Enantiomeric access to pentatomic biaryls is challenging due to their relatively low rotational barrier. Reported herein is the mild and highly enantioselective synthesis of 2,3′-biindolyls via ...underexplored integration of C–H activation and alkyne cyclization using a unified chiral Rh(III) catalyst. The reaction proceeded via initial C–H activation followed by alkyne cyclization. A chiral rhodacyclic intermediate has been isolated from stoichiometric C–H activation, which offers direct mechanistic insight.
Conspectus Modified nucleosides show therapeutic promise for antiviral therapies. However, issues including the emergence of drug resistance, toxicity, and coinfections have posed new challenges for ...nucleoside-based antiviral drug discovery, particularly in the era of the coronavirus disease 2019 (COVID-19) pandemic. Chemical manipulation could impact the antiviral potency, safety, and drug resistance of nucleosides. Generally, modified nucleosides are difficult to recognize by intracellular important enzymes as substrates and thus exhibit low toxicity. 4′-Modified nucleosides represent an important subclass of modified nucleosides for antiviral therapies. To prevent the occurrence of drug resistance, 4′-modified nucleosides should have 3′-OH, which should also be chemically unreactive for proviral DNA biosynthesis. The absence of 3′-OH may explain the occurrence of drug resistance for censavudine. The introduction of 4′-substituents improves enzymatic and acidic stability and makes the nucleosides more lipophilic, thus improving cell permeability and bioavailability. Steric hindrance between the 4′-substituent and 3′-OH changes the furanose conformation to the 3′-endo type, in which the oxygen lone pair on the furanose ring could not form an oxocarbonium ion for glycolysis. Currently, seven 4′-modified nucleoside drug candidates such as azvudine (also known as FNC), islatravir, censavudine, balapiravir, lumicitabine, AL-335, and 4-azidothymidine have progressed into clinical stages for treating viral infections. Of note, FNC was officially approved by NMPA in July 2021 for use in adult patients with high HIV-1 virus loads (nos. H20210035 and H20210036), providing an alternative therapeutic for patients with HIV-1. The long-term cellular retention of FNC suggests its potential as a long-lasting pre-exposure prophylaxis (PrEP) agent for preventing HIV-1 infection. Mechanistically, FNC not only inhibited HIV-1 reverse transcription and replication but also restored A3G expression in peripheral blood CD4+ T cells in HIV-1 patients receiving FNC. The 4′-azido group in azvudine stabilizes the 3′-C-endo (north) conformation by steric effects and the formation of an intramolecular hydrogen bond with the 3′-OH group, thus decreasing the nucleophilicity of 3′-OH. The north conformation may also enhance the phosphorylation efficiency of FNC by cellular kinases. Encouragingly, FNC, islatravir, and balapiravir show promise for the treatment of coronaviruses, of which FNC has advanced to phase 3 clinical trials in different countries to treat patients with COVID-19 (clinical trial numbers: NCT04668235 and NCT04425772). FNC cured the COVID-19 disease in almost all patients and showed better therapeutic efficacy than remdesivir. In this Account, we provide an overview of 4′-modified nucleoside analogs in clinical stages for antiviral therapies, highlighting the drug discovery strategies, structure–activity relationship studies, and preclinical/clinical studies and also give our perspectives on nucleoside-based antiviral drug discovery.
Phytosulfokine (PSK) is a disulfated pentapeptide that has a ubiquitous role in plant growth and development. PSK is perceived by its receptor PSKR, a leucine-rich repeat receptor kinase (LRR-RK). ...The mechanisms underlying the recognition of PSK, the activation of PSKR and the identity of the components downstream of the initial binding remain elusive. Here we report the crystal structures of the extracellular LRR domain of PSKR in free, PSK- and co-receptor-bound forms. The structures reveal that PSK interacts mainly with a β-strand from the island domain of PSKR, forming an anti-β-sheet. The two sulfate moieties of PSK interact directly with PSKR, sensitizing PSKR recognition of PSK. Supported by biochemical, structural and genetic evidence, PSK binding enhances PSKR heterodimerization with the somatic embryogenesis receptor-like kinases (SERKs). However, PSK is not directly involved in PSKR-SERK interaction but stabilizes PSKR island domain for recruitment of a SERK. Our data reveal the structural basis for PSKR recognition of PSK and allosteric activation of PSKR by PSK, opening up new avenues for the design of PSKR-specific small molecules.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
A facile and practical oxidative cyclization reaction of enamines to 2H-azirines has been developed, employing molecular iodine. The features of the present synthetic approach include no use of ...transition metals, mild reaction conditions, and simplicity of operation. Under the optimal reaction conditions, a variety of 2H-azirine derivatives were synthesized from simple and readily accessible enamine precursors in an efficient and scalable fashion.
