ABSTRACT
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.
Subject(s)
Fluorescent Dyes/chemistry , Ligands , Retinoid X Receptors/agonists , Umbelliferones/chemistry , Binding, Competitive , Genes, Reporter , Humans , Hydrophobic and Hydrophilic Interactions , Inhibitory Concentration 50 , Protein Binding , Retinoid X Receptors/genetics , Retinoid X Receptors/metabolism , Tetrahydronaphthalenes/chemistry , Umbelliferones/metabolismABSTRACT
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.
Subject(s)
Radiopharmaceuticals/chemical synthesis , Radiopharmaceuticals/pharmacology , Retinoid X Receptors/agonists , Tetrahydronaphthalenes/chemical synthesis , Tetrahydronaphthalenes/pharmacology , Triazoles/chemical synthesis , Triazoles/pharmacology , Animals , Autoradiography , Brain/diagnostic imaging , Brain/metabolism , Carbon Dioxide/chemistry , Carbon Radioisotopes , Drug Partial Agonism , Lithium/chemistry , Male , Mice, Inbred ICR , Organotin Compounds/chemistry , Positron-Emission Tomography , Radiopharmaceuticals/administration & dosage , Tetrahydronaphthalenes/administration & dosage , Triazoles/administration & dosageABSTRACT
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.
Subject(s)
Indoles/chemistry , Methicillin-Resistant Staphylococcus aureus/drug effects , Quinolines/chemistry , Quinolines/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Drug Resistance, Bacterial/drug effects , Microbial Sensitivity Tests , Quinolines/chemical synthesis , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Camphor/analogs & derivatives , Coumarins/chemistry , Coumarins/pharmacology , HIV Infections/drug therapy , HIV/drug effects , Anti-HIV Agents/chemical synthesis , Coumarins/chemical synthesis , Humans , Isomerism , Structure-Activity RelationshipABSTRACT
A structure involving the absolute configuration of acinetobactin (1b) was clarified. It was reconfirmed that preacinetobactin (1a) produced 1b by a rearrangement reaction.
Subject(s)
Acinetobacter baumannii/chemistry , Imidazoles/chemical synthesis , Oxazoles/chemical synthesis , Imidazoles/chemistry , Molecular Structure , Oxazoles/chemistryABSTRACT
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).
