608-34-4Relevant academic research and scientific papers
Pyrimidinedione derivative capable of inhibiting monocarboxylate transporter
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Paragraph 0192; 0193, (2019/03/26)
The invention relates to a pyrimidinedione derivative capable of inhibiting a monocarboxylate transporter, the pyrimidinedione derivative is a formula (I) compound and/or a pharmaceutically acceptablesalt thereof, and/or a stereoisomer thereof, and/or a solvate thereof, the compound has the effect of inhibiting the activity of the monocarboxylate transporter, and also comprises a pharmaceutical composition containing the formula (I) compound and the use of the pharmaceutical composition in treatment.
Design and synthesis of uracil urea derivatives as potent and selective fatty acid amide hydrolase inhibitors
Qiu, Yan,Ren, Jie,Ke, Hongwei,Zhang, Yang,Gao, Qi,Yang, Longhe,Lu, Canzhong,Li, Yuhang
, p. 22699 - 22705 (2017/07/10)
Fatty acid amide hydrolase (FAAH) is one of the key enzymes involved in the biological degradation of endocannabinoids, especially anandamide. Pharmacological blockage of FAAH restores the levels of endocannabinoids, providing therapeutic benefits in the management of inflammation, depression and multiple sclerosis. In this study, a series of uracil urea derivatives as FAAH inhibitors were designed and synthesized. Structural modifications at the C5 position and side chain of N-hexyl-2,4-dioxo-3,4-dihydropyrimidine-1(2H)-carboxamide (1a) led to FAAH inhibitors with improved potency and selectivity. Structure-activity relationship (SAR) studies indicated that C5 electron-withdrawing substituents were preferred for optimal potency but not for selectivity, whereas replacement of the alkyl chain with phenylalkyl moieties or biphenyl groups significantly improved both inhibitory potency and selectivity towards FAAH. Two highly potent picomolar FAAH inhibitors (4c, IC50 = 0.3 ± 0.05 nM; 4d, IC50 = 0.8 ± 0.1 nM) were developed. Compound 4c inhibited FAAH in a rapid, selective, noncompetitive, and irreversible pattern. This study provides several highly potent and selective FAAH inhibitors and an optimized chemical scaffold for the development of FAAH inhibitors. We anticipate that these FAAH inhibitors will enable new possibilities in understanding FAAH functions and development of therapeutics for pain and inflammatory diseases.
Discovery of a new class of highly potent inhibitors of acid ceramidase: Synthesis and structure-activity relationship (SAR)
Pizzirani, Daniela,Pagliuca, Chiara,Realini, Natalia,Branduardi, Davide,Bottegoni, Giovanni,Mor, Marco,Bertozzi, Fabio,Scarpelli, Rita,Piomelli, Daniele,Bandiera, Tiziano
supporting information, p. 3518 - 3530 (2013/06/27)
Acid ceramidase (AC) is an intracellular cysteine amidase that catalyzes the hydrolysis of the lipid messenger ceramide. By regulating ceramide levels in cells, AC may contribute to the regulation of cancer cell proliferation and senescence and to the response to cancer therapy. We recently identified the antitumoral agent carmofur (4a) as the first nanomolar inhibitor of intracellular AC activity (rat AC, IC50 = 0.029 μM). In the present work, we expanded our initial structure-activity relationship (SAR) studies around 4a by synthesizing and testing a series of 2,4-dioxopyrimidine-1- carboxamides. Our investigations provided a first elucidation of the structural features of uracil derivatives that are critical for AC inhibition and led us to identify the first single-digit nanomolar inhibitors of this enzyme. The present results confirm that substituted 2,4-dioxopyrimidine-1-carboxamides are a novel class of potent inhibitors of AC. Selected compounds of this class may represent useful probes to further characterize the functional roles of AC.
Oxidative damage of pyrimidine nucleosides by the environmental free radical oxidant NO3? in the absence and presence of NO2? and other radical and non-radical oxidants
Goeschen, Catrin,White, Jonathan M.,Gable, Robert W.,Wille, Uta
experimental part, p. 427 - 437 (2012/08/07)
Analysis of the products formed in the reaction of the environmental free radical oxidant NO3? with permethylated uridine 1 and thymidine 2 in solution revealed highly complex reaction pathways following initial NO3? induced oxidative electron transfer at the pyrimidine ring. Product formation was found to depend not only on the nature of the nucleobase, but also on the presence of other free radical oxidants, namely NO2?. In the reaction of 1 with NO3?, which was generated through CAN photolysis, apart from formation of the highly oxidized nucleoside derivative 4 as the major product, cleavage of the CN glycosidic bond did also occur, resulting in formation of ribolactone 5 and the free nucleobase 6. The suggested mechanism involves in situ generation of NO2? during the course of the reaction, which promotes conversion of the initially formed radical cation 7 to 4 in an autocatalytic fashion.When the reaction of NO 2? with O3 was used to generate NO 3?, the initially formed radical cation 7 in the reaction with permethylated uridine 1 is rapidly trapped by NO2 ? to give 5-nitrouridine 18 in a radical mediated vinylic substitution reaction. In contrast to this, under similar conditions in the reaction involving thymidine 2 the highly oxidized products 20 and 21 are obtained as major compounds, which result from addition to the C5C6 double bond. No direct reaction between NO3? and the carbohydrate moiety in 1 and 2 was found. Also, no reaction occurred between the nucleosides and mixtures of NO2?/N2O4 and O3/O2, respectively.
