Brønsted acid catalyzed Ficini [2 + 2] cycloaddition of ynamides with enones.

Herein, we describe a novel metal-free Brønsted acid-catalyzed Ficini [2 + 2] cycloaddition of ynamides with enones under mild reaction conditions, leading to the formation of various cyclobutenamides in generally good to excellent yields within short reaction times. This work represents the first example of ynamides involved in a nonmetal-catalyzed [2 + 2] cycloaddition with enones.

Umpolung reactivity of strained C-C σ-bonds without transition-metal catalysis.

Umpolung is an old and important concept in organic chemistry, which significantly expands the chemical space and provides unique structures. While, previous research focused on carbonyls or imine derivatives, the umpolung reactivity of polarized C-C σ-bonds still needs to explore. Herein, we report an umpolung reaction of bicyclo[1.1.0]butanes (BCBs) with electron-deficient alkenes to construct the C(sp3)-C(sp3) bond at the electrophilic position of C-C σ-bonds in BCBs without any transition-metal catalysis. Specifically, this transformation relies on the strain-release driven bridging σ-bonds in bicyclo[1.1.0]butanes (BCBs), which are emerged as ene components, providing an efficient and straightforward synthesis route of various functionalized cyclobutenes and conjugated dienes, respectively. The synthetic utilities of this protocol are performed by several transformations. Preliminary mechanistic studies including density functional theory (DFT) calculation support the concerted Alder-ene type process of C-C σ-bond cleavage with hydrogen transfer. This work extends the umpolung reaction to C-C σ-bonds and provides high-value structural motifs.

TMSOTf-Catalyzed [4 + 2] Annulation of Ynamides and ß-(2-Aminophenyl)-α,ß-ynones for the Synthesis 2-Aminoquinolines.

A metal-free TMSOTf-catalyzed [4 + 2] annulation of ynamides with ß-(2-aminophenyl)-α,ß-ynones enables the regiospecific and facile assembly of 2-aminoquinoline frameworks. The catalyst TMSOTf presented a remarkable advancement compared to previously reported transition-metal catalysts. A wide range of 3-aryl/alkyl-substituted 2-aminoquinolines were generated in moderate to excellent yields due to the mild conditions.

Iodine-Mediated δ-Amination of sp3 C-H Bonds.

We present a direct δ-amination reaction of sp3 C-H bonds, employing molecular iodine (I2) as the sole oxidant under transition-metal-free conditions. This remote C-H functionalization approach is operationally simple and provides facile, efficient access to pyrrolidines and related heterocyclic derivatives from readily accessible substrates.

The novel selective TLR7 agonist GY101 suppresses colon cancer growth by stimulating immune cells.

Toll-like receptor (TLR) 7, a transmembrane signal transduction receptor expressed on the surface of endosomes, has become an attractive target for antiviral and cancer immunotherapies. TLR7 can induce signal transduction by recognizing single-stranded RNA or its analogs, leading to the release of cytokines such as IL-6, IL-12, TNF-α and type-I IFN. Activation of TLR7 helps to enhance immunogenicity and immune memory by stimulating immune cells. Herein, we identified a novel selective TLR7 agonist, GY101, and determined its ability to activate TLR7. In summary, in vitro, compound GY101 significantly induced the secretion of IL-6, IL-12, TNF-α and IFN-γ in mouse splenic lymphocytes; in vivo, peritumoral injection of GY101 significantly suppressed colon cancer CT26, as well as poorly immunogenic B16-F10 and 4T1 cancer cell-derived tumor growth by activating the infiltration of lymphocytes and polarization of M2-like macrophages into M1-like macrophages. These results demonstrate that GY101, as a potent TLR7 agonist, holds great potential for cancer immunotherapy.

Annulations of Ynamides with 1,2-Benzisothiazoles to Construct 1,4-Benzothiazepines and 3-Aminoisoquinolines.

Two distinct TMSOTf-catalyzed annulation reactions between ynamides and 1,2-benzisothiazoles have been developed. The direction of the reaction could be easily switched by applying different thermodynamic-controlled conditions. At room temperature, ynamides undergo a [5 + 2] annulation reaction with 1,2-benzisothiazoles to afford 1,4-benzothiazepines, whereas under heating conditions a desulfurizative annulation reaction proceeds well to access 3-aminoisoquinolines. These two protocols provide biologically important 1,4-benzothiazepines and 3-aminoisoquinolines with high efficiency with broad substrate scopes under mild reaction conditions.

Synthesis of 2,2-difunctionalized 2H-azirines via I2-mediated annulation of enamines.

Various 2,2-difunctionalized 2H-azirines were synthesized via I2-mediated annulation reactions of readily accessible enamines in the presence of nitrogen or non-nitrogen nucleophiles. The features of the present synthesis process also include no use of transition metals, simple operation, mild reaction conditions, a broad substrate scope, and gram-scale synthesis.

Design, Synthesis, and Activity Evaluation of Fluorine-Containing Scopolamine Analogues as Potential Antidepressants.

