ABSTRACT
The efficient oxidation of benzylic alcohols to carbonyl compounds was performed using chloramine-T and a catalytic amount of indium(III) triflate. The primary benzylic alcohols were converted to the corresponding aldehydes in a good yield, and the secondary benzylic alcohols were oxidized to ketones in a high yield. The optimized reaction conditions required 0.3 eq of indium(III) triflate and the use of acetonitrile as a solvent.
Subject(s)
Benzyl Alcohol/chemistry , Chloramines/chemistry , Ketones/chemical synthesis , Tosyl Compounds/chemistry , Ketones/chemistry , Molecular Structure , Oxidation-ReductionABSTRACT
AIMS: The P2Y6 nucleotide receptor is widely involved in inflammatory responses, and is a promising molecular target for the treatment of inflammatory diseases. Although several P2Y6 receptor antagonists have been developed and evaluated thus far, none has successfully been developed into a therapeutic drug. In this study, we explored new promising compounds that inhibit the human P2Y6 receptor. MAIN METHODS: High-throughput screening (HTS) was used to study the effects of various compounds on human P2Y6 receptors expressed in 1321N1 human astrocytoma cells by monitoring intracellular Ca2+ concentration ([Ca2+]i) levels using an FDSS7000 real-time fluorescence detector. IL-8 concentration was measured by enzyme-linked immunosorbent assay. KEY FINDINGS: Among structurally diverse chemical libraries totalling 141,700 compounds, 43 compounds with an inhibitory activity against the P2Y6 receptor were identified. Further studies using a dose-response assay, receptor selectivity assay, and chemokine measurement assay revealed the selective P2Y6 receptor inhibitor TIM-38, which inhibited UDP-induced [Ca2+]i elevation in a dose-dependent manner. TIM-38 had an IC50 value of 4.3µM and inhibited P2Y6 without affecting the response induced by four other human P2Y or muscarinic receptors. In addition, TIM-38 inhibited UDP-induced interleukin-8 release in a dose-dependent manner without affecting releases caused by other stimulus such as interleukin-1ß or tumour necrosis factor-α. Analyses of TIM-38 derivatives revealed that the nitro moiety is vital to P2Y6 receptor inhibition. SIGNIFICANCE: TIM-38 acts as a novel structural antagonist of P2Y6 receptor and may be a good lead compound for developing a P2Y6 receptor-targeted anti-inflammatory drug.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Drug Design , High-Throughput Screening Assays/methods , Purinergic P2Y Receptor Antagonists/pharmacology , Receptors, Purinergic P2/drug effects , Anti-Inflammatory Agents/administration & dosage , Anti-Inflammatory Agents/chemistry , Astrocytoma/metabolism , Calcium/metabolism , Cell Line, Tumor , Dose-Response Relationship, Drug , Enzyme-Linked Immunosorbent Assay , Humans , Inhibitory Concentration 50 , Interleukin-1beta/metabolism , Interleukin-8/metabolism , Purinergic P2Y Receptor Antagonists/administration & dosage , Purinergic P2Y Receptor Antagonists/chemistry , Receptors, Purinergic P2/metabolism , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Four hexaglycosides of methyl 3S,12S-dihydroxyhexadecanoate (1-4) were provided after treatment of the crude convolvulin fraction from Rhizoma Jalapae Braziliensis (the root of Ipomoea operculata (GOMES) MART., Convolvulaceae) with indium(III) chloride in methanol. The structures of 1-4 were elucidated on the basis of spectroscopic and chemical methods. Their sugar moieties were partially acylated with organic acids including (3S,9R)-3,6:6,9-diepoxydecanoic (exogonic) acid, (E)-2-methylbut-2-enoic (tiglic) acid, and isovaleric acid.
Subject(s)
Acids/chemical synthesis , Glycosides/chemical synthesis , Indium/chemistry , Methanol/chemistry , Methyl Ethers/chemical synthesis , Resins, Plant/chemistry , Acids/chemistry , Acylation , Convolvulaceae/chemistry , Glycosides/chemistry , Methyl Ethers/chemistry , Molecular Structure , Plant Roots/chemistryABSTRACT
Gadolinium(III) ion (Gd(3+)) complexes are widely used as contrast agents in magnetic resonance imaging (MRI), and many attempts have been made to couple them to sensor moieties in order to visualize biological phenomena of interest inside the body. However, the low sensitivity of MRI has made it difficult to develop practical MRI contrast agents for in vivo imaging. We hypothesized that practical MRI contrast agents could be designed by targeting a specific biological environment, rather than a specific protein such as a receptor. To test this idea, we designed and synthesized a Gd(3+)-based MRI contrast agent, 2BDP3Gd, for visualizing atherosclerotic plaques by linking the Gd(3+)-complex to the lipophilic fluorophore BODIPY to stain lipid-rich environments. We found that 2BDP3Gd was selectively accumulated into lipid droplets of adipocytes at the cellular level. Atherosclerotic plaques in the aorta of Watanabe heritable hyperlipidemic (WHHL) rabbits were clearly visualized in T1-weighted MR images after intravenous injection of 2BDP3Gd in vivo.