The fluoroalkyl-containing organic molecules are widely used in drug discovery and material science. Herein, we report ligand regulated nickel(0)-catalyzed regiodivergent hydrosilylation of ...α-(fluoroalkyl)styrenes without defluorination, providing an atom- and step-economical synthesis route of two types of fluoroalkyl substituted silanes with exclusive regioselectivity. The anti-Markovnikov addition products (β-fluoroalkyl substituted silanes) are formed with monodentate phosphine ligand. Noteworthy, the bidentate phosphine ligand promote the generation of the more challenging Markovnikov products (α-fluoroalkyl substituted silanes) with tetrasubstituted saturated carbon centers. This protocol features with easy available starting materials and commercially available nickel catalysis, a wide range of substrates and excellent regioselectivity. The structure divergent products undergo a variety of transformations. Comprehensive mechanistic studies including the inverse kinetic isotope effects demonstrate the regioselectivity controlled by ligand structure through α-CF3 nickel intermediate. DFT calculations reveal a distinctive mechanism involving an open-shell singlet state, which is crucial for generating intricate tetra-substituted Markovnikov products.The fluoroalkyl-containing organic molecules are widely used in drug discovery and material science. Herein, the authors report ligand regulated nickel(0)-catalyzed regiodivergent hydrosilylation of α-(fluoroalkyl)styrenes without defluorination.
Pattern recognition receptors confer plant resistance to pathogen infection by recognizing the conserved pathogen-associated molecular patterns. The cell surface receptor chitin elicitor receptor ...kinase 1 of Arabidopsis (AtCERK1) directly binds chitin through its lysine motif (LysM)-containing ectodomain (AtCERK1-ECD) to activate immune responses. The crystal structure that we solved of an AtCERK1-ECD complexed with a chitin pentamer reveals that their interaction is primarily mediated by a LysAA and three chitin residues. By acting as a bivalent ligand, a chitin octamer induces AtCERK1-ECD dimerization that is inhibited by shorter chitin oligomers. A mutation attenuating chitin-induced AtCERK1-ECD dimerization or formation of nonproductive AtCERK1 dimer by overexpression of AtCERK1-ECD compromises AtCERK1-mediated signaling in plant cells. Together, our data support the notion that chitin-induced AtCERK1 dimerization is critical for its activation.
Nucleotide-binding and oligomerization domain–like receptor (NLR) proteins oligomerize into multiprotein complexes termed inflammasomes when activated. Their autoinhibition mechanism remains poorly ...defined. Here, we report the crystal structure of mouse NLRC4 in a closed form. The adenosine diphosphate–mediated interaction between the central nucleotide-binding domain (NBD) and the winged-helix domain (WHD) was critical for stabilizing the closed conformation of NLRC4. The helical domain HD2 repressively contacted a conserved and functionally important α-helix of the NBD. The C-terminal leucine-rich repeat (LRR) domain is positioned to sterically occlude one side of the NBD domain and consequently sequester NLRC4 in a monomeric state. Disruption of ADP-mediated NBD-WHD or NBD-HD2/NBD-LRR interactions resulted in constitutive activation of NLRC4. Together, our data reveal the NBD-organized cooperative autoinhibition mechanism of NLRC4 and provide insight into its activation.
Biaryl scaffolds are prevalent in natural products and drug molecules, and biaryl-containing compounds have been shown to exhibit diverse and interesting biological activities. To date, numerous ...synthetic methods, particularly direct C–H bond activation, have been developed for the construction of such scaffolds, due to their interesting structural features and biological profiles. We highlight herein recent advances in the construction of biologically important biaryl fragments through direct C–H bond activation and also demonstrate the application of direct C–H arylation in the total synthesis of biaryl-containing natural products and drug molecules.
Graphic Abstract
Selected biaryl-containing compounds
The synthesis and application of a newly designed C 2-symmetric chiral-substituted 1,16-dihedroxytetraphenylene (DHTP) is reported. Efficient syntheses of enantiopure substituted DHTP were ...accomplished, and these enantiopure compounds were used as organocatalysts in asymmetric allylboration of ketones under very mild conditions. Accordingly, several tertiary alcohols were generated in moderate to good yields with up to 99% ee by using the catalyst (S)-2,15-Br2-DHTP. A gram-scale reaction was achieved in 99% yield with 96% ee.
