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1.
ACS Med Chem Lett ; 15(5): 722-730, 2024 May 09.
Artículo en Inglés | MEDLINE | ID: mdl-38746878

RESUMEN

Colony stimulating factor-1 receptor (CSF1R or c-FMS), a class III receptor tyrosine kinase expressed on members of the mononuclear phagocyte system (MPS), plays a key role in the proper functioning of macrophages, microglia, and related cells. Aberrant signaling through CSF1R has been associated with a variety of disease states, including cancer, inflammation, and neurodegeneration. In this Letter, we detail our efforts to develop novel CSF1R inhibitors. Drawing on previously described compounds, including GW2580 (4), we have discovered a novel series of compounds based on the imidazo[4,5-b]pyridine scaffold. Initial structure-activity relationship studies culminated in the identification of 36, a lead compound with potent CSF1R biochemical and cellular activity, acceptable in vitro ADME properties, and oral exposure in rat.

2.
Food Chem ; 445: 138771, 2024 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-38394912

RESUMEN

Zanthoxylum bungeanum essential oil (ZBEO) Pickering emulsion was incorporated into rice protein (RP)/sodium alginate (SA)-based film to enhance the antioxidant activity and compatibility. With increasing ZBEO content from 2 % to 4 %, the average size of ZBEO Pickering emulsion ranged from 124.28 to 165.65 nm. The best mechanical property with a tensile strength of 14.56 MPa and hydrophobicity with a water vapor permeability of 2.11 × 10-12 g⋅cm-1⋅s-1⋅Pa-1 of emulsion film were achieved with 0.8 % ZBEO. In addition, the loss of ZBEO in the emulsion films was reduced by 11-14 %. The DPPH radical scavenging activity of emulsion film with 1.2 % ZBEO was 65.54 % in 95 % ethanol. The results of Fourier transform infrared spectroscopy and molecular dynamics simulation showed that electrostatic interactions played a leading role in film formation. Overall, ZBEO Pickering emulsion is an effective method to enhance the antioxidant activity, mechanical strength and hydrophobicity of RP/SA film.


Asunto(s)
Aceites Volátiles , Zanthoxylum , Aceites Volátiles/química , Alginatos/química , Antioxidantes/química , Zanthoxylum/química , Emulsiones
3.
Org Lett ; 25(13): 2338-2343, 2023 Apr 07.
Artículo en Inglés | MEDLINE | ID: mdl-36975042

RESUMEN

An intriguing visible-light-induced strategy has been established for the P-H insertion reaction between acylsilanes and H-phosphorus oxides that, upon a subsequent acidic process, deliver a wide variety of α-hydroxyphosphorus oxides in good yields (up to 93% yield). The metal-free protocol represents a unique example of P-H insertion for C-P bond formation through in situ generation of siloxycarbenes. This methodology features the advantages of operational simplicity, mild conditions, broad substrate scope, and column free in gram-scale synthesis.

4.
SLAS Discov ; 26(6): 783-797, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33955247

RESUMEN

Classical high-throughput screening (HTS) technologies for the analysis of ionic currents across biological membranes can be performed using fluorescence-based, radioactive, and mass spectrometry (MS)-based uptake assays. These assays provide rapid results for pharmacological HTS, but the underlying, indirect analytical character of these assays can be linked to high false-positive hit rates. Thus, orthogonal and secondary assays using more biological target-based technologies are indispensable for further compound validation and optimization. Direct assay technologies for transporter proteins are electrophysiology-based, but are also complex, time-consuming, and not well applicable for automated profiling purposes. In contrast to conventional patch clamp systems, solid supported membrane (SSM)-based electrophysiology is a sensitive, membrane-based method for transporter analysis, and current technical developments target the demand for automated, accelerated, and sensitive assays for transporter-directed compound screening. In this study, the suitability of the SSM-based technique for pharmacological compound identification and optimization was evaluated performing cell-free SSM-based measurements with the electrogenic amino acid transporter B0AT1 (SLC6A19). Electrophysiological characterization of leucine-induced currents demonstrated that the observed signals were specific to B0AT1. Moreover, B0AT1-dependent responses were successfully inhibited using an established in-house tool compound. Evaluation of current stability and data reproducibility verified the robustness and reliability of the applied assay. Active compounds from primary screens of large compound libraries were validated, and false-positive hits were identified. These results clearly demonstrate the suitability of the SSM-based technique as a direct electrophysiological method for rapid and automated identification of small molecules that can inhibit B0AT1 activity.