This study aimed to develop novel rapid-acting antidepressants with sustained efficacy and favorable safety profiles. We designed and synthesized a series of fluorine-containing scopolamine analogues and evaluated their antidepressant potential. In vitro cytotoxicity assays showed that most of these compounds exhibited minimal toxicity against neuronal and non-neuronal mammalian cell lines (IC50 > 100 µM). The antidepressant activities of the compounds were evaluated using the tail suspension test, and S-3a was identified as a lead compound with potent and sustained antidepressant effects. Behaviorally, S-3a alleviated depressive symptoms in mice and displayed a higher cognitive safety margin than scopolamine. Toxicological assessments confirmed S-3a's safety, while pharmacokinetics showed a rapid clearance (half-life: 16.6 min). Mechanistically, S-3a antagonized M1 receptors and elevated BDNF levels, suggesting its potential as an antidepressant for further exploration.

Redox-Regulated Synthetic Channels: Enabling Reversible Ion Transport by Modulating the Ion-Permeation Pathway.

Natural redox-regulated channel proteins often utilize disulfide bonds as redox sensors for adaptive regulation of channel conformations in response to diverse physiological environments. In this study, we developed novel synthetic ion channels capable of reversibly switching their ion-transport capabilities by incorporating multiple disulfide bonds into artificial systems. X-ray structural analysis and electrophysiological experiments demonstrated that these disulfide-bridged molecules possess well-defined tubular cavities and can be efficiently inserted into lipid bilayers to form artificial ion channels. More importantly, the disulfide bonds in these molecules serve as redox-tunable switches to regulate the formation and disruption of ion-permeation pathways, thereby achieving a transition in the transmembrane transport process between the ON and OFF states.

Investigation of steric hindrance effect on the interactions between four alkaloids and HSA by isothermal titration calorimetry and molecular docking.

The binding of four alkaloids with human serum albumin (HSA) was investigated by isothermal titration calorimetry (ITC), spectroscopy and molecular docking techniques. The findings demonstrated that theophylline or caffeine can bind to HAS, respectively. The number of binding sites and binding constants are obtained. The binding mode is a static quenching process. The effects of steric hindrance, temperature, salt concentration and buffer solution on the binding indicated that theophylline and HSA have higher binding affinity than caffeine. The fluorescence and ITC results showed that the interaction between HSA and theophylline or caffeine is an entropy-driven spontaneous exothermic process. The hydrophobic force was the primary driving factor. The experimental results were consistent with the molecular docking data. Based on the molecular structures of the four alkaloids, steric hindrance might be a major factor in the binding between HSA and these four alkaloids. This study elucidates the mechanism of interactions between four alkaloids and HSA.

TMSOTf-Catalyzed Reactions of N-Arylynamides with Sulfilimines To Construct 2-Aminoindoles and α-Arylated Amidines.

Here, we disclose an efficient TMSOTf-catalyzed C-H annulation of aryl-terminated N-arylynamides with sulfilimines, leading to the practical assembly of various valuable 2-aminoindoles in generally moderate to excellent yields with a broad range of functional groups, while nonaryl terminated N-arylynamides undergo TMSOTf-catalyzed aminative arylation with sulfilimines providing α-arylated amidines.

Synthesis of Spirocyclohexadienones via Palladium-Catalyzed Dearomatization of Dibenzoxaborins.

The development of Pd(II)-catalyzed dearomatization transformation of dibenzoxaborins with alkynes triggered by transmetalation from boron to palladium has been achieved, leading to the synthesis of spirocyclohexadienones, an important skeleton demonstrating potential biomedical utility. The [3 + 2] spiroannulation exhibits remarkable regioselectivity and broad substrate scope under mild reaction conditions. This methodology employs dibenzoxaborin as a substrate to establish the formal dearomatization of 2-phenylphenol, which poses a formidable energy barrier to the destruction of aromaticity.

Chiral-Boron-Complex-Catalyzed Asymmetric [3 + 2] Cycloaddition of ß-Trifluoromethyl α,ß-Unsaturated Ketones with N,N'-Cyclic Azomethine Imines.

The (R)-3,3'-(3,5-(CF3)2-C6H3)2-BINOL-boron-complex-catalyzed asymmetric 1,3-dipolar cycloaddition of ß-trifluoromethyl α,ß-unsaturated ketone with N,N'-cyclic azomethine imines was developed to afford N,N'-bicyclic pyrazolidine derivatives bearing a stereogenic carbon center containing CF3 motifs in high yields with excellent diastereo- and enantioselectivities (up to >20:1 dr, and >99% ee). This catalytic system features mild reaction conditions, high efficiency, and a broad substrate scope.

Phase III, randomized, double-blind, placebo-controlled clinical study: a study on the safety and clinical efficacy of AZVUDINE in moderate COVID-19 patients.

