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.
3-Substituted xanthines as promising candidates for quadruplex formation: Computational, synthetic and analytical studies
Szolomajer, Janos,Paragi, Gabor,Batta, Gyula,Guerra, Celia Fonseca,Bickelhaupt, F. Matthias,Kele, Zoltan,Padar, Petra,Kupihar, Zoltan,Kovacs, Lajos
, p. 476 - 482 (2011)
Our computational studies suggest that 3-substituted xanthines are good candidates for tetrad and quadruplex structures. 3-Methylxanthine (3MX) has been synthesized from 7-benzylxanthine, and the existence of tetrameric and octameric aggregates of 3MX with NH4+, Na+ and K+ ions in the gas phase (MS) and in DMSO-d6 solution (NMR) has been observed. The "internal" H-bonds (N1H...O6) are stronger than the "external" ones (N7H...O2) in these clusters (NMR).
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.
Characterization of Human Cytochromes P450 Involved in Theophylline 8-Hydroxylation
Zhang, Zhi-Yi,Kaminsky, Laurence S.
, p. 205 - 212 (1995)
Studies were undertaken to determine which human P450 enzymes catalyze the metabolism of theophylline to 1,3-dimethyluric acid (1,3-DU), to facilitate predictions of theophylline drug-drug interactions, and to develop a noninvasive test for human P4501A2. Microsomes from a human cell line transfected individually with human P450 cDNAs for P4501A1, 1A2, 2A6, 2B6, 2C9, 2D6, 2E1, or 3A4 were used to demonstrate that only P4501A2 exhibited catalytic activity for theophylline metabolism to 1,3-DU with high affinity and low capacity (Km = 0.6 mM, Vmax = 37.8, pmol/min/mg), while P4502D6, 2E1, and 3A4 (Km = 14.4, 19.9, and 25.1 mM, respectively, and Vmax = 219.8, 646.4, and 20.8 pmol/min/mg, respectively) exhibited activities with low affinity and variable capacities. Correlations of rates of theophylline 8-hydroxylation to 1,3-DU with other P450 form-specific activities, in a series of ten human liver microsomal preparations, at 5 and 40 mM theophylline concentrations, revealed that at low concentrations the metabolism was catalyzed primarily by P4501A2, while at high substrate concentrations P4502E1 was primarily responsible for catalysis. The results with individually expressed P450s and hepatic microsomal preparations were consistent, indicating that the former system provides a qualitatively accurate reflection of the function of the heterogeneously expressed liver P450s. At pharmacologic theophylline concentrations achieved in vivo, its metabolism must thus be catalyzed primarily by P4501A2.
Multiplicity of cytochrome P-450 species involved in theophylline metabolism in mouse hepatic microsomes
Konishi,Morita,Yamaji
, p. 576 - 580 (1995)
To ascertain the multiplicity of the cytochrome P-450 (P-450) species participating in the individual metabolic conversion of theophylline by 8-hydroxylation, 3-demethylation and 1-demethylation in mice, kinetics were studied under various conditions using untreated and inducer-treated mouse hepatic microsomes. Eadie-Hofstee plots of 1-demethylation in untreated microsomes exhibited a straight line, whereas those of 8-hydroxylation and 3-demethylation were curved lines. The biphasic kinetics indicated the contribution of two P-450 populations to the respective metabolic pathways; one characterized by high affinity and low capacity, the other by low affinity and high capacity. The high affinity population was efficiently induced by β-naphthoflavone (β-NF), and was highly susceptible to inhibition by a specific CYP1A inhibitor. The low affinity population was sensitive to induction by phenobarbital (PB), and was markedly inhibited by preferential inhibitors for PB-inducible P-450 species. The present results indicated that two P-450 populations contributed to the theophylline metabolism in mouse hepatic microsomes, and that the high and low affinity populations corresponded, respectively, to CYP1A, and a PB-inducible P-450 species having a much higher capacity than CYP1A.
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.
Preparation method of hypoglycemic drug linagliptin intermediate
-
Paragraph 0049-0057, (2021/04/21)
The invention provides a preparation method of a hypoglycemic drug linagliptin intermediate, wherein the method comprises the steps: in the presence of a catalyst and an organic solvent, carrying out condensation reaction on o-aminoacetophenone (1) and 2-chloroacetamide (2) to obtain an intermediate II; carrying out condensation, bromination, substitution and other reactions on 4-(methylamino)-1H-imidazol-5-carboxamide (3) to generate an intermediate III; and finally, carrying out alkylation reaction on the intermediate II and the intermediate III to generate an intermediate I. According to the preparation method, generation of side reactions are avoided. Moreover, the reaction cost is saved, the operation conditions are mild, the yield is high, the post-treatment is simple, and the method is suitable for industrial large-scale production.
Linagliptin intermediate compound IV
-
Paragraph 0188; 0192, (2020/09/09)
The invention belongs to the field of pharmaceutical chemicals, and discloses a linagliptin intermediate IV and a novel route for synthesizing an important linagliptin intermediate from the linagliptin intermediate IV. The linagliptin intermediate IV synthesized in the invention has the advantages of high yield, simple operation, substantial reduction of production cost, suitableness for industrial production; and the synthesis route solves the problems of self-coupling of linagliptin intermediates and generation of large impurities in the prior art.
Linagliptin intermediate compound V
-
Paragraph 0185; 0189; 0196; 0199, (2020/09/09)
The invention belongs to the field of pharmaceutical chemicals, and provides a linagliptin intermediate compound V and an important intermediate for synthesizing linagliptin by using the intermediateV. The method solves the problems of self-coupling of linagliptin intermediates and generation of large impurities in the prior art, and the synthesized novel intermediate compound V has the advantages of high yield, simple operation, significantly reduced production cost, and suitableness for industrial production.
