- Potent, Selective, and Cell Active Protein Arginine Methyltransferase 5 (PRMT5) Inhibitor Developed by Structure-Based Virtual Screening and Hit Optimization
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PRMT5 plays important roles in diverse cellular processes and is upregulated in several human malignancies. Besides, PRMT5 has been validated as an anticancer target in mantle cell lymphoma. In this study, we found a potent and selective PRMT5 inhibitor by performing structure-based virtual screening and hit optimization. The identified compound 17 (IC50 = 0.33 μM) exhibited a broad selectivity against a panel of other methyltransferases. The direct binding of 17 to PRMT5 was validated by surface plasmon resonance experiments, with a Kd of 0.987 μM. Kinetic experiments indicated that 17 was a SAM competitive inhibitor other than the substrate. In addition, 17 showed selective antiproliferative effects against MV4-11 cells, and further studies indicated that the mechanism of cellular antitumor activity was due to the inhibition of PRMT5 mediated SmD3 methylation. 17 may represent a promising lead compound to understand more about PRMT5 and potentially assist the development of treatments for leukemia indications.
- Mao, Ruifeng,Shao, Jingwei,Zhu, Kongkai,Zhang, Yuanyuan,Ding, Hong,Zhang, Chenhua,Shi, Zhe,Jiang, Hualiang,Sun, Dequn,Duan, Wenhu,Luo, Cheng
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p. 6289 - 6304
(2017/08/02)
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- HEPATITIS C VIRUS INHIBITORS
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Hepatitis C virus inhibitors having the general formula (I) are disclosed. Compositions comprising the compounds and methods for using the compounds to inhibit HCV are also disclosed.
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- HETEROCYCLIC ACETAMIDE COMPOUND
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[Problem] A compound which is useful as a dopamine D1 receptor positive allosteric modulator (D1 PAM) is provided. [Means for Solution] The present inventors have studied a compound which has a dopamine D1 receptor positive allosteric modulating activity and is useful as an active ingredient of a pharmaceutical composition for preventing and/or treating cognitive impairment, negative symptoms of schizophrenia, Parkinson's disease, Alzheimer's disease, Huntington's disease, drug addictions, or the like, and they have thus found that a heterocyclic acetamide compound has a dopamine D1 receptor positive allosteric modulating activity, thereby completing the present invention. The heterocyclic acetamide compound of the present invention has a dopamine D1 receptor positive allosteric modulating activity and can be used as an agent for preventing and/or treating cognitive impairment, negative symptoms of schizophrenia, Parkinson's disease, Alzheimer's disease, Huntington's disease, drug addictions, or the like.
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Paragraph 0223
(2014/10/29)
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- Phototransformations of 6-X-5-nitroquinoxalines
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Photophysical properties and photochemical activity of 6-X-5- nitroquinoxalines with electron-donor substituents (X = H, CH3, Cl, OC2H5, NH2) ortho to the nitro group were studied. The quantum yield of the formation of 5-hydroxyquinoxaline from the corresponding nitro derivative depends on the nature of the substituent and irradiation conditions. Phototransformations can go through nitro-nitrite rearrangement with the participation of two alternative T(nπ*) levels, depending on the size and electronic effects of the substituent. The latter factor is largely determined by the population on excitation of different charge-transfer states involving the nitro group.
- Rtishchev,Selitrennikov
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p. 428 - 437
(2007/10/03)
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- Reaction of 5-halo-1,2,3-thiadiazoles with aliphatic diamines. Synthesis and intramolecular cyclization of bis(1,2,3-triazolyl-1,2,3-thiadiazolyl)sulfides
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Bis[1,2,3]triazolo[1,5-f:5′,1′-b][1,3,6]thiadiazepine and [1,5-g:5′,1′-b][1,3,7]thiadiazocine ring systems have been synthesized from 5-halo-1,2,3-thiadiazoles and aliphatic diamines. We have found that the last step of the process is the cyclization of initially formed bis(1,2,3-triazolyl-1,2,3-thiadiazolyl)sulfides. The structures of the intermediates and products were supported by different NMR spectroscopic methods (1H coupled 13C NMR, 2D HETCOR, HMBC and 1D INADEQUATE experiments) and mass spectrometry. Differences in the reaction pathway for aliphatic and less nucleophilic aromatic diamines were determined.
- Volkova, Natalya N.,Tarasov, Evgeniy V.,Kodess, Mikhail I.,Van Meervelt,Dehaen, Wim,Bakulev, Vasiliy A.
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p. 4030 - 4038
(2007/10/03)
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- BASICITY AND STRUCTURE OF 5-HYDROXYBENZIMIDAZOLES IN NITROMETHANE
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Examination of the acid-base properties of 5-hydroxybenzimidazoles has shown them to exist in nitromethane as the 5-hydroxy-tautomers.Substituents in the 2-position have a predominantly inductive effect on the basicity of the 3-nitrogen, rationalized as in other nitrogen heterocycles by the proximity of the substituents to the reaction center. Keywords: 5-hydroxybenzimidazole, its tautomers and derivatives; acid-base properties and the effect thereon of substituents; Taft and inductive constants.
- Korolev, B. A.,Osmolovskaya, L. A.,Kuznetsov, Yu. V.,Stolyarova, L. G.,Smirnov, L. D.
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p. 333 - 336
(2007/10/02)
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- Inhibition of Rat Hepatic Microsomal Aminopyrine N-Demethylase Activity by Benzimidazole Derivatives. Quantitative Structure-Activity Relationships
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Eighty-two benzimidazole derivatives have been prepared and tested for the ability to inhibit cytochrome P-450 mediated enzyme activity (aminopyrine N-demethylase) from phenobarbitone-induced rat hepatic microsomes.Using physicochemical parameters and multiple regression analysis, we derived a quantitative structure-activity relationship (QSAR) that describes up to 87percent of the data variance in terms of hydrophobic and electronic effects and the molar refractivity of the substituent in the 2-position of the benzimidazole ring.
- Murray, Michael,Ryan, Adrian J.,Little, Peter J.
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p. 887 - 892
(2007/10/02)
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- Process for the manufacture of benzimidazolones-(2)
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Process for the manufacture of benzimidazolones-(2) wherein an o-phenylenediamine is reacted with optionally alkylated urea in the ratio of 1 to 1.3 moles per mole o-phenylenediamine in an organic solvent which has a solubility in water of not more than 5 g/l and has a boiling point above 100° C, at a temperature between 100° and 200° C.
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