Background: In 2019, a highly pathogenic coronavirus named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) surfaced and resulted in the outbreak of coronavirus disease 2019 (COVID-19). With the aim of finding effective drugs to fight against the disease, several trials have been conducted since COVID-19 can only be considered a treatable disease, from a clinical point of view, after the availability of specific and effective antivirals. AZVUDINE (FNC), initially developed for treating HIV, is a potential treatment for COVID-19 as it has the capability to lower the patient's viral load and promote recovery. Methods: Volunteers infected with SARS-CoV-2 confirmed by reverse transcription polymerase chain reaction (RT-PCR), with good kidney and liver function, who were not using other antivirals or monoclonal antibodies were eligible. Samples from patients were assessed for viral load every 48 h during treatment using reverse transcription quantitative polymerase chain reaction (RT-qPCR) and droplet digital polymerase chain reaction (ddPCR). Results: The study's primary outcome measure was the percentage of participants showing an improvement in clinical scores, while the secondary outcome measure was the percentage of participants with a clinical outcome of cure. These measures were used to assess the safety and efficacy of FNC for treating COVID-19. In the analysis of sociodemographic variables, no significant differences were detected between patients in the FNC and the placebo group for race, age group, or sex. The results showed a potential benefit to participants who received FNC during the study, as observed in the shorter hospital stay, shorter negative conversion time of SARS-CoV-2, and a significant reduction in viral load. Furthermore, the reduction in fever and chills were significant at D1, D2, and D3. In this study, a total of 112 adverse events cases were noted, with 105 cases being categorized as non-serious and only 7 cases as serious adverse events. Conclusion: The pandemic is not being effectively controlled and is causing multiple waves of infection that require extensive medical resources. However, FNC has demonstrated potential to reduce the treatment duration of moderate COVID-19 cases, thereby saving significant medical resources. This makes FNC a promising candidate for COVID-19 treatment.Clinical trial registration: [clinicaltrials.gov], identifier [NCT04668235].

Highly Enantioselective Chiral Diol-Catalyzed Conjugate Addition of Boronic Acids to α,ß-Unsaturated Trifluoromethyl Ketones.

The (R)-3,3'-(3,5-(CF3)2-C6H3)2-BINOL-catalyzed enantioselective conjugate addition of organic boronic acids to α,ß-unsaturated 1,1,1-trifluoromethyl ketones affords corresponding addition products bearing a stereogenic center at the ß-position in moderate to high yields and excellent enantioselectivities (up to 99% ee), without any 1,2-addition product formation. Moreover, this catalytic protocol features mild reaction conditions, a broad substrate scope, suitability for alkenylboronic acids and (hetero)arylboronic acids, and easy scale-up.

Copper-Catalyzed Synthesis of N-Fused Quinolines via C(sp3)-H Activation-Radical Addition-Cyclization Cascade.

A novel copper-catalyzed cyclization reaction for the synthesis of pyrazolo[1,5-a]quinoline, triazolo[1,5-a]quinoline, and pyrrolo[1,2-a]quinoline derivatives is described. The process is initiated by di-tert-butyl peroxide-mediated C(sp3)-H activation to generate the α-functionalized radical, which supervenes a cascade radical addition/cyclization sequence to access the N-fused quinolines in good yields with broad functional group tolerance.

Chiral-Boron-Complex Catalyzed Asymmetric Inverse-Electron-Demand Aza-Diels-Alder Reaction of ß-Trifluoromethyl α,ß-Unsaturated Ketones with Cyclic N-Sulfonyl Ketimines.

A highly efficient asymmetric inverse-electron-demand aza-Diels-Alder reaction of ß-trifluoromethyl α,ß-unsaturated ketone with cyclic N-sulfonyl ketimines catalyzed by (R)-3,3'-I2-BINOL-boron-complex was developed. A broad range of fused piperidine derivatives bearing stereogenic carbon containing CF3 motifs were prepared in high yields with excellent diastereo- and enantioselectivities (up to >20:1 dr, and >99% ee). This protocol had the characteristics of mild reaction conditions, high efficiency, and high stereoselectivity.

4'-Ethynyl-2'-deoxy-2'-ß-fluoro-2-fluoroadenosine: A Highly Potent and Orally Available Clinical Candidate for the Treatment of HIV-1 Infection.

2'-Deoxy-2'-ß-fluoroadenosines bearing 4'-azido or 4'-ethynyl groups designed for the treatment of HIV-1 infection have been synthesized. All these compounds possess nanomolar anti-HIV-1 activity, with the 4'-ethynyl-2-fluoroadenosine analog 1c (CL-197) being the most potent compound with low cytotoxicity (EC50 = 0.9 nM, CC50 > 100 µM). It also shows potent inhibitory activities on drug resistant and clinical HIV-1 strains. Oral administration of 1c to Beagle dogs resulted in high levels of its bioactive form 1c-TP in peripheral blood mononuclear cells, the HIV-1 target cells, where the resulting triphosphate exhibited a long-term intracellular retention and could prevent HIV-1 infection for an extended time. 1c displayed low in vivo toxicity and favorable pharmacokinetics profiles in Sprague-Dawley rats. The preclinical data support further development of 1c as a highly potent and orally bioavailable clinical candidate to treat HIV-1 infection. Currently, CL-197 is in clinical trials in China (registration number: CXHL2200529).