611-08-5Relevant articles and documents
Electron-deficient heteroarenium salts: An organocatalytic tool for activation of hydrogen peroxide in oxidations
?turala, Ji?í,Bohá?ová, Soňa,Chudoba, Josef,Metelková, Radka,Cibulka, Radek
, p. 2676 - 2699 (2015/03/18)
A series of monosubstituted pyrimidinium and pyrazinium triflates and 3,5-disubstituted pyridinium triflates were prepared and tested as simple catalysts of oxidations with hydrogen peroxide, using sulfoxidation as a model reaction. Their catalytic efficiency strongly depends on the type of substituent and is remarkable for derivatives with an electron-withdrawing group, showing reactivity comparable to that of flavinium salts which are the prominent organocatalysts for oxygenations. Because of their high stability and good accessibility, 4-(trifluoromethyl)pyrimidinium and 3,5-dinitropyridinium triflates are the catalysts of choice and were shown to catalyze oxidation of aliphatic and aromatic sulfides to sulfoxides, giving quantitative conversions, high preparative yields and excellent chemoselectivity. The high efficiency of electron-poor heteroarenium salts is rationalized by their ability to readily form adducts with nucleophiles, as documented by low pKR+ values (pKR+ red > -0.5 V). Hydrogen peroxide adducts formed in situ during catalytic oxidation act as substrate oxidizing agents. The Gibbs free energies of oxygen transfer from these heterocyclic hydroperoxides to thioanisole, obtained by calculations at the B3LYP/6-311++g(d,p) level, showed that they are much stronger oxidizing agents than alkyl hydroperoxides and in some cases are almost comparable to derivatives of flavin hydroperoxide acting as oxidizing agents in monooxygenases.
Optimisation of LRRK2 inhibitors and assessment of functional efficacy in cell-based models of neuroinflammation
Munoz, Lenka,Kavanagh, Madeline E.,Phoa, Athena F.,Heng, Benjamin,Dzamko, Nicolas,Chen, Ew-Jun,Doddareddy, Munikumar Reddy,Guillemin, Gilles J.,Kassiou, Michael
supporting information, p. 29 - 34 (2015/03/30)
LRRK2IN1 is a highly potent inhibitor of leucine-rich repeat kinase 2 (LRRK2, IC50 = 7.9 nM), an established target for treatment of Parkinson's disease. Two LRRK2IN1 analogues 1 and 2 were synthesised which retained LRRK2 inhibitory activity (1: IC50 = 72 nM; 2: IC50 = 51 nM), were predicted to have improved bioavailability and were efficacious in cell-based models of neuroinflammation. Analogue 1 inhibited IL-6 secretion from LPS-stimulated primary human microglia with EC50 = 4.26 μM. In order to further optimize the molecular properties of LRRK2IN1, a library of truncated analogues was designed based on docking studies. Despite lacking LRRK2 inhibitory activity, these compounds show antineuroinflammatory efficacy at micromolar concentration. The compounds developed were valuable tools in establishing a cell-based assay for assessing anti-neuroinflammatory efficacy of LRRK2 inhibitors. Herein, we present data that IL-1β stimulated U87 glioma cell line is a reliable model for neuroinflammation, as data obtained in this model were consistent with results obtained using primary human microglia and astrocytes.
Synthesis and characterization of 9-methyl-2-morpholin-4-yl-8-substituted phenyl-1H-purine derivatives using polyphosphoric acid (PPA) as an efficient catalyst
Sadanandam,Jyothi,Adharvana Chari,Das, Parthasarathi,Mukkanti
body text, p. 5521 - 5524 (2011/10/30)
We demonstrate the synthesis of various purine derivatives through the coupling of N4-methyl-2-morpholin-4-yl-pyrimidine-4,5-diamine with various aldehydes by using polyphosphoric acid (PPA) as an efficient catalyst in DMF at reflux temperature
The role of phosphate in the action of thymidine phosphorylase inhibitors: Implications for the catalytic mechanism
Jain, Harsh V.,Rasheed, Roshni,Kalman, Thomas I.
