RESUMEN
This work reports a method for the catalytic synthesis of C(3) SCF3-substituted pyrrolidinindoline using a small-ring organophosphorus-based catalyst and a hydrosilane reductant, with trifluoromethanesulfonyl chloride as the electrophilic SCF3 reagent. This method can drive the conversion of tryptamine to the C(3) SCF3-substituted pyrrolidine indoline. The readily available, inexpensive trifluoromethanesulfonyl chloride could be activated as an electrophilic SCF3 source by PIII/PV redox catalysis and could efficiently participate in the reaction of tryptamines, thus providing various substituted C(3) SCF3-substituted pyrrolidinoindoline in moderate to excellent yields. This presented strategy features a broad substrate scope, and the structure has value for in-depth research.
RESUMEN
Programmed death-ligand 1 (PD-L1) has emerged as a promising therapeutic target for various cancers due to its crucial role in promoting tumor immune evasion. Here, we report a novel class of chroman-like small-molecule PD-L1 inhibitors exhibiting significant activity in inhibiting the PD-1/PD-L1 interaction. Employing a "ring-close" strategy for conformational restriction, we have achieved compound C27, which demonstrates superior PD-1/PD-L1 inhibitory activity compared to the positive control. Molecular dynamics simulation and binding free energy calculation predict that (R)-C27 with inhibitory activity surpassed (S)-C27. The experimental results from bioassay and X-ray structural analysis corroborate these findings. All these results collectively indicate that (R)-C27 is a promising lead compound deserving further exploration.
Asunto(s)
Antígeno B7-H1 , Cromanos , Diseño de Fármacos , Receptor de Muerte Celular Programada 1 , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/metabolismo , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/metabolismo , Humanos , Cromanos/química , Cromanos/farmacología , Simulación de Dinámica MolecularRESUMEN
An organophosphorus catalytic method for the synthesis of substituted 2-amidopyridines is reported. The method employs a small-ring organophosphorus-based catalyst and a hydrosilane reductant to drive the conversion of ketoximes and pyridine-N-oxides into 2-amidopyridines through sequential Beckmann rearrangement followed by [2,3]-sigmatropic rearrangement. The readily available ketoximes could be activated to nitrilium ions in PIII/PV redox catalysis and could efficiently participate in the domino reaction of pyridine-N-oxides, thus providing various substituted 2-amidopyridines in moderate to excellent yields. This presented strategy features excellent functional group tolerance and a broad substrate scope.
RESUMEN
Programmed death-ligand 1 (PD-L1) has surfaced as a promising therapeutic target for various cancers due to its pivotal role in facilitating tumor immune evasion. Herein, we report a series of novel small-molecule PD-L1 inhibitors exhibiting remarkable inhibitory activity against the PD-1/PD-L1 interaction (X18: IC50 = 1.3 nM) and reinstating the suppressive effect of PD-L1 on T cells (X18: EC50 = 152.8 nM). Crystallographic studies revealed the binding mode of X18 and PD-L1. Through a rational prodrug design approach, we have successfully optimized the oral pharmacokinetic properties of X22, effectively addressing the poor oral pharmacokinetic profile of PD-L1 small-molecule inhibitors. Notably, X22 demonstrated significant antitumor efficacy in murine models of MC38 and CT26 colon cancer through the upregulation of tumor infiltration and cytotoxicity of CD8+ T cells partially. These findings offer promising prospects for the advancement of PD-L1 inhibitors as innovative agents in cancer immunotherapy.
Asunto(s)
Neoplasias del Colon , Inhibidores de Puntos de Control Inmunológico , Animales , Ratones , Inhibidores de Puntos de Control Inmunológico/farmacología , Linfocitos T CD8-positivos , Antígeno B7-H1 , Línea Celular Tumoral , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismoRESUMEN
Liver fibrosis is commonly occurred in chronic liver diseases, but there is no approved drug for clinical use. The nuclear receptor peroxisome proliferator-activated receptors (PPARs) could not only regulate metabolic homeostasis but also possess anti-inflammatory and antifibrotic effects, and pan-PPARs agonist was considered as a potential anti-liver fibrosis agent. In this study, a series of novel piperazine pan-PPARs agonists were developed, and the preferred compound 12 displayed potent and well-balanced pan-PPARs agonistic activity. Moreover, compound 12 could dose-dependently stimulate the PPARs target genes expression and showed high selectivity over other related nuclear receptors. Importantly, compound 12 exhibited excellent pharmacokinetic profiles and good anti-liver fibrosis effects in vivo. Collectively, compound 12 holds promise for developing an anti-liver fibrosis agent.
Asunto(s)
Compuestos Heterocíclicos , Receptores Activados del Proliferador del Peroxisoma , Humanos , Receptores Activados del Proliferador del Peroxisoma/agonistas , Cirrosis Hepática/tratamiento farmacológico , Receptores Citoplasmáticos y Nucleares , Hipoglucemiantes , PiperazinasRESUMEN
Patients with arterial embolic disease have benefited greatly from antiplatelet therapy. However, hemorrhage risk of antiplatelet agents cannot be ignored. Herein, we describe the discovery of 2,3-dihydro[1,4]dioxino[2,3-g]benzofuran compounds as novel PAR4 antagonists. Notably, the isomers 36 and 37 with the chemotype of phenoxyl methylene substituted on the 2,3-dihydro-1,4-dioxine ring exhibited potent in vitro antiplatelet activity (IC50 = 26.13 nM for 36 and 14.26 nM for 37) and significantly improved metabolic stability in human liver microsomes (T1/2 = 97.6 min for 36 and 11.1 min for BMS-986120). 36 also displayed good oral PK profiles (mice: T1/2 = 7.32 h and F = 45.11%). Both of them showed overall potent ex vivo antiplatelet activity at concentrations of 6 and 12 mg/kg, with no impact on the coagulation system and low bleeding liability. Our work will facilitate development of novel PAR4 antagonists as a safer therapeutic option for arterial embolism.
Asunto(s)
Benzofuranos , Trombosis , Humanos , Ratones , Animales , Receptores de Trombina , Inhibidores de Agregación Plaquetaria/metabolismo , Hemorragia/inducido químicamente , Hemorragia/tratamiento farmacológico , Hemorragia/metabolismo , Coagulación Sanguínea , Trombosis/tratamiento farmacológico , Benzofuranos/uso terapéutico , Agregación Plaquetaria , Receptor PAR-1/metabolismo , Receptor PAR-1/uso terapéutico , Plaquetas/metabolismoRESUMEN
A metal-free and thiol-free organophosphorus-catalyzed method for forming thioethers was disclosed, driven by PIII/PVâO redox cycling. In this work, one-step dehydroxylative thioetherification of alcohols was fulfilled with various hypervalent organosulfur compounds. This established strategy features an excellent functional group tolerance and broad substrate scope, especially inactivated alcohols. The scale-up reaction and further transformation of the product were also successful. Additionally, this method offers a protecting-group-free and step-efficient approach for synthesizing peroxisome proliferator-activated receptor agonists which exhibited promising potential for treating osteoporosis in mammals.