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A novel method of synthesizing trans-N-cyclohexyl-2',5'-10b,10c-tetramethylpyrrolo{3,4-e}-10b,10c- dihydropyrene, as well as its heteroaromaticity was described through the use of furan-annelated thiacyclophane as the precursor. The approach featured the use of P2S5 or sulfur melt on the 1,4-diketone to yield furan instead of thiophene. The compound which was the first example of an iso{17}annulenopyrrole has increased energy barriers of rotation secondary to the 2,5-dimethyl groups on the pyrrole ring.

The synthesis and characterization of anti furanocyclophanene, trans-2',5',10b,10c-tetramethylfurano(3,4-e)-10b,10c-dihydropyrene, are described. The scheme involves the oxidative coupling of the benzyl methyl ketone to form a 1,4-dicarbonyl compound which was dehydrated to yield the 3,4-diarylfuran. Functional group transformations and subsequent intramolecular cyclization affords the anti isomer of furanothiacyclophane which yields the target compound after a Wittig rearrangement-Hoffmann elimination sequence and subsequent ring contraction.

A copper-based catalytic system has been described to enable the efficient 1,4-sulfonylindolylation of 1,3-dienes with sulfonyl chloride and indoles. This protocol offers a practical method for the synthesis of allylsulfone-containing indole derivatives with a broad range of compatible functionalities and excellent chemo- and regioselectivities. Mechanistic studies suggest that the copper catalyst plays the dual role of initiating sulfonyl radicals and prompting indole coupling in this conjugated diene-selective 1,4-difunctionalization strategy.

Tunnel-type-structure Na 0.44 MnO 2 has been extensively researched for cathode material in aqueous rechargeable sodium-ion battery owing to its high specific capacity (120 mA h g -1 ), large channels facilitating Na extraction/insertion, chemical and electrochemical stability in aqueous electrolytes, and low cost. However, the low average working potential (0.1 V versus standard hydrogen electrode, SHE) and no more than half of its available theoretical capacity within full batteries limit the practical application. Herein, we develop an Fe-based tunnel-type Na 0.66 [Mn 0.33 Fe 0.33 Ti 0.3 Sn 0.04 ]O 2 cathode, delivering a high reversible specific capacity (95 mA h g -1 ) under a high working voltage (0.75 V versus SHE). A full battery, assembled with a NaTi 2 (PO 4 ) 3 @C anode, exhibits a high energy density of 80 W h kg -1 (total mass of cathode and anode active materials) and a long cycle life with 84% capacity retention after 1000 cycles at 1 C.

We herein report a photochemical Truce-Smiles rearrangement reaction of N -sulfinyl acrylamides with bromodifluoroacetamides resulting in the synthesis of a series of aryl difluoroglutaramides in moderate to good yields. The asymmetric synthesis using chiral sulfinamides produced quaternary carbon - centered glutaramide products with a modest enantioselectivity. This protocol effectively complements previous Truce-Smiles rearrangement methods involving N -sulfonyl acrylamides.

Conventional methods for detecting single nucleotide polymorphisms (SNPs) in clinical practice often require substantial time, labor, and specialized equipment, limiting their widespread application. To address this limitation, we refined our previous SNP detection method, IMAS-RPA [introducing an extra mismatched base adjacent to the single-base mutant site by recombinase polymerase amplification (RPA)], resulting in an updated version termed IMAS-RPAv2. We began by introducing a suboptimal protospacer adjacent motif (PAM) sequence, GTTG, into the double-stranded DNA (dsDNA) products using either RPA or reverse transcription RPA. This modification decreased the efficiency with which CRISPR RNA (crRNA) recognizes the PAM and locally unwinds the dsDNA to form an R loop. After a delay, the R loop forms. However, due to the intentional incorporation of a mismatched base on the crRNA relative to the wild-type double-stranded DNA (WT-dsDNA), a continuous two-base mismatch is established between the crRNA and WT-dsDNA. Consequently, WT-dsDNA does not activate CRISPR/Cas12a's cleavage activity within a short time, while variant-type dsDNA continues to activate CRISPR/Cas12a and produce a robust fluorescence signal. This improvement significantly enhances the SNP discrimination sensitivity, allowing for detection at the single-copy level. Results were observed using both a conventional microplate reader and a specially designed portable device created through 3D printing. This device allows a direct fluorescence observation without the need for additional equipment. Consequently, the entire detection process becomes independent of large-scale equipment. This greatly expands its range of applications and offers promising prospects for clinical use.

