactivated alkenes (including cyclic and acyclic olefins, dienes, and enynes) are effectively converted to the corresponding difunctionalized hydroxylamine derivatives with excellent atom economy. The versatility of MFHAs was demonstrated through the synthesis of various nitrogen-containing molecules. Density functional theory (DFT) calculations and molecular dynamics simulations, together with mechanistic experiments, indicate that the reaction proceeds through a radical chain addition mechanism initiated by a polar-to-radical crossover step.

Aberrantly glycosylated membrane proteins represent promising targets for cancer immunotherapy. However, glycan diversity and heterogeneity pose a challenge to developing effective vaccines against tumors expressing different glycoantigens. To broaden the immune response and enhance the vaccine's efficacy by targeting a wide variety of glycosylation patterns on tumor cells, herein we developed a Mosaic glycopeptide vaccine by simultaneously presenting three different glycopeptides on the carrier protein tetanus toxoid (TT). Immunological evaluation revealed that the Mosaic vaccine elicited higher antibody titers than single-glycopeptide formulations, primarily mediating tumor cell lysis via antibody-dependent cellular cytotoxicity (ADCC) and significantly suppressing tumor growth in both wild-type and transgenic murine models. Notably, the Mosaic vaccine exhibited not only preventive but also therapeutic effects, demonstrating clear antitumor activity in transgenic mice. Combination therapy with PD-1 blockade further enhanced antitumor efficacy. In-depth mechanistic studies demonstrated that the Mosaic vaccine effectively activated antigen-presenting cells and T cells. Furthermore, serum antibodies from Mosaic vaccine-immunized mice exhibited selective binding to patient-derived pancreatic tumor tissues, suggesting their clinical translational potential.