Structure-based design of 2-arylamino-4-cyclohexylmethoxy-5-nitroso-6-aminopyrimidine inhibitors of cyclin-dependent kinase 2

An efficient synthesis of 2-substituted O(4)-cyclohexylmethyl-5-nitroso-6-aminopyrimidines from 6-amino-2-mercaptopyrimidin-4-ol has been developed and used to prepare a range of derivatives for evaluation as inhibitors of cyclin-dependent kinase 2 (CDK2). The structure-activity relationships (SARs) are similar to those observed for the corresponding O(6)-cyclohexylmethoxypurine series with the 2-arylsulfonamide and 2-arylcarboxamide derivatives showing excellent potency. Two compounds, 4-(6-amino-4-cyclohexylmethoxy-5-nitrosopyrimidin-2-ylamino)-N-(2-hydroxyethyl)benzenesulfonamide (7q) and 4-(6-amino-4-cyclohexylmethoxy-5-nitrosopyrimidin-2-ylamino)-N-(2,3-dihydroxypropyl)benzenesulfonamide (7s), were the most potent with IC50 values of 0.7 +/- 0.1 and 0.8 +/- 0.0 nM against CDK2, respectively. The SARs determined in this study are discussed with reference to the crystal structure of 4-(6-amino-4-cyclohexylmethoxy-5-nitrosopyrimidin-2-ylamino)-N-(2,3-dihydroxypropyl)benzenesulfonamide (7j) bound to phosphorylated CDK2/cyclin A.     

Radical catalyzed debromination of bromo-alkanes by formate in aqueous solutions via a hydrogen atom transfer mechanism

CO₂⁻ radicals catalyze the dehalogenation of bromo-alkanes by formate via a hydrogen atom transfer mechanism.     

FURTHER CHARACTERIZATION OF ANESTHETIC-TREATED PURPLE MEMBRANES

Abstract— The absorption maximum of bacteriorhodopsin is shifted from 568 nm to 480 nm when halogenated volatile anesthetics (enflurane; halothane) are added to purple membranes. Analysis of the rate of formation of this new species upon addition of the anesthetic and of the back-formation of native bacteriorhodopsin upon its removal indicate that in purple membranes, the dark-adapted chromophore is much less reactive than its light-adapted counterpart. Lipid-soluble molecules thus have a lower accessibility to the dark-adapted chromophore.
In addition, activity of the 480 nm bacteriorhodopsin was investigated. Flash and steady-state photolysis experiments reveal that this blue shifted chromophore has full photochemical activity. It has a meta-intermediate absorbing maximally at 380 nm. The photocycle ofBR–480 is mainly characterized by a slow decay of the "O" intermediate, enabling the direct observation of the branching reaction between the "M" intermediate and the parentBR–480 pigment.     

Chimeras in leaky integrate-and-fire neural networks: effects of reflecting connectivities

The effects of attracting-nonlocal and reflecting connectivity are investigated in coupled Leaky Integrate-and-Fire (LIF) elements, which model the exchange of electrical signals between neurons. Earlier investigations have demonstrated that repulsive-nonlocal and hierarchical network connectivity can induce complex synchronization patterns and chimera states in systems of coupled oscillators. In the LIF system we show that if the elements are nonlocally linked with positive diffusive coupling on a ring network, the system splits into a number of alternating domains. Half of these domains contain elements whose potential stays near the threshold and they are interrupted by active domains where the elements perform regular LIF oscillations. The active domains travel along the ring with constant velocity, depending on the system parameters. When we introduce reflecting coupling in LIF networks unexpected complex spatio-temporal structures arise. For relatively extensive ranges of parameter values, the system splits into two coexisting domains: one where all elements stay near the threshold and one where incoherent states develop, characterized by multi-leveled mean phase velocity profiles.     

Cellular and molecular responses of E. fetida c?lomocytes exposed to TiO2 nanoparticles

An in vitro approach using c?lomocytes of Eisenia fetida was investigated to evaluate toxicity of TiO₂ nanoparticles. C?lomocytes were exposed to well-dispersed suspension of small aggregates (130?nm) of TiO₂ nanoparticles (1?C25???g/ml) during 4, 12 and 24?h. Intracellular localisation suggested that the main route of uptake was endocytosis. Cellular responses showed that TiO₂ nanoparticles were not cytotoxic and had no effect on phagocytosis at any of the four concentrations for each time tested. Concerning molecular responses, an increase of fetidin and metallothionein mRNA expression was observed starting from 4?h of exposure. In contrast, expression of coelomic cytolytic factor mRNA decreased for 10 and 25???g/ml after 4?h. Superoxide dismutase, catalase and glutathione-S-transferase expression were not modified suggesting that oxidative stress was not induced by TiO₂ in our experimental conditions. This in vitro approach showed that TiO₂ nanoparticles were taken up by c?lomocytes and they could modify the molecular response of immune and detoxification system.