Subject(s)
Boron Compounds/chemistry , Contrast Media/chemistry , Coordination Complexes/chemistry , Fluorescent Dyes/chemistry , Gadolinium/chemistry , Plaque, Atherosclerotic/diagnosis , Adipocytes/metabolism , Adipocytes/pathology , Animals , Aorta/metabolism , Aorta/pathology , Aorta/ultrastructure , Apolipoproteins E/deficiency , Apolipoproteins E/genetics , Contrast Media/administration & dosage , Coordination Complexes/administration & dosage , Drug Design , Injections, Intravenous , Lipid Droplets/metabolism , Magnetic Resonance Imaging , Mice , Mice, Knockout , Plaque, Atherosclerotic/metabolism , Plaque, Atherosclerotic/pathology , RabbitsABSTRACT
Four new acylated glycosidic acid methyl esters were isolated after treatment of the crude ether-insoluble resin glycoside (convolvulin) fraction obtained from the seeds of Quamoclit pennata BOJER (Convolvulaceae) with indium(III) chloride in methanol. Their structures were elucidated on the basis of spectroscopic data and chemical conversions.
Subject(s)
Acids/isolation & purification , Convolvulaceae/chemistry , Glycosides/chemistry , Resins, Plant/chemistry , Seeds/chemistry , Acids/chemistry , Acylation , Chlorides/chemistry , Esters , Indium/chemistry , Methanol/chemistry , MethylationABSTRACT
Three new acylated methyl glycosides and two new acylated glycosidic acid methyl esters were isolated after treatment of the crude ether-insoluble resin glycoside (convolvulin) fraction from seeds of Quamoclit pennata BOJER (Convolvulaceae) with indium(III) chloride in methanol. Their structures were elucidated on the basis of spectroscopic data and chemical conversions.
Subject(s)
Glycosides/chemistry , Indium/chemistry , Methanol/chemistry , Resins, Plant/chemistry , Seeds/chemistry , Acylation , Ether/chemistryABSTRACT
Treatment of the ether-insoluble resin glycoside (convolvulin) fraction from seeds of Quamoclit pennata (Convolvulaceae) with indium(III) chloride in methanol provided three oligoglycosides of hydroxy fatty acid (glycosidic acid) methyl esters and two methyl glycosides, which were partially acylated by a glycosidic acid, 7S-hydroxydecanoic acid 7-O-ß-D-quinovopyranoside (quamoclinic acid B) and/or two organic acids, (E)-2-methylbut-2-enoic (tiglic) acid and/or 3R-hydroxy-2R-methylbutyric (nilic) acid. Their structures were elucidated on the basis of spectroscopic data and chemical conversions.
Subject(s)
Convolvulaceae/chemistry , Glycosides/chemistry , Methyl Ethers/chemistry , Resins, Plant/chemistry , Seeds/chemistry , Acylation , Glycosides/isolation & purification , Indium/chemistry , Methanol/chemistry , Methyl Ethers/isolation & purification , Resins, Plant/isolation & purificationABSTRACT
An oxidative methyl esterification of aldehydes was effectively achieved. The trivalent indium reagent, indium(III) triflate, was revealed to accelerate the reactions in many cases. Aromatic aldehydes with various substituents were subjected to this method, and each produced the corresponding methyl esters in good to excellent yields within a relatively short reaction time.
Subject(s)
Aldehydes/chemistry , Hydrocarbons, Aromatic/chemistry , Mesylates/chemistry , Sulfuric Acids/chemistry , Esterification , Methylation , Oxidation-ReductionABSTRACT
We studied the photobleaching of a library of boron dipyrromethene (BODIPY) derivatives with a range of electron densities, and found that the photobleaching rate is influenced by the electron-withdrawing capacity of the substituents. Electron-deficient BODIPYs generated less singlet oxygen, were less reactive to singlet oxygen, and were highly resistant to photobleaching. We confirmed the utility of one of these fluorophores, 2,6-diCO(2)R-BDP, for visualizing EGF receptor dynamics in cells expressing an SNAP-tagged EGF receptor.