body text, p. 1648 - 1651 (2010/08/20)
The design and synthesis of 5-fluoro-6-[(2-aminoimidazol-1-yl)methyl]uracil (AIFU), a potent inhibitor of thymidine phosphorylase (TP) with Ki-values of 11 nM (ecTP) and 17 nM (hTP), are described. Kinetic studies established that the type of inhibition of TP by AIFU is uncompetitive with respect to inorganic phosphate (or arsenate). The results obtained suggest that AIFU and other zwitterionic thymine analog inhibitors of TP act as transition state analogs, mimicking the anionic thymine leaving group, consistent with an SN2-type catalytic mechanism, and anchored by their protonated side chains to the enzyme-bound phosphate by electrostatic and H-bonding interactions.
INHIBITORS OF JANUS KINASES
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Page/Page column 77, (2010/01/12)
The instant invention provides for compounds that inhibit the four known mammalian JAK kinases (JAK1, JAK2, JAK3 and TYK2) and PDK1. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting the activity of JAK1, JAK2, JAK3, TYK2 and PDK1 by administering the compound to a patient in need of treatment for myeloproliferative disorders or cancer.
Ozone-mediated Nitration of Pyrazole, Imidazole and Uracil with Nitrogen Dioxide
Suzuki, Hitomi,Nonoyama, Nobuaki
, p. 244 - 245 (2007/10/03)
In the presence of ozone, pyrazole and uracil were easily N-nitrated with nitrogen dioxide in dichloromethane at 0°C to give the corresponding 1-nitro derivatives, whilst imidazole was C-nitrated in the additional presence of methanesulfonic acid as catalyst to afford the 4-nitro derivative, each product being obtained in a satisfactory yield.
Structure-Activity Relations. Part 12. Antibacterial Activity of a Series of 2,4-Diamino-6-substituted 5-(4-pyridylmethylamino)pyrimidines and 2,4-Diamino-5-(4-substituted benzylamino)pyrimidines.
Bowden, Keith,Bright, Andrew C.
, p. 514 - 539 (2007/10/02)
A series of 6-substituted 2,4-diamino-5-(4-pyridylamino)pyrimidines and of 2,4-diamino-5-(4-substituted benzylamino)pyrimidines has been prepared.Their antibacterial activity towards L. casei, S. aureus and E. coli has been investigated.These activities have been successfully correlated by Hansch-type relations.Dependence on both lipophilicity and electronic (polar) factors has been found.The results are related to the structure and interactions with the receptor.
Kinetics of Electron Transfer from Nitroaromatic Radical Anions in Aqueous solutions. Effects of Temperature and Steric Configuration
Meot-Ner, Michael,Neta, P.
, p. 4648 - 4650 (2007/10/02)
Rate constants for electron transfer from various nitroaromatic radical anions to other nitroaromatic compounds in aqueous solutions have been determined by kinetic spectrophotometric pulse radiolysis.The rate constants were found to increase from ca. 105 to ca. 108 M-1 s-1 upon increase in driving force (ΔE) from 0 to ca. 300mV, while the activation energies decrease from ca. 6 to ca 3 kcal/mol.Nitro compounds with ortho substituents exhibit lower reduction potentials due to rotation of the nitro group away from the ring plane.Anion radicals of such compounds transfer their electrons much more slowly (k down to ca. 106 M-1 s-1) despite the apparent increase in ΔE (to ca. 550 mV).This behavior is rationalized by an increase in solvent reorganization energies around these radical anions caused by localization of the charge.In general, nitroaromatic radical anions donate electrons much more slowly than other radical anions, in reactions with similar driving forces, due to low self-exchange rates for ArNO2/ArNO-..The kinetics show no anomalies in supercooled solutions.
