Synthesis of tri- and tetramines containing two 2,3-dihydroxypyrrolidine moieties and their inhibitory activity toward α-mannosidases

Through the reductive amination of N-[(tert-butoxy)carbonyl]-2,5-dideoxy-2,5-imino-3,4-Oisopropylidene-L-ribose with tetramethylenediamine, hexamethylenediamine, 2,7- diaminofluorene, 4,4'-diaminodiphenylmethane and 1,4-(diaminomethyl)benzene, five tetramines containing two (2R,3R,4S)-2-aminomethylpyrrolidine-3,4-diol moieties have been prepared and assayed for their inhibitory activities toward 24 glycosidases. Tetramines containing the tetramethylene or benzene-1,4-dimethylene linkers are more potent αmannosidase inhibitors than simple (2R,3R,4S)-2-aminomethylpyrrolidine-3,4-diols. Triamines such as (2S,3R,4S)-bis(3,4-dihydroxy-pyrrolidin-2-ethyl)amine were also prepared and shown to be better α-mannosidase inhibitors than (2S,3R,4S)-2-(2-aminoethyl)pyrrolidin-3,4-diol.The Swiss National Science Foundation (grants n° 20-63667.00 and 2100-063567.00/1)European COST (COST D13/0001/99) programOffice Fédéral de l'Education et de la Science (Bern)Dirección General de Investigación Científica y Técnica of Spain (grant n° BQU-2001-3779)SOCRATES (EPFL/Sevilla) progra

Synthesis of tri- and tetramines containing two 2,3-dihydroxypyrrolidine moieties and their inhibitory activity toward α-mannosidases

Through the reductive amination of N-[(tert-butoxy)carbonyl]-2,5-dideoxy-2, 5-imino-3,4-O-isopropylidene-L-ribose with tetramethylenediamine, hexamethylenediamine, 2,7-diaminofluorene, 4,4′-diaminodiphenylmethane and 1,4-(diaminomethyl)benzene, five tetramines containing two (2R,3R,4S)-2- aminomethylpyrrolidine-3,4-diol moieties have been prepared and assayed for their inhibitory activities toward 24 glycosidases. Tetramines containing the tetramethylene or benzene-1,4-dimethylene linkers are more potent α-mannosidase inhibitors than simple (2R,3R,4S)-2-aminomethylpyrrolidine- 3,4-diols. Triamines such as (2S,3R,4S)-bis(3,4-dihydroxy-pyrrolidin-2-ethyl) amine were also prepared and shown to be better α-mannosidase inhibitors than (2S,3R,4S)-2-(2-aminoethyl)pyrrolidin-3,4-diol

Synthesis and Biological Evaluation of Modified 2-Deoxystreptamine Dimers

Aminoglycosides are powerful antibiotics, but the emergence of resistant bacterial strains has prompted the search for analogues with better pharmacological profiles. The synthesis of 2-deoxystreptamine (2-DOS) dimers linked by polyamines and analogues based on furylcarbopeptoid skeletons is described. Potent and selective ligands for bacterial 16S rRNA were identified using microarray techniques by determining the affinity of these derivatives toward bacterial and human ribosomal RNA

Functionalized pyrrolidines as alpha-mannosidase inhibitors and growth inhibitors of human glioblastoma and melanoma cells

New substituted pyrrolidine-3,4-diol derivatives were prepared from D-(-)- and L-(+)-phenyl glycinol. The influence of the configuration and the substitution of the lateral side chain of these derivatives on the inhibition of 25 commercial glycosidases were determined. (2R,3R,4S)-2-({[(1R)-2-Hydroxy-1-phenylethyl]amino}methyl)pyrrolidine-3,4-diol ((+)-7a) was a potent and selective inhibitor of jack bean alpha-mannosidase (Ki = 135 nM). However, when evaluated on human tumor cells, 7a, and the reference compound swainsonine, did not efficiently inhibit the growth of glioblastoma cells. Further derivatization of the hydroxyl group with lipophilic groups to increase bioavailability improved their growth inhibitory properties for human glioblastoma and melanoma cells. In particular the 4-bromobenzoyl derivative 26 demonstrated high efficacy for human tumor cells whereas primary human fibroblasts were less sensitive to 26. Therefore functionalized pyrrolidines have the potential to inhibit the growth of tumor cells and display selectivity for tumor cells compared to normal cells

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Performance and Operation of the CMS Electromagnetic Calorimeter

The operation and general performance of the CMS electromagnetic calorimeter using cosmic-ray muons are described. These muons were recorded after the closure of the CMS detector in late 2008. The calorimeter is made of lead tungstate crystals and the overall status of the 75848 channels corresponding to the barrel and endcap detectors is reported. The stability of crucial operational parameters, such as high voltage, temperature and electronic noise, is summarised and the performance of the light monitoring system is presented

Overexpression of cathepsin K during silica-induced lung fibrosis and control by TGF-β

BACKGROUND: Lung fibrosis is characterized by tissue remodeling resulting from an imbalance between synthesis and degradation of extracellular organic matrices. To examine whether cathepsin(s) (Cat) are important in the development of pulmonary fibrosis, we assessed the expression of four Cat known for their collagenolytic activity in a model of silica-induced lung fibrosis. METHODS: Different strains of mice were transorally instilled with 2.5 mg crystalline silica or other particles. Cat expression (Cat K, S, L and B) was quantified in lung tissue and isolated pulmonary cells by quantitative RT-PCR. In vitro, we assessed the effect of different cytokines, involved in lung inflammatory and fibrotic responses, on the expression of Cat K by alveolar macrophages and fibroblasts. RESULTS: In lung tissue, Cat K transcript was the most strongly upregulated in response to silica, and this upregulation was intimately related to the fibrotic process. In mouse strains known for their differential response to silica, we showed that the level of Cat K expression following silica treatment was inversely related to the level of TGF-β expression and the susceptibility of these strains to develop fibrosis. Pulmonary macrophages and fibroblasts were identified as Cat K overproducing cells in the lung of silicotic mice. In vitro, Cat K was downregulated in mouse and human lung fibroblasts by the profibrotic growth factor TGF-β1. CONCLUSION: Altogether, these data suggest that while Cat K may contribute to control lung fibrosis, TGF-β appears to limit its overexpression in response to silica particles

Calibration of the CMS Drift Tube Chambers and Measurement of the Drift Velocity with Cosmic Rays

Peer reviewe

CMS physics technical design report : Addendum on high density QCD with heavy ions

Peer reviewe

CMS Data Processing Workflows during an Extended Cosmic Ray Run

Peer reviewe