Subject(s)
Boron Compounds/chemistry , ErbB Receptors/chemistry , Fluorescent Dyes/chemistry , Animals , COS Cells , Chlorocebus aethiops , Microscopy, Confocal , Molecular Dynamics Simulation , Photobleaching , Reactive Oxygen Species/chemistry , Spectrometry, FluorescenceABSTRACT
Treatment of the crude ether-insoluble resin glycoside (convolvulin) from seeds of Pharbitis nil (Pharbitis Semen), called pharbitin, with indium(III) chloride in methanol provided seven oligoglycosides of hydroxy fatty acid methyl esters partially acylated by 2-methyl-3-hydroxybutyric (nilic) and 2S-methylbutyric acids. Their structures were elucidated on the basis of NMR and MS data and chemical conversions.
Subject(s)
Fatty Acids/isolation & purification , Glycosides/isolation & purification , Ipomoea nil/chemistry , Resins, Plant/isolation & purification , Esters , Fatty Acids/chemistry , Glycosides/chemistry , Indium/pharmacology , Methanol , Molecular Structure , Nuclear Magnetic Resonance, Biomolecular , Plants, Medicinal , Resins, Plant/chemistry , Seeds/chemistryABSTRACT
A new dolabellane diterpene glycoside, named squoside A, and three new cycloartane glycosides, named squarrosides V, VI, and VII, have been isolated from the dried aerial parts of Thalictrum squarrosum (Ranunculaceae). Their structures were determined by two dimensional (2D) NMR spectroscopic analysis and chemical evidence.
Subject(s)
Diterpenes/chemistry , Glycosides/chemistry , Plant Components, Aerial/chemistry , Ranunculaceae/chemistry , Diterpenes/isolation & purification , Glycosides/isolation & purification , Magnetic Resonance Spectroscopy , Molecular Conformation , Plant Extracts/chemistry , Plant Extracts/isolation & purification , Plants, Medicinal/chemistry , StereoisomerismABSTRACT
A convergent one-step transformation of tetrahydropyranyl (THP) ethers is described. According to our earlier experiments, indium(III) triflate has proven to be an efficient catalyst for the transformation of THP ethers into their corresponding acetates. In further intensive work, we have developed a useful transforming reaction of THP ethers using various anhydride moieties. Indium(III) triflate was confirmed as a suitable catalyst, furnishing good to excellent yields. The details of this one-step transformation are described.
Subject(s)
Indium/chemistry , Mesylates/chemistry , Organometallic Compounds/chemistry , Pyrones/chemistry , Catalysis , Pyrones/chemical synthesisABSTRACT
[Structure: see text] Carboxyfluoresceins are widely utilized as fluorescence labeling reagents, but we recently found that their emission intensity is markedly decreased after esterification. On the basis of our hypothesis that the fluorescence decrease is due to a donor-excited photoinduced electron transfer (d-PeT) process, we have developed novel carboxyfluorescein derivatives in which the d-PeT process is hampered, and the emission intensity is not decreased upon esterification. These novel dye derivatives display high quantum yields and are expected to be useful as labeling agents.
Subject(s)
Coloring Agents/chemistry , Fluoresceins/chemistry , Electrons , PhotochemistryABSTRACT
The carboxylic acids are efficiently converted into the methyl esters in methanol using indium(III) chloride as the catalyst. This method is applicable for aromatic and aliphatic carboxyl moieties as well as amino acids in high yields.
Subject(s)
Indium/chemistry , Amino Acids/chemistry , Carboxylic Acids/chemistry , Catalysis , Chlorides/chemistry , Esterification , Hydrocarbons, Aromatic/chemistry , Methanol/chemistryABSTRACT
A convergent and versatile racemic total synthesis of the anti-influenza agent BCX-1812 (RWJ-270201) was accomplished on the basis of a sequence of stereoselective reactions. Despite intensive research to develop neuraminidase inhibitors to treat infections due to influenza, currently available agents are still in the need of optimization with respect to selectivity and potency, as well as to minimize adverse effects. Our synthetic approach, introduced in this report, is highly exploitable for further derivatization due to flexibility that will eventually accommodate diversified substituents. In addition, the size of the core ring can be varied depending on the size of the diene used for the preparation of the key cycloadduct 10 using an acylnitroso-based hetero-Diels-Alder reaction. Elaboration of 10 to methyl ester 14 followed by a precedented [3+2] dipolar cycloaddition gave bicyclic isoxazoline 17 in a regio- and stereoselective fashion. Incorporation of the peripheral guanidino group and subsequent deprotection provided the target molecule. The details of the synthesis are described herein.
