The diarylisoxazole molecular scaffold is found in several NSAIDs, especially those with high selectivity for COX-1. Here, we have determined the structural basis for COX-1 binding to two ...diarylisoxazoles: mofezolac, which is polar and ionizable, and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole (P6) that has very low polarity. X-ray analysis of the crystal structures of COX-1 bound to mofezolac and 3-(5-chlorofuran-2-yl)-5-methyl-4-phenylisoxazole allowed the identification of specific binding determinants within the enzyme active site, relevant to generate structure/activity relationships for diarylisoxazole NSAIDs.
Display omitted
•X-ray analysis of the crystal structure of COX-1 bound to mofezolac.•X-ray analysis of the crystal structure of COX-1 bound to P6.•Binding determinants for highly selective COX-1 inhibition.•Selective diarylisoxazole scaffold inhibitors as tools to study COX-1 active site.
Neuroinflammation is the earliest stage of several neurological and neurodegenerative diseases. In the case of neurodegenerative disorders, it takes place about 15–20 years before the appearance of ...specific neurodegenerative clinical symptoms. Constitutive microglial COX-1 is one of the pro-inflammatory players of the neuroinflammation. Novel compounds 3, 14 and 15 (Galmof0, Galmof5 and Galmof11, respectively) were projected, and their synthetic methodologies developed, by linking by an ester bond, directly or through a C5 or C11 unit linker the highly selective COX-1 inhibitor mofezolac (COXs selectivity index > 6000) to galactose in order to obtain substances capable to cross blood-brain barrier (BBB) and control the CNS inflammatory response. 3, 14 and 15 (Galmofs) were prepared in good to fair yields. Galmof0 (3) was found to be a selective COX-1 inhibitor (COX-1 IC50 = 0.27 μM and COX-2 IC50 = 3.1 μM, selectivity index = 11.5), chemically and metabolically stable, and capable to cross Caco-2 cell monolayer, resembling BBB, probing that its transport is GLUT-1-mediated. Furthermore, Galmof0 (3) powerfully inhibits PGE2 release higher than mofezolac (1) in LPS-stimulated mouse BV2 microglial cell line, a worldwide recognized neuroinflammation model. In addition, Fingerprints for Ligands and Proteins (FLAP) was used to explain the different binding interactions of Galmofs with the COX-1 active site.
Display omitted
•Selective COX-1 inhibitors.•Mofezolac-galactose conjugates to affect neuroinflammation.•LPS-stimulated BV2 microglial cell as a neuroinflammatory model.•Evidence of active transport through Caco-2 cell layer.•BBB permeation.
A set of novel diarylisoxazoles has been projected using mofezolac (1) as a lead compound to investigate structure-inhibitory activity relationships of new compounds and the cyclooxygenases (COXs) ...catalytic activity. Mofezolac was chosen because is the most potent and selective reversible COX-1 inhibitor COX-1 IC50 = 0.0079 μM and COX-2 IC50 > 50 μM, with a selectivity index (SI) in favor of COX-1 higher than 6300. Seventeen new compounds were synthesized in fair to good yields and evaluated for their COXs inhibitory activity and selectivity. SIs ranged between 1 and higher than 1190.3,4-Bis(4-methoxyphenyl)-5-vinylisoxazole (22) has the highest SI with COX-1 IC50 = 0.042 μM and COX-2 IC50 > 50 μM. 1 and 22 were superior to aspirin in inhibiting platelet aggregation (IC50 = 0.45, 0.63 and 1.11 μM, respectively) in human platelet rich plasma (hPRP) assay. They did not induce blood coagulation and hemolysis, and are neither genotoxic nor mutagen. 1 and 22 slightly increase bortezomib cytotoxic effect on multiple myeloma (MM) cell lines (NCI-H929 and RPMI-8226) and affects MM cell cycle and apoptosis when co-administered with the proteasome inhibitor bortezomib, a drug clinically used to treat plasma cell neoplasms including MM. In addition, structure-based binding mode of 1 and 22, through Fingerprints for Ligands and Proteins (FLAG) calculation, allowed to explain the one order of magnitude difference between COX-1 IC50 values of the two compounds. Specifically, the higher inhibitory potency seems due to the formation of a H-bond between COX-1 S530 and the carboxyl, present in 1 and absent in 22.
Display omitted
•Mofezolac-derived COX-1 inhibitors combined with bortezomib.•Mofezolac structure-inhibitory activity relationships.•Cytotoxic effect on multiple myeloma cell lines when Bortezomib is co-administered with COX-1 inhibitors.
