- Design, synthesis of 1,3-dimethylpyrimidine-2,4-diones as potent and selective aldehyde dehydrogenase 1A1 (ALDH1A1) inhibitors with glucose consumption improving activity
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LDH1A1, one of 19 NAD(P)+-dependent aldehyde dehydrogenases, participates in multiple metabolic pathways and has been indicated to play an important role in obesity and diabetes. In this study, a series of 1,3-dimethylpyrimidine-2,4-diones were designed, synthesized and evaluated as novel selective aldehyde dehydrogenase 1A1 inhibitors. Among them, compounds 46, 50, 53, 56 and 57 exhibited excellent inhibitory activity against ALDH1A1 with IC50 values in the low nanomolar range and high selectivity over ALDH1A2, ALDH1A3, ALDH2 and ALDH3A1. Furthermore, in vitro study demonstrated that compound 57 effectively improved glucose consumption in HepG2 cells compared to compound 1 (CM026).
- Jiang, Cheng,Jiang, Ling,Li, Guoxin,Li, Luanfeng,Liang, Dailin,Liu, Li,Ma, Zonghui
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Read Online
- The impact of 5-substituted uracil derivatives on immortalized embryo lung cells
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Background: Pyrimidine-based drugs stimulate tissue regeneration and immunity, two components that need to be improved in a number of respiratory diseases of different etiology (e.g. influenza and asthma). In the present study we investigated relationships between the character of substitutions in the uracil structure and the impact of the respective uracil derivatives on the immortalized lung cells. Methods: The level of cell proliferation, maximum tolerated dose and toxic effect of 5-substituted uracil derivatives (12 compounds) were studied on the immortalized lung epithelial cells and compared with the ones of 6-methyluracil. Results: 5-Carboxyuracil and 1,3-dimethyl-5-carboxyuracil had the lowest cytotoxicity among the studied compounds. Their maximal tolerated dosage values were 5 times higher whereas the proliferation index was increased by 25% and 75%, respectively, compared to 6-methyluracil, known for its positive effects on cell regeneration. Conclusion: 5-Carboxyuracil and 1,3-dimethyl-5-carboxyuracil have the best perspectives for further studies on their biological effects.
- Kabal’nova, Natalia N,Grabovskiy, Stanislav A.,Andriayshina, Nadezhda M.,Egorov, Vladislav I.,Valiullin, Lenar R.,Nabatov, Alexey A.,Raginov, Ivan S.,Murinov, Yurii I.
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p. 1409 - 1414
(2017/12/28)
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- IMIDAZOPYRROLIDINONE COMPOUNDS
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The invention relates to compounds of formula (I): (I) as described herein, pharmaceutical preparations comprising such compounds, uses and methods of use for such compounds in the treatment of a disorder or a disease mediated by the activity of MDM2 and/or MDM4, and combinations comprising such compounds.
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Page/Page column 280
(2013/08/15)
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- Dehydrogenation, oxidative denitration and ring contraction of N,N-dimethyl-5-nitrouracil by a Bacillus nitroreductase Nfr-A1
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Nfr-A1, a Bacillus subtilis nitroreductase, catalyzes the nitroreduction of a large panel of aromatic and heterocyclic nitro compounds, except those belonging to nitrouracil class of molecules. Besides nitroreduction, Nfr-A1 exhibits a strong NADH oxidase activity in the presence of oxygen, leading to high concentration of H2O2 (up to 200 μM). In the presence of (N,N)-dimethyl-5-nitrouracil 1 (dim-NU), Nfr-A1 achieves the reduction of dim-NU double bond to compounds 2 and 3 and in parallel the oxidation of dim-NU to the denitrated five membered derivatives 4 and 5. The reduction is catalyzed by the reduced flavin Fl-Red and resembles those catalyzed by dihydropyrimidine dehydrogenases (DPD), during the catabolism of pyrimidines. The oxidative denitration is catalyzed in part by hydrogen peroxide generated through the NADH-oxidase activity, and certainly by the peroxyflavin intermediate Fl-OOH for the other part. The mechanisms of reaction were proposed according to experimental data and literature. These findings together with our previous results on the potential biological role of Nfr-A1, confirm the large spectrum of catalysis supported by this enzyme. The oxidative denitration is sporadically reported in literature and represents a safe and green alternative for the remediation of nitro-compounds.
- Cortial, Sylvie,Chaignon, Philippe,Sergent, Didier,Dezard, Sophie,Ouazzani, Jamal
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experimental part
p. 1 - 8
(2012/04/17)
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- A novel method of caffeine synthesis from uracil
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An inexpensive and novel method of caffeine synthesis starting from uracil in six simple steps is described. Uracil 1 is first converted to I, 3-dimethyluracil 2, followed by nitration, reduction, and cyclization to theophylline and finally methylation of theophylline forms caffeine.
- Zajac, Matthew A.,Zakrzewski, Anthony G.,Kowal, Mark G.,Narayan, Saraswathi
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p. 3291 - 3297
(2007/10/03)
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- Novel Reaction of Uracil Derivatives Possessing Electron-withdrawing Groups at the 5-Position with Amines: Exchange Reaction between the N1-Portion of Uracils and Amines
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The reaction of 1,3-disubstituted uracils possessing an electron-withdrawing group such as nitro, carbamoyl, and cyano at 5-position with primary amines resulted in the exchange of the N1-portion of the uracil ring with the amine moiety.The exchange reactions were influenced by the nature of substituents at the 5- and N1-position.The reaction sequence is explained in terms of addition, ring-opening, and ring-closure.
- Hirota, Kosaku,Kitade, Yukio,Sajiki, Hironao,Maki, Yoshifumi,Yogo, Motoi
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p. 367 - 373
(2007/10/02)
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- NOVEL REACTION OF 5-NITRO(OR CARBAMOYL)URACIL DERIVATIVES WITH AMINES. THERMAL EXCHANGE REACTION OF N1-PORTION OF THE URACILS FOR AMINES VIA RING-OPENING AND RING-CLOSURE PROCESSES
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The reaction of 1,3-disubstituted uracils possessing an electron withdrawing group at the 5-position with amines induced exchange of N1-portion of the uracil ring for amines.This reaction was accelerated by substitution of phenyl groups at the N1-position.
- Hirota, Kosaku,Kitade, Yukio,Sajiki, Hironao,Maki, Yoshifumi
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p. 3263 - 3266
(2007/10/02)
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- NITRATION OF AROMATIC HETEROCYCLES WITH PALLADIUM(II) ACETATE AND SODIUM NITRITE.
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Treatments of 1,3-dimethyluracil, 1-methyl-2-pyridone, and thiophene with palladium(II) acetate and sodium nitrite gave the corresponding nitro-substituted products.
- Itahara,Ebihara,Kawasaki
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p. 2171 - 2172
(2007/10/02)
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- Alkylation des pyrimidines en catalyse par transfert de phase
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Nous rapportons ici, la premiere etude concernant l'alkylation simple et efficace, en catalyse par transfert de phase, de dianions pyrimidiques ambidents derives de l'uracile, de la thymine, du nitro-5 uracile, du fluoro-5 uracile, du chloro-6 uracile, de la tetrahydro-1,2,3,4 dioxo-2,4 quinazoline, conduisant selectivement et avec de hauts rendements, aux derives N1,N3-dialkyles correspondants.
- Hedayatullah, Mir
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p. 339 - 342
(2007/10/02)
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