Ibuzatrelvir (1) was recently disclosed and patented by Pfizer for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has received fast-track status from the USA Food and Drug Administration (FDA) and has entered phase III clinical trials as a possible replacement for Paxlovid. Like nirmatrelvir (2) in Paxlovid, this orally active drug candidate is designed to target viral main proteases (M pro ) through reversible covalent interaction of its nitrile warhead with the active site thiol of the chymotrypsin-like cysteine protease (3CL protease). Inhibition of M pro hinders the processing of the proteins essential for viral replication in vivo . However, ibuzatrelvir apparently does not require ritonavir (3), which is coadministered in Paxlovid to block human oxidative metabolism of nirmatrelvir. Here, we report the crystal structure of the complex of ibuzatrelvir with the active site of SARS-CoV-2 M pro at 2.0 Å resolution. In addition, we show that ibuzatrelvir also potently inhibits the M pro of Middle East respiratory syndrome-related coronavirus (MERS-CoV), which is fortunately not widespread but can be dangerously lethal (∼36% mortality). Co-crystal structures show that the binding mode of the drug to both active sites is similar and that the trifluoromethyl group of the inhibitor fits precisely into a critical S2 substrate binding pocket of the main proteases. However, our results also provide a rationale for the differences in potency of ibuzatrelvir for these two proteases due to minor differences in the substrate preferences leading to a weaker H-bond network in MERS-CoV M pro . In addition, we examined the reversibility of compound binding to both proteases, which is an important parameter in reducing off-target effects as well as the potential immunogenicity. The crystal structures of the ibuzatrelvir complexes with M pro of SARS-CoV-2 and of MERS-CoV will further assist drug design for coronaviral infections in humans and animals., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

The photoredox/PPh 3 -mediated cyclization of 2-isocyanobiaryls has been developed. A substantial range of functional-group-rich phenanthridine derivatives were synthesized at room temperature in a highly selective and atom-economic manner. Mechanistic studies suggested that the cyclization process is probably mediated both by Ph 3 P radical cation with key 1,2-hydride transfer and hydrogen atom generated through O-H bond homolytic cleavage of Ph 3 P-OH radical intermediate.

This study explores the relationship between structural alterations of nirmatrelvir, such as homologation and deuteration, and metabolic stability of newly synthesized derivatives. We developed a reliable synthetic protocol toward dideutero-nirmatrelvir and its homologated analogues with high isotopic incorporation. Deuteration of the primary metabolic site of nirmatrelvir provides a 3-fold improvement of its human microsomal stability but is accompanied by an increased metabolism rate at secondary sites. Homologation of the lactam ring allows the capping group modification to decrease and delocalize the molecule's lipophilicity, reducing the metabolic rate at secondary sites. The effect of deuteration was less pronounced for the 6-membered lactam than for its 5-membered analogue in human microsomes, but the trend is reversed in the case of mouse microsomes. X-ray data revealed that the homologation of the lactam ring favors the orientation of the drug's nitrile warhead for interaction with the catalytic sulfur of the SARS-CoV-2 M pro , improving its binding. Comparable potency against SARS-CoV-2 M pro from several variants of concern and selectivity over human cysteine proteases cathepsin B, L, and S was observed for the novel deuterated/homologated derivative and nirmatrelvir. Synthesized compounds displayed a large interspecies variability in hamster, rat, and human hepatocyte stability assays. Overall, we aimed to apply a rational approach in changing the physicochemical properties of the drug to refine its biochemical and biological parameters., Competing Interests: The authors declare the following competing financial interest(s): The Governors of the University of Alberta has filed a patent application that also contains a few of the molecules in this manuscript and currently some authors are listed as inventors., (© 2023 The Authors. Published by American Chemical Society.)

Heterocyclic compounds, especially oxygen-containing heterocyclic compounds, are crucial moieties in bioactive compounds and drug leads. Substituted chroman-4-ones are a kind of the most significant structural skeletons. Herein, we report a visible-light-induced dual acylation of alkenes for constructing 3-substituted chroman-4-ones, which undergoes a radical tandem cyclization reaction through carbon-carbon bond cleavage of oxime esters by a nitrogen-centered radical strategy. A series of 3-substituted chroman-4-ones were prepared with up to 86% yield.

The capture of sustainable energy from a salinity gradient, in particular, using renewable biomass-derived functional materials, has attracted significant attention. In order to convert osmotic energy to electricity, many membrane materials with nanofluidic channels have been developed. However, the high cost, complex preparation process, and low output power density still restrict the practical application of traditional membranes. Herein, we report the synthesis of highly flexible and mechanically robust nanofiber-arrays-based carbonaceous ordered mesoporous nanowires (CMWs) through a simple and straightforward soft-templating hydrothermal carbonization approach. This sequential superassembly strategy shows a high yield and great versatility in controlling the dimensions of CMWs with the aspect ratio changes from about 3 to 39. Furthermore, these CMWs can be used as novel building blocks to construct functional hybrid membranes on macroporous alumina. This nanofluidic membrane with asymmetric geometry and charge polarity exhibits low resistance and high-performance energy conversion. This work opens a solution-based route for the one-pot preparation of CMWs and functional heterostructure membranes for various applications.

