1076-22-8Relevant articles and documents
Synthesis, radiolabelling and initial biological characterisation of 18F-labelled xanthine derivatives for PET imaging of Eph receptors
Belter, Birgit,Caflisch, Amedeo,K?ckerling, Martin,Kinski, Elisa,Mamat, Constantin,Neuber, Christin,Pietzsch, Jens,Pretze, Marc,Steinbach, J?rg
, p. 3104 - 3116 (2020)
Eph receptor tyrosine kinases, particularly EphA2 and EphB4, represent promising candidates for molecular imaging due to their essential role in cancer progression and therapy resistance. Xanthine derivatives were identified to be potent Eph receptor inhibitors with IC50 values in the low nanomolar range (1-40 nm). These compounds occupy the hydrophobic pocket of the ATP-binding site in the kinase domain. Based on lead compound 1, we designed two fluorine-18-labelled receptor tyrosine kinase inhibitors ([18F]2/3) as potential tracers for positron emission tomography (PET). Docking into the ATP-binding site allowed us to find the best position for radiolabelling. The replacement of the methyl group at the uracil residue ([18F]3) rather than the methyl group of the phenoxy moiety ([18F]2) by a fluoropropyl group was predicted to preserve the affinity of the lead compound 1. Herein, we point out a synthesis route to [18F]2 and [18F]3 and the respective tosylate precursors as well as a labelling procedure to insert fluorine-18. After radiolabelling, both radiotracers were obtained in approximately 5% radiochemical yield with high radiochemical purity (>98%) and a molar activity of >10 GBq μmol-1. In line with the docking studies, first cell experiments revealed specific, time-dependent binding and uptake of [18F]3 to EphA2 and EphB4-overexpressing A375 human melanoma cells, whereas [18F]2 did not accumulate at these cells. Since both tracers [18F]3 and [18F]2 are stable in rat blood, the novel radiotracers might be suitable for in vivo molecular imaging of Eph receptors with PET.
Inhibition kinetics of theophylline metabolism by mexiletine and its metabolites
Ogiso,Iwaki,Uno
, p. 75 - 81 (1995)
To further characterize the mode of drug interaction between theophylline (TP) and mexiletine (ME), in vitro kinetic studies were carried out using rat liver microsomes and 9000 x g supernatant. The kinetic study revealed that the K, value and V(max)/K(m) ratio for the metabolic conversion of TP to 1,3-dimethyluric acid (1,3-DMU) were the second lowest and the highest, respectively, of four metabolic pathways. Thus, the rank of efficiency of the oxidative metabolism by microsomal cytochrome P-450 (P-450) isozymes was TP to 1,3-DMU > TP to 1-methylxanthine (1-MX) > TP to 3-MX > 1,3-DMU to 1-methyluric acid, suggesting that the isozyme metabolizing TP would have a higher affinity for the oxidation at the 8-position in TP molecules than at the 1- and 3-positions. Lineweaver-Burk plots showed that the conversion of TP to 3-MX and to 1,3-DIMU was inhibited competitively by ME and its metabolites, and that the pathway of TP to 1-MX was inhibited noncompetitively. In consideration of the K(i) values calculated, it seems probable that deamino-p-hydroxy ME (DApHME) might be the most potent inhibitor of the metabolic pathways of TP, and that the rank order of inhibition is approximately DApHME > p-hydroxy ME > deamino-hydroxymethyl ME > ME > hydroxymethyl ME, with some exceptions. The mechanism of the interaction between TP and ME is probably due to the metabolic antagonism in the liver, and TP, ME and their metabolites share' some of the same metabolic pathways, mediated by P-450 isozymes.