PROCESS FOR STRAIGHTENING KERATIN FIBRES WITH A HEATING MEANS AND DENATURING AGENTS
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, (2010/03/02)
The invention relates to a process for straightening keratin fibres, comprising: (i) a step in which a straightening composition containing at least two denaturing agents is applied to the keratin fibres, (ii) a step in which the temperature of the keratin fibres is raised, using a heating means, to a temperature of between 110 and 250° C.
Reactions of trimethylsilyl fluorosulfonyldifluoroacetate with purine and pyrimidine nucleosides
Rapp, Magdalena,Cai, Xiaohong,Xu, Wei,Dolbier Jr., William R.,Wnuk, Stanislaw F.
experimental part, p. 321 - 328 (2009/12/04)
Difluorocarbene, generated from trimethylsilyl fluorosulfonyldifluoroacetate (TFDA), reacts with the uridine and adenosine substrates preferentially at the enolizable amide moiety of the uracil ring and the 6-amino group of the purine ring. 2′,3′-Di-O-ben
Synthesis of uracil derivatives by oxidation of Fischer tungsten-carbene uracil complexes
Sala, Giorgio Della,Artillo, Antonietta,Ricart, Susagna,Spinella, Aldo
, p. 1623 - 1627 (2007/10/03)
A study on the oxidation of Fischer tungsten-carbene uracil complexes has been carried out. Several commonly used oxidants gave results strongly influenced by the presence of substituent on nitrogen atoms. In particular, usual oxidants failed in the oxidation of 3-alkyl uracil carbene complexes. Finally, we showed that t-butyl hydroperoxide is able to oxidize successfully also 3-alkyl uracil carbene complexes and can be used as a good alternative to the other methods.
HSAB-driven chemoselective N1-alkylation of pyrimidine bases and their 4-methoxy- or 4-acetylamino-derivatives
Gambacorta, Augusto,Tofani, Daniela,Loreto, Maria Antonietta,Gasperi, Tecla,Bernini, Roberta
, p. 6848 - 6854 (2007/10/03)
The lithium salts of the conjugated bases of 4-methoxy- and 4-acetylamino-2(1H)-pyrimidinones 1-3 undergo highly chemoselective N1-methylation or ethylation when treated with methyl- or ethylsulfate (hard electrophiles) in dry dioxane, while the use of DMF as solvent results in competitive O2-alkylation. Potassium salts of the same bases in DMF undergo prevalent O2-attack. Under the same conditions, a similar but less chemoselective behaviour is observed in alkylation of thymine and uracil, where some N3-attack occurs. This can be rationalised in terms of the HSAB principle.
Synthesis and pharmacology of willardiine derivatives acting as antagonists of kainate receptors
Dolman, Nigel P.,Troop, Helen M.,More, Julia C. A.,Alt, Andrew,Knauss, Jody L.,Nistico, Robert,Jack, Samantha,Morley, Richard M.,Bortolotto, Zuner A.,Roberts, Peter J.,Bleakman, David,Collingridge, Graham L.,Jane, David E.
, p. 7867 - 7881 (2007/10/03)
The natural product willardiine (8) is an AMPA receptor agonist while 5-iodowillardiine (10) is a selective kainate receptor agonist. In an attempt to produce antagonists of kainate and AMPA receptors analogues of willardiine with substituents at the N3 position of the uracil ring were synthesized. The N3-4-carboxybenzyl substituted analogue (38c) was found to be equipotent at AMPA and GLUK5-containing kainate receptors in the neonatal rat spinal cord. The N3-2-carboxybenzyl substituted analogue (38a) proved to be a potent and selective GLUK5 subunit containing kainate receptor antagonist when tested on native rat and human recombinant AMPA and kainate receptor subtypes. The GLUK5 kainate receptor antagonist activity was found to reside in the S enantiomer (44a) whereas the R enantiomer (44b) was almost inactive. 5-Iodo substitution of the uracil ring of 44a gave 45, which was found to have enhanced potency and selectivity for GLU K5.
Effect of the structure of 1- and 3-methylpyrimidin-4-ones on the rate of nucleophilic substitution of the 2-methylsylfanyl group
Kheifets,Gindin,Nikolova
, p. 104 - 113 (2007/10/03)
Rate constants for substitution of the 2-methylsulfanyl group in 1- and 3-methyl-2-methylsulfanyl-pyrimidin-4-ones and their 5-fluoro analogs were measured in the reaction with butylamine, alkaline hydrolysis, and methanolysis. The rate of substitution in 1-methyl isomers having a zwitterionic structure is greater by a factor of ～2 than the rate of substitution in 3-methyl isomers with conjugated double bonds in the ring. The presence of a fluorine atom in position 5 accelerates nucleophilic substitution in 1-methyl isomers, while 5-fluoro-3-methyl-2-methylsulfanylpyrimidin-4-ones react at a lower rate than their 5-unsubstituted analogs. According to the NMR data, the reactions involve formation of a tetrahedral intermediate. Anchimeric effect of the methyl group on N1 hampers attack by basic reagent on the C6 atom.
