Chuanjun Song

Precise control over the regioselectivity of C–C bond formation constitutes an effective strategy for constructing complex molecules in organic synthesis.

Herein, we report an efficient photoinduced/palladium synergistic catalysis for the construction of dihydropyridine derivatives via the allylic (3 + 3) annulations of a sulfonium salt with N -sulfonyl ketimines.

Molecules with inherent chirality, which stems from their overall conformation rather than local stereogenic centers, present a notable synthetic challenge. This is especially evident for bioactive, saddle-shaped tricyclic diazepinones, whose conformational flexibility has hampered asymmetric synthesis. Herein, we address this issue through a late-stage organocatalytic asymmetric N-H alkylation strategy. By introducing torsional strain via strategic N-H functionalization, we lock the molecular chiral conformation and enable direct synthesis of diverse enantioenriched tricyclic diazepinones from prochiral precursors. The modular nature of this approach is demonstrated through the kinetic resolution of racemic substrates, as well as in, to our knowledge, the first enantioselective synthesis and absolute configuration confirmation of the drug molecule (+)-telenzepine.

Saddle-shaped seven-membered rings with inherent chirality remain challenging targets due to their high conformational mobility and low inversion barriers. Herein, we report a palladium-catalyzed enantioselective intramolecular C-H arylation of azepine precursors enabled by 2,2,3,3-tetramethylcyclopropylcarboxylic acid (TMCPA) as a sterically hindered carboxylic acid additive. This protocol provides efficient access to a range of inherently chiral saddle-shaped azepines in up to 96% yield and 95% ee. Thermal racemization studies further show that representative products possess useful configurational stability. We further demonstrate the synthetic applicability of this protocol and report an initial chiroptical evaluation, highlighting its potential for functional material development.

The synthesis of spiroheterocycles via the controllable in situ generation of o-quinodimethanes (o-QDMs) bearing a tetrasubstituted exocyclic C═C bond remains a long-standing synthetic challenge. Herein, we report an aryne relay-triggered three-component (four-molecule) cascade reaction that enables the transition-metal-free assembly of N,O-spiroheterocycles (32 examples, up to 94% yield, mostly d.r. > 20:1) and benzo[f]isoindole-1,3(2H)-diones (27 examples, up to 84% yield). This transformation uses readily available 2-benzyl oxazolines, aryne precursors, and electron-deficient alkenes as starting materials, proceeding through the in situ generation and selective trapping of the aforementioned o-QDM intermediates. The protocol exhibits a broad substrate scope, and its synthetic utility is further validated by gram-scale synthesis and versatile product derivatization.

The first use of 1,2-benzisothiazoles for sulfuration in modular multicomponent reactions to access benzo[ b ]thiophene-fused N,O-heterocycles.

The continuous evolution of coronaviruses compromises the efficacy of existing therapeutic antibodies and replication inhibitors, necessitating antiviral strategies that are resilient to viral escape. Distinct from conventional antibody cocktails that remain vulnerable to spike protein mutations, we evaluated a multi-mechanistic therapy targeting three discrete stages of the viral life cycle: receptor binding, membrane fusion, and viral replication. Using pseudotyped and authentic human coronaviruses (HCoVs), including SARS-CoV-2 and HCoV-OC43, in cell culture models, we demonstrated that combining the pan-coronavirus fusion inhibitor EK1 with a receptor-binding domain-specific broadly neutralizing antibody (bnAb) and/or a main protease (M ^pro ) inhibitor yields synergistic inhibition. Collectively, our findings establish a conceptual framework for a trident antiviral regimen that theoretically restricts the evolutionary space for viral escape, although clinical translation will require optimizing delivery strategies to reconcile the distinct pharmacokinetic profiles of these agents. IMPORTANCE: The continuous emergence of highly transmissible and immune-evasive SARS-CoV-2 variants highlights an urgent need for broad-spectrum antiviral approaches capable of countering rapid viral evolution and future coronavirus outbreaks. Here, we designed a dual- or triple-stage antiviral strategy centered on the membrane fusion inhibitor EK1, in combination with a receptor-binding domain-targeting antibody and/or a small-molecule viral replication inhibitor (M ^pro inhibitor). In cell culture models, our results demonstrate marked synergy between EK1 and the antibody and/or the replication inhibitor. These combinations not only enhance antiviral potency but are also anticipated to maintain efficacy against emerging variants. By targeting non-overlapping stages of the viral life cycle, this approach theoretically raises the genetic barrier to resistance. While clinical translation will require reconciling the distinct pharmacokinetic profiles of these components, our study provides a conceptual framework for developing a trident anti-coronavirus therapy.

Background: The tumor vasculature exhibits immature development characterized by inadequate pericyte coverage, resulting in excessive permeability, poor perfusion, and hypoxia. The aberrant vascular network not only facilitates metastasis but also confers therapeutic resistance. Accumulating evidence indicates that inducing tumor vascular normalization represents a promising antitumor strategy. Given the pivotal role of the APLN/APLNR axis in vascular maturation positions it as a promising therapeutic target for anti-tumor vascular therapy.This study aims to discover novel APLNR antagonists, investigate their effects on tumor vascular normalization, and evaluate their combinatorial efficacy with existing anticancer therapies. Methods: Initially, based on a drug repurposing strategy, we employed computer-aided virtual screening to identify compounds with high binding affinity to APLNR from the FDA-approved drug library. And further utilized a zebrafish retinal vascular abnormality model to screen out the candidate compound that could induce vascular normalization. Then, we assessed the impact of the candidate compound on vascular normalization by detecting the proliferation, migration and tubule formation abilities of HUVEC in vitro and investigating tumor vascular maturity, vascular perfusion and hypoxia in vivo. Additionally, we explored the molecular mechanisms underlying the regulation of vascular normalization by the candidate compound using western blot and comet assay. Finally, we employed a breast cancer mouse model to examine the antitumor efficacy of the candidate compound when used alone or in combination with Sunitinib. Results: Employing a drug repurposing strategy combined with computational screening, we identified Candesartan, an approved antihypertensive drug with a well-established safety profile, as a high-affinity APLNR antagonist. Additionally, in vitro, Candesartan significantly inhibited HUVEC proliferation, migration, and tube formation. In vivo, it promoted tumor vascular maturation, improved vascular perfusion, and alleviated hypoxia. Mechanistically, Candesartan activated the ROS/dsDNA/cGAS/STING pathway to drive vascular normalization. Notably, Candesartan synergistically potentiated sunitinib’s antitumor efficacy while inhibiting pulmonary metastasis and ameliorating Sunitinib-induced hepatotoxicity. Conclusion: This study provides a novel direction for APLNR antagonist development and demonstrates that combining Candesartan with the standard antiangiogenic agent Sunitinib leverages the advantage of drug repurposing, suggesting a promising and rapidly translatable strategy for optimized cancer therapy.