A novel metal-free C-H [5 + 1] carbonylative annulation of 2-alkenyl/pyrrolylanilines with dioxazolones has been established for the assembly of the privileged quinolinones and pyrrolyl-fused quinoxalinones. Entirely differing from the existing reports, the dioxazolones herein behave with an innovative chemistry and first emerge as carbonylating reagents to participate in annulation reactions. Moreover, this process features exceedingly simple operation (only solvent) and tolerates both vinyl and aryl substrates. Comprehensive mechanistic studies indicate that the formed isocyanate intermediate plays a crucial role in enabling the carbonylation annulation.

Histone post-translational modifications (HPTMs) serve as signal platforms for recruitment of binding proteins (readers) to regulate gene expression. Accumulated evidence suggests that the intensive distribution of HPTMs may result in crosstalk, which increases or inhibits the recruitment of reader proteins, further altering the functional outcome of HPTMs. Therefore, the comprehensive identification of multiple interactions between combinatorial HPTMs and reading domains is essential to understand the chromatin-templated processes. However, it is still a big challenge to profile these complicated interactions due to various limitations including rather weak, transient and multiple interactions between HPTMs and readers, the high dynamic property of HPTMs as well as the low abundance of reader proteins. Here we developed an integrated approach to profile the complicated interactions between combinatorial HPTMs and dual domains. Based on a combinatorial HPTM peptide library (trimethylation of histone H3 lysine 4 and its neighboring PTMs) and five affinity tag proteins containing tandem-domain probes, histone interactions can be profiled by pull-down assay combined with mass spectrometry analysis. The interactions were further verified by isothermal titration calorimetry and proximity ligation assay, as well as molecular docking. By use of combinatorial HPTMs, we demonstrated that this integrated approach can be successfully utilized for the characterization of multiple interactions between reading domains and combinatorial HPTMs including novel HPTMs with low stoichiometry. Thus, a novel chemical proteomics tool for profiling of multiple PTM-mediated protein-protein interactions was successfully developed and can be adapted for broad biomedical applications.

A novel and convenient visible light-catalyzed tandem radical cyclization of N -propargylindoles with acyl chlorides for accessing 2-acyl-9 H -pyrrolo[1,2- a ]indoles is established. This transformation involves sequential addition of the acyl radical to the carbon-carbon triple bond, intramolecular cyclization with the 2-position of indole, and isomerization of the carbon-carbon double bond. The experimental results show that this reaction contains a radical pathway and a radical chain process is not the major pathway for the formation of products.

Constructing an effective therapeutic cancer vaccine is very attractive and promising for cancer immunotherapy. However, the poor immunogenicity of tumor antigens and suppression of the immune system in the tumor microenvironment are two major obstacles for developing effective cancer vaccines. Invariant NKT cells (iNKT cells), which are essential bridges between the innate and adaptive immune systems, can be rapidly activated by their agonists and, consequently, evoke whole immune systems. Herein, we conjugated a potent agonist of the iNKT cell, α-galactosylceramide (α-GalCer), with the tumor-associated MUC1 glycopeptide antigens as novel self-adjuvanting cancer vaccines through click chemistry. Immunological studies revealed that the mouse immune system was potently evoked and that high levels of tumor-specific IgG antibodies were elicited by vaccine conjugates without an external adjuvant. The produced antibodies could specifically recognize and bind to antigen-expressing cancer cells and, subsequently, induce cytotoxicity through complement-dependent cytotoxicity. Thus, the insertion of α-GalCer significantly improved the immunogenicity of the MUC1 glycopeptide and induced strong antigen-specific antitumor responses, indicating that α-GalCer is an effective built-in adjuvant for constructing potent chemical synthetic antitumor vaccines.

A novel ruthenium-catalyzed [5 + 1] annulation of 2-alkenylanilines with sulfoxonium ylides was developed for the rapid assembly of highly functionalized quinolines. This new catalytic process employs challenging but synthetically ideal free amino functionality to achieve alkenyl C-H activation with sulfoxonium ylides as one-carbon coupling partners. Various 2-acylquinolines could be obtained with good yields and excellent functional group tolerance. Moreover, the potential synthetic application of this methodology was exemplified by several chemical transformations.