The effects of side chain modification and chirality in linezolid-like 1,2,4-oxadiazoles have been studied to design new potent antibacterials against Gram-positive multidrug-resistant pathogens. The ...adopted strategy involved a molecular modelling approach for the design of active enantiomers, the synthesis and biological evaluation of the designed compounds, enantiomers separation and absolute configuration assignment. Display omitted
The effects of side chain modification and chirality in linezolid-like 1,2,4-oxadiazoles have been studied to design new potent antibacterials against Gram-positive multidrug-resistant pathogens. The adopted strategy involved a molecular modelling approach, the synthesis and biological evaluation of new designed compounds, enantiomers separation and absolute configuration assignment. Experimental determination of the antibacterial activity of the designed (S)-1-((3-(4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-oxazolidin-2-one-5-yl)methyl)-3-methylthiourea and (S)-1-((3-(3-fluoro-4-(3-methyl-1,2,4-oxadiazol-5-yl)phenyl)-oxazolidin-2-one-5-yl)methyl)-3-methylthiourea against multidrug resistant linezolid bacterial strains was higher than that of linezolid.
The Political Transition in Italy Di Cosimo, G; Cossiri, Angela
Bulletin of the Transilvania University of Brașov. Series VII, Social sciences, law,
2013
2
Journal Article
Recenzirano
Odprti dostop
Italy is in a transitional phase to a new party system, which will probably lead to a different method of institutional functioning. This essay illustrates the transition from the Berlusconi ...Government to Monti Government end after to the “Grand coalition” Government. This step opens an unprecedented phase of the Italian democracy which seems to mark a break with the characteristics that the political and institutional life had taken in recent years. Although it is too early to describe the characteristics of the new phase, we can highlight some points which justify the assessment of the discontinuity. Among the main features of institutional life in the era of Berlusconism, can be mentioned the charismatic leadership, the context of heightened corporatism of the political class, the mortification of the Parliament and the transfer of its legislative powers to the Government, the constant aggression against Constitution and Fundamental Rights, the attempt to impose ethical views by the majority.
The KLOE detector is designed primarily for the study of direct CP violation in K
0 decays. The electromagnetic calorimeter, EmC, is a most demanding element of the detector. Two prototypes of the ...EmC (one for the
barrel and one for the
end-cap region) have been built at Frascati and tested at PSI (Switzerland) using beams of electrons, muons and pions of 40 to 290 MeV/
c momentum, and at the Frascati LADON facility using photons of 20 to 80 MeV. We observe excellent linearity from 20 to 290 MeV. The energy resolution is
σ(E)/E ∼ 4.4% / ”E(
GeV)
and the time resolution is ∼ 34 ps/”
E(GeV). We found little dependence on incidence angle and entry position. We also determined that some
π
μ
identification is possible.
The ADCs and TDCs for the KLOE electromagnetic calorimeter Antonelli, M.; Barbiellini, G.; Bertolucci, S. ...
Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
05/1998, Letnik:
409, Številka:
1-3
Journal Article
Recenzirano
Odprti dostop
The KLOE electromagnetic calorimeter processes signals arriving over an interval of ≈200ns before the trigger time. The KLOE ADC is based on two continuously analog baseline subtraction systems. A ...high stability monostable circuit is used at the input of the TDC operating in common start mode.
The construction of the KLOE lead-scintillating fibres electromagnetic calorimeter has been completed. The final results of the extensive quality checks of all the calorimeter modules are presented ...here. The measurements have been done in the Frascati Laboratories at a cosmic ray test facility using minimum ionizing particles. The results show that all the calorimeter modules are well fulfilling the design specifications concerning time and energy resolutions. Furthermore, by using the same cosmic ray facility, all the calorimeter elements have been also pre-calibrated.
The KLOE electromagnetic calorimeter Antonelli, M.; Anulli, F.; Barbiellini, G. ...
Nuclear physics. B, Proceedings supplement/Nuclear physics. B, Proceedings supplements,
02/1998, Letnik:
61, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Test beam results of a full scale barrel prototype of the KLOE electromagnetic calorimeter satisfied the experimental requirements, so initiating the calorimeter mass production.
At the Frascati ...National Laboratory of INFN a test stand was set up to use cosmic rays for quality control and first calibrations of the modules produced in mass construction. The results show that the fibers and photomultipllers performances exceed our expectations. Combining cosmic rays and test beam measurements a time resolution of 55 ps/√E(GeV) and an energy resolution of 4.7%/√E(GeV) are expected for electromagnetic showers. The end of modules assembling and calibration is foreseen for the early 1997.
Fast luminosity monitor at LEP
Nuclear instruments and methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment/Nuclear instruments & methods in physics research. Section A, Accelerators, spectrometers, detectors and associated equipment,
09/1994
Journal Article
PDF
