RESUMEN
Ligands for retinoid X receptors (RXRs), "rexinoids", are attracting interest as candidates for therapy of type 2 diabetes and Alzheimer's and Parkinson's diseases. However, current screening methods for rexinoids are slow and require special apparatus or facilities. Here, we created 7-hydroxy-2-oxo-6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2H-chromene-3-carboxylic acid (10, CU-6PMN) as a new fluorescent RXR agonist and developed a screening system of rexinoids using 10. Compound 10 was designed based on the fact that umbelliferone emits strong fluorescence in a hydrophilic environment, but the fluorescence intensity decreases in hydrophobic environments such as the interior of proteins. The developed assay using 10 enabled screening of rexinoids to be performed easily within a few hours by monitoring changes of fluorescence intensity with widely available fluorescence microplate readers, without the need for processes such as filtration.
Asunto(s)
Colorantes Fluorescentes/química , Ligandos , Receptores X Retinoide/agonistas , Umbeliferonas/química , Unión Competitiva , Genes Reporteros , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Concentración 50 Inhibidora , Unión Proteica , Receptores X Retinoide/genética , Receptores X Retinoide/metabolismo , Tetrahidronaftalenos/química , Umbeliferonas/metabolismoRESUMEN
The retinoid X receptor (RXR) partial agonist 1-[(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl)amino]benzotriazole-5-carboxylic acid (1; CBt-PMN, Emax = 75%, EC50 = 143 nM) is a candidate for treatment of central nervous system (CNS) diseases such as Alzheimer's and Parkinson's diseases based on reports that RXR-full agonist 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene) shows therapeutic effects on these disease in rodent models. Here, we synthesized carbon-11-labeled ([11C]1) as a tracer for positron emission tomography (PET) and used it in a PET imaging study to examine the brain uptake and biodistribution of 1. We found that 11CO2 fixation after tin-lithium exchange at -20 °C afforded [11C]1. This methodology may also be useful for synthesizing 11CO2H-PET tracer derivatives of other compounds bearing π-rich heterocyclic rings. A PET/CT imaging study of [11C]1 in mice indicated 1 is distributed to the brain and is thus a candidate for treatment of CNS diseases.
Asunto(s)
Radiofármacos/síntesis química , Radiofármacos/farmacología , Receptores X Retinoide/agonistas , Tetrahidronaftalenos/síntesis química , Tetrahidronaftalenos/farmacología , Triazoles/síntesis química , Triazoles/farmacología , Animales , Autorradiografía , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Dióxido de Carbono/química , Radioisótopos de Carbono , Agonismo Parcial de Drogas , Litio/química , Masculino , Ratones Endogámicos ICR , Compuestos Orgánicos de Estaño/química , Tomografía de Emisión de Positrones , Radiofármacos/administración & dosificación , Tetrahidronaftalenos/administración & dosificación , Triazoles/administración & dosificaciónRESUMEN
Indolo[3,2-b]quinoline analogs (3a-3s), 4-(acridin-9-ylamino) phenol hydrochloride (4), benzofuro[3,2-b]quinoline (3t), indeno[1,2-b]quinolines (3u and 3v) have been synthesized. Those compounds were found to exhibit anti-bacterial activity towards Methicillin-resistant Staphylococcus aureus (anti-MRSA activity). Structure-activity relationship studies were conducted that indoloquinoline ring, benzofuroquinoline ring and 4-aminophenol group are essential structure for anti-MRSA activity.
Asunto(s)
Indoles/química , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Quinolinas/química , Quinolinas/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Antibacterianos/farmacología , Farmacorresistencia Bacteriana/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Quinolinas/síntesis química , Relación Estructura-ActividadRESUMEN
Optically active structural isomers (1b-f and dst-1b-f) of 3',4'-di-(O)-(-)-camphanoyl-(+)-khellactone (DCK) were synthesized and their anti-human immunodeficiency virus (HIV) activity was investigated. The value of the sensitivity index (SI) of 1b was greater than that of DCK.
Asunto(s)
Fármacos Anti-VIH/química , Fármacos Anti-VIH/farmacología , Alcanfor/análogos & derivados , Cumarinas/química , Cumarinas/farmacología , Infecciones por VIH/tratamiento farmacológico , VIH/efectos de los fármacos , Fármacos Anti-VIH/síntesis química , Cumarinas/síntesis química , Humanos , Isomerismo , Relación Estructura-ActividadRESUMEN
A structure involving the absolute configuration of acinetobactin (1b) was clarified. It was reconfirmed that preacinetobactin (1a) produced 1b by a rearrangement reaction.
Asunto(s)
Acinetobacter baumannii/química , Imidazoles/síntesis química , Oxazoles/síntesis química , Imidazoles/química , Estructura Molecular , Oxazoles/químicaRESUMEN
A palladium-assisted coupling reaction of aryl triflate with arene was investigated, and a novel Pd reagent prepared from equimolar Pd(OAc)2, 1,3-Bis[diphenylphosphino]propane (DPPP), and Bu3P was developed. This method is useful for intramolecular biaryl coupling reactions, not only between aryl triflate and arene (triflate-amide), but also between aryl halide and arene (halo-amide).
