RESUMO
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.
Assuntos
Corantes Fluorescentes/química , Ligantes , Receptores X de Retinoides/agonistas , Umbeliferonas/química , Ligação Competitiva , Genes Reporter , Humanos , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Ligação Proteica , Receptores X de Retinoides/genética , Receptores X de Retinoides/metabolismo , Tetra-Hidronaftalenos/química , Umbeliferonas/metabolismoRESUMO
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.
Assuntos
Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacologia , Receptores X de Retinoides/agonistas , Tetra-Hidronaftalenos/síntese química , Tetra-Hidronaftalenos/farmacologia , Triazóis/síntese química , Triazóis/farmacologia , Animais , Autorradiografia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Dióxido de Carbono/química , Radioisótopos de Carbono , Agonismo Parcial de Drogas , Lítio/química , Masculino , Camundongos Endogâmicos ICR , Compostos Orgânicos de Estanho/química , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/administração & dosagem , Tetra-Hidronaftalenos/administração & dosagem , Triazóis/administração & dosagemRESUMO
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.
Assuntos
Indóis/química , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Quinolinas/química , Quinolinas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Farmacorresistência Bacteriana/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Quinolinas/síntese química , Relação Estrutura-AtividadeRESUMO
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.
Assuntos
Fármacos Anti-HIV/química , Fármacos Anti-HIV/farmacologia , Cânfora/análogos & derivados , Cumarínicos/química , Cumarínicos/farmacologia , Infecções por HIV/tratamento farmacológico , HIV/efeitos dos fármacos , Fármacos Anti-HIV/síntese química , Cumarínicos/síntese química , Humanos , Isomerismo , Relação Estrutura-AtividadeRESUMO
A structure involving the absolute configuration of acinetobactin (1b) was clarified. It was reconfirmed that preacinetobactin (1a) produced 1b by a rearrangement reaction.
Assuntos
Acinetobacter baumannii/química , Imidazóis/síntese química , Oxazóis/síntese química , Imidazóis/química , Estrutura Molecular , Oxazóis/químicaRESUMO
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).