Synthesis and bio-evaluation of a novel selective butyrylcholinesterase inhibitor discovered through structure-based virtual screening
Chen, Yao,Chen, Ying,Feng, Feng,Jiao, Mengxia,Li, Qi,Liu, Wenyuan,Lu, Weixuan,Sun, Haopeng,Wang, Yuanyuan,Xing, Shuaishuai,Xiong, Baichen
, p. 1352 - 1364 (2021)
In recent years, butyrylcholinesterase (BChE) has gradually gained worldwide interests as a novel target for treating Alzheimer's disease (AD). Here, two pharmacophore models were generated using Schr?dinger suite and used to virtually screen ChemDiv database, from which three hits were obtained. Among them, 2513–4169 displayed the highest inhibitory activity and selectivity against BChE (eeAChE IC50 > 10 μM, eqBChE IC50 = 3.73 ± 1.90 μM). Molecular dynamic (MD) simulation validated the binding pattern of 2513–4169 in BChE, and it could form a various of receptor-ligand interactions with adjacent residues. In vitro cytotoxicity assay proved the safety of 2513–4169 on diverse neural cell lines. Moreover, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay performed on SH-SY5Y cells proved the neuroprotective effect of 2513–4169 against toxic Aβ1–42. In vivo behavioral study further confirmed the great efficacy of 2513–4169 on reversing Aβ1–42-induced cognitive impairment of mice and clearing the toxic Aβ1–42 in brains. Moreover, 2513–4169 was proved to be able to cross blood-brain barrier (BBB) through a parallel artificial membrane permeation assay of BBB (PAMPA-BBB). Taken together, 2513–4169 is a promising lead compound for future optimization to discover anti-AD treating agents.
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Townsend,Robins
, p. 3008,3011 (1962)
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Ayrey,Yeomans
, p. 323,338 (1976)
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Facile syntheses of xanthines from uric acids
Takayama,Ashizawa,Suzuki,Sekiya
, p. 1200 - 1202 (1974)
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Novel, Dual Target-Directed Annelated Xanthine Derivatives Acting on Adenosine Receptors and Monoamine Oxidase B
Brockmann, Andreas,Doroz-P?onka, Agata,Ja?ko, Piotr,Kie?-Kononowicz, Katarzyna,Kuder, Kamil J.,Latacz, Gniewomir,Müller, Christa E.,Olejarz-Maciej, Agnieszka,Schabikowski, Jakub,Za?uski, Micha?
, (2020)
Annelated purinedione derivatives have been shown to act as possible multiple-target ligands, addressing adenosine receptors and monoaminooxidases. In this study, based on our previous results, novel annelated pyrimido- and diazepino[2,1-f]purinedione derivatives were designed as dual-target-directed ligands combining A2A adenosine receptor (AR) antagonistic activity with blocking monoamine oxidase B. A library of 19 novel compounds was synthesized and biologically evaluated in radioligand binding studies at AR subtypes and for their ability to inhibit MAO-B. This allowed 9-(2-chloro-6-fluorobenzyl)-3-ethyl-1-methyl-6,7,8,9-tetrahydropyrimido[2,1-f]purine-2,4(1H,3H)-dione (13 e; Ki human A2AAR: 264 nM and IC50 human MAO-B: 243 nM) to be identified as the most potent dual-acting ligand from this series. ADMET parameters were estimated in vitro, and analysis of the structure-activity relationships was complemented by molecular-docking studies based on previously published X-ray structures of the protein targets. Such dual-acting ligands, by selectively blocking A2A AR, accompanied by the inhibition of dopamine metabolizing enzyme MAO-B, might provide symptomatic and neuroprotective effects in, among others, the treatment of Parkinson disease.
Studies on xanthine and related compounds. V. Uracil cyclization of (acylaminocyanoacetyl) ureas
Sekiya,Osaki
, p. 854 - 856 (1966)
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Preparation method of theobromine
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, (2021/01/11)
The invention discloses a preparation method of theobromine, and relates to the technical field of preparation of heterocyclic compounds containing purine ring systems. The method comprises the following steps: adding oxalyl chloride into cyanoacetic acid and a solvent at the temperature of -10-20 DEG C, concentrating to remove the solvent and oxalyl chloride after reaction, adding monomethylureaand the solvent at the temperature of 0-30 DEG C, adding alkali as an acid-binding agent, adding water after reaction, stirring, and filtering to obtain monomethyl cyanoacetylurea; adding water to dissolve cyanuric chloride, adding liquid caustic soda to adjust the pH value to 8-11, and reacting at 80-100 DEG C to generate methyl 4AU; dissolving monomethyl 4AU in formic acid, adding sodium nitrite, reacting at room temperature, adding a catalyst, keeping the temperature at 30-70 DEG C, recovering the catalyst after the reaction is finished, and concentrating mother liquor to recover formic acid, thereby obtaining monomethyl FAU; adding water and liquid caustic soda into monomethyl FAU, carrying out ring-closure reaction, and then adding acid to adjust to be neutral, so as to obtain 3-methyl xanthine; and carrying out a methylation reaction on 3-methylxanthine, and refining to obtain theobromine. The method has the advantages of few reaction steps, few side reactions, high yield and stable product quality.