Asunto(s)
Sistemas de Transporte de Aminoácidos Neutros/metabolismo , Fenómenos Electrofisiológicos , Ensayos Analíticos de Alto Rendimiento/métodos , Sistemas de Transporte de Aminoácidos Neutros/agonistas , Sistemas de Transporte de Aminoácidos Neutros/antagonistas & inhibidores , Animales , Bioensayo/métodos , Transporte Biológico/efectos de los fármacos , Células CHO , Membrana Celular/metabolismo , Cricetulus , Humanos , Ratones , Técnicas de Placa-Clamp/métodos , Reproducibilidad de los Resultados , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología
5.
Artículo en Inglés | MEDLINE | ID: mdl-33519947

RESUMEN

OBJECTIVE: The possible core active compounds and potential mechanism of action of Shiyifang Vinum were explored through network pharmacology and in vitro enzyme activity verification experiments. METHODS: We screened the core active components and the action targets of Shiyifang Vinum through the TCMSP database and literature mining and drew a Venn map of the intersection with anti-inflammatory and analgesic-related gene targets. Go and KEGG analyses were enriched with the David database. The compound target pathway network was constructed using Cytoscape 3.6.1. The binding strength of core active compounds and target proteins was verified through molecular docking, and the direct effects of Shiyifang Vinum and four monomer compounds on COX-2 enzyme activity were detected through an in vitro enzyme activity test. RESULTS: 14 active compounds and 11 targets were screened out from Shiyifang Vinum through TCMSP database and literature mining; 252 GO entries were obtained by GO analysis, and 114 signal pathways were screened by KEGG analysis. The results of the molecular docking showed that the core compounds and target proteins had strong binding activity. In vitro validation experiments showed that both the Shiyifang Vinum and the four monomer compounds could inhibit the activity of COX-2. CONCLUSION: This study preliminarily explored the potential active compounds and target proteins of the anti-inflammatory and analgesic effects of Shiyifang Vinum, which could provide a scientific basis for further study on the anti-inflammatory and analgesic mechanism and material basis of this recipe.

6.
Acc Chem Res ; 36(10): 773-82, 2003 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-14567711

RESUMEN

This Account highlights recent studies describing utility of allenamides in stereoselective inter- and intramolecular synthetic methodologies. It is written to raise interest in the chemistry of allenamides.

7.
J Org Chem ; 68(5): 1729-35, 2003 Mar 07.
Artículo en Inglés | MEDLINE | ID: mdl-12608785

RESUMEN

A detailed account regarding a formal [3 + 3] cycloaddition method using 4-hydroxy-2-pyrones and 1,3-diketones is described here. This formal cycloaddition reaction or annulation reaction is synthetically useful for constructing 2H-pyranyl heterocycles. The usage of alpha,beta-unsaturated iminium salts is significant in controlling competing reaction pathways to give exclusively 2H-pyrans. Most significantly, experimental evidence is provided to support the mechanism of this reaction that involves a sequential Knoevenagel condensation and a reversible 6pi-electron electrocyclic ring-closure of 1-oxatrienes.


Asunto(s)
Química Orgánica/métodos , Cetonas/química , Piranos/síntesis química , Pironas/química , Alquenos/química , Catálisis , Cristalografía por Rayos X , Ciclización , Iminas/química , Indicadores y Reactivos , Espectroscopía de Resonancia Magnética , Estructura Molecular , Oxidación-Reducción , Sales (Química)/síntesis química , Estereoisomerismo
8.
J Am Chem Soc ; 124(35): 10435-42, 2002 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-12197745

RESUMEN

Evidence is described here to support that a highly stereoselective 6pi-electron electrocyclic ring closure of 1-azatrienes is a key step in formal [3 + 3] cycloaddition or annulation reactions of chiral vinylogous amides with alpha,beta-unsaturated iminium salts. This would represent the first highly stereoselective 6pi-electron electrocyclic ring closure of 1-azatrienes. We have also unambiguously demonstrated that these specific ring closures are reversible, leading to the major diastereomer that is also thermodynamically more stable, and that a rotation preference likely also plays a role. A synthetic application is illustrated here to stereoselectively transform the resulting dihydropyridines to cis-1-azadecalins with unique anti relative stereochemistry at C2 and C2a, leading to synthesis of epi isomers of (-)-pumiliotoxin C.


Asunto(s)
Alcaloides/síntesis química , Venenos de Anfibios/síntesis química , Naftalenos/síntesis química , Quinolinas , Alcaloides/química , Alquenos/química , Venenos de Anfibios/química , Compuestos Aza/síntesis química , Compuestos Aza/química , Ciclización , Naftalenos/química , Estereoisomerismo
10.
Angew Chem Int Ed Engl ; 40(8): 1516-1518, 2001 Apr 17.
Artículo en Inglés | MEDLINE | ID: mdl-29712373

RESUMEN

Complex piperidinyl heterocycles (for example, 2) were accessed by using a novel intramolecular formal [3+3] cycloaddition reaction of vinylogous amides tethered with enals (for example, 1). This method has been applied to a formal total synthesis of (+)-gephyrotoxin (3).

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