A novel [5 + 1] cyclization of 2-vinylanilines with polyfluoroalkanoic acids under catalyst- and additive-free conditions was successfully implemented. The approach directly employs very low-cost and readily available polyfluoroalkanoic acids as both C1 synthons and fluoroalkyl building blocks. This method provides concise access to diverse 2-fluoroalkylated (CF 3 , C 2 F 5 , C 3 F 7 , CF 2 H, CF 2 Cl, and CF 2 Br) quinolines in good yields with excellent functional group tolerance in high yield on a gram scale.

Combinatorial histone post-translational modifications (HPTMs) form a complex epigenetic code that can be decoded by specific binding proteins, termed as readers. Their specific interplays have been thought to determine gene expression and downstream biological functions. However, it is still a big challenge to analyze such interactions due to various limitations including rather weak, transient, and complicated interactions between HPTMs and readers, the high dynamic property of HPTMs, and the low abundance of reader proteins. Here we sought to take advantage of DNA-templated and photo-cross-linking techniques to design a group of combinatorial histone PTM peptide probes for the identification of multivalent interactions among histone PTMs and readers. By use of trimethylation on histone H3K4 (H3K4me3) and phosphorylation on H3T3, we demonstrated that this approach can be successfully utilized for identification of the PTM crosstalk on the same histone. By use of H3K4me3 and acetylation on H4K16, we showed the potential application of the probe in the multivalent interactions among PTMs on different histones. Thus, this new chemical proteomics tool combined with mass spectrometry holds a promising potential in profiling of the readers of combinatorial HPTMs and characterization of crosstalk among multiple PTMs on histones and can be adapted for broad biomedical applications.

Cancer cells metastasize and are transported in the bloodstream, easily reaching any site in the body through the blood circulation. A method designed to assess the number of circulating tumor cells (CTCs) should be validated as a clinical tool for predicting the response to therapy and monitoring the disease progression in patients with cancer. Although CTCs are detectable in many cases, they remain unavailable for clinic usage because of their high testing cost, tedious operation, and poor clinical relevance. Herein, we developed a regeneratable microchip for isolating CTCs, which is available for robust cell heterogeneity assays on-site without the need for a sterile environment. The ivy-like hierarchical roughened zinc oxide (ZnO) nanograss interface was synthesized and directly integrated into the microfluidic devices and enables effective CTC capture and flexible, nontoxic CTC release during incubation in a mildly acidic solution, thus enabling cellular and molecular analyses. The microchip can be regenerated and recycled to capture CTCs with the remaining ZnO without affecting the efficiency, even after countless cycles of cell release. Moreover, microbial infection is avoided during its storage, distribution, and even in the open space usage, which ideally appeals to the demands of point-of-care (POC) and home testing and meets to the requirements for blood examinations in undeveloped or resource-limited settings. Furthermore, the findings generated using this platform based on the cocktail of antiepithelial cell adhesion molecule and antivimentin antibodies indicate that CTC capture was more precise and reasonable for patients with advanced cancer.

Multichannel nerve guide conduits (MCNGCs) have been widely studied and exhibited outstanding nerve repair function. However, the effect of the geometric structure of MCNGCs on the nerve repair function was still not clear. Herein, we postulated that MCNGCs with different inner surface area-to-volume ratios (ISA/V) of the channels inside the nerve guide conduits (NGCs) would show different nerve repair functions. Therefore, in current work, we constructed a series of hydroxyethyl cellulose/soy protein sponge-based nerve conduit (HSSN) with low, medium, and high ISA/V from hydroxyethyl cellulose (HEC)/soy protein isolate (SPI) composite sponges, which were abbreviated as HSSN-L, HSSN-M and HSSN-H, respectively. These NGCs were applied to bridge and repair a 10 mm long sciatic nerve defect in a rat model. Finally, the influence of ISA/V on nerve repair function was evaluated by electrophysiological assessment, histological investigation, and in vivo biodegradability testing. The results of electrophysiological assessment and histological investigation showed that the regenerative nerve tissues bridged with HSSN-H and HSSN-M had higher compound muscle action potential amplitude ratio, higher percentage of positive NF200 and S100 staining, larger axon diameter, lower G -ratio, and greater myelination thickness. Furthermore, the regenerative nerve tissues bridged with HSSN-H also showed higher density of regenerated myelinated nerve fibers and more number of myelin sheath layers. On the whole, the repair efficiency of the peripheral nerve in HSSN-H and HSSN-M groups might be better than that in HSSN-L. These results indicated that higher ISA/V based on HEC/SPI composite sponge may result in greater nerve repair functions. The conclusion provided a probable guiding principle for the structural designs of NGCs in the future., Competing Interests: The authors declare no competing financial interest.