Synthesis and antimicrobial activity of 2-alkenylchroman-4-ones, 2-alkenylthiochroman-4-ones and 2-alkenylquinol-4-ones

2-Alkenylchroman-4-ones, 2-alkenylthiochroman-4-ones, and 2-alkenylquinol-4-ones were prepared with very good regioselectivity by Me3SiOTf-mediated conjugate addition of alkenylmagnesium bromides and alkenyllithium compounds to chromones thiochromones, and quinol-4-ones. A number of products exhibit a considerable antimicrobial activity. The best activity, with respect to the spectrum of antimicrobial activity, was observed for 2-vinylchroman-4-ones containing an unsubstituted vinyl group and a chloride group located at the chromanone moiety.     

GRK2 interacts with and phosphorylates Nedd4 and Nedd4-2

Epithelial Na(+) channels (ENaC) mediate the transport of sodium (Na) across epithelia in the kidney, gut, and lungs and are required for blood pressure regulation. They are inhibited by ubiquitin protein ligases, such as Nedd4 and Nedd4-2, which bind to proline-rich motifs (PY motifs) present in the C-termini of ENaC subunits. Loss of inhibition leads to hypertension. ENaC channels are maintained in the active state by G-protein-coupled receptor kinase 2 (GRK2), an enzyme implicated in the development of essential hypertension. Here, we report that GRK2 interacts not only with ENaC, but also with both Nedd4 and Nedd4-2. Additionally, GRK2 is capable of phosphorylating both Nedd4 and Nedd4-2 at multiple sites. Of possible significance is the phosphorylation of the threonine at position 466 in Nedd4, which is located in the area of the ww3 domain that binds ENaC. These results support and extend the role of GRK2 in sodium transport regulation.     

2S,4R-carboxy-2-acetylamino-4-piperidine dans les feuilles de Calliandra haematocephala

A new naturally occurring pipecolic acid derivative has been isolated from leaves of the legume Calliandra haematocephala. Its structure was shown to be 2S,4R-carboxy-2-acetylamino-4-piperidine by chemical and spectrosopic methods.     

COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke

Collagen, type IV, alpha 1 (COL4A1) and alpha 2 (COL4A2) form heterotrimers and are abundant components of basement membranes, including those of the cerebral vasculature. COL4A1 mutations are an increasingly recognized cause of multisystem disorders, including highly penetrant cerebrovascular disease and intracerebral hemorrhage (ICH). Because COL4A1 and COL4A2 are structurally and functionally associated, we hypothesized that variants in COL4A2 would also cause ICH. We sequence COL4A2 in 96 patients with ICH and identify three rare, nonsynonymous coding variants in four patients that are not present in a cohort of 144 ICH-free individuals. All three variants change evolutionarily conserved amino acids. Using a cellular assay, we show that these putative mutations cause intracellular accumulation of COL4A1 and COL4A2 at the expense of their secretion, which supports their pathogenecity. Furthermore, we show that Col4a2 mutant mice also have completely penetrant ICH and that mutations in mouse and human lead to retention of COL4A1 and COL4A2 within the endoplasmic reticulum (ER). Importantly, two of the three putative mutations found in patients trigger ER stress and activate the unfolded protein response. The identification of putative COL4A2 mutations that might contribute to ICH in human patients provides insight into the pathogenic mechanisms of this disease. Our data suggest that COL4A2 mutations impair COL4A1 and COL4A2 secretion and can also result in cytotoxicity. Finally, our findings suggest that, collectively, mutations in COL4A1 and COL4A2 contribute to sporadic cases of ICH.     

Synthesis of 2-acetamido-2-deoxy-4-O-alpha-L-fucopyranosyl-alpha-D-glucopyranose]

Condensation of 2,3,4-tri-O-benzyl-alpha-L-fucopyranosyl bromide with benzyl 2-acetamido-3,6-di-O-benzyl-alpha-D-glucopyranoside in dichloromethane-N,N-dimethylformamide, in the presence of tetraethylammonium bromide, diisopropylethylamine, and molecular sieve (halide ion-catalyzed reaction), gave benzyl 2-acetamido-3,6-di-O-benzyl-2 deoxy-4-O-(2,3,4-tri-O-benzyl-alpha-L-fucopyranosyl)-alpha-D-glucopyranoside in crystalline form in 82% yield. Hydrogenolysis of the benzyl groups gave the title disaccharide, in crystalline form in 90% yield, which was characterized by a crystalline peracetylated alpha-D derivative.     

4-hydroxy-2-nonenal as a COX-2 inducer

4-hydroxy-2-nonenal (HNE) activates a variety of signaling pathways. We have recently evaluated the effect of oxidized fatty acid metabolites on cyclooxygenase-2 (COX-2) induction in rat liver epithelial RL34 cells and found that, among the compounds tested, HNE most dramatically induced COX-2. A p38 mitogen-activated protein kinase (p38 MAPK) pathway has been shown to play a key role in the mechanism of the HNE-induced COX-2 expression. It appears that the HNE-induced activation of p38 MAPK leads to the stabilization of COX-2 mRNA.     

Synthesis of 4-formyl-4-imidazolin-2-one nucleosides, isomers of uridine and 2'-deoxyuridine

The syntheses of the ribo- and deoxyribonucleoside derivatives of 4-formyl-4-imidazolin-2-one, isosteric isomers of uridine and 2'-deoxyuridine, respectively, were carried out by ring contraction of the corresponding 5-bromouracil nucleosides, followed by conversion of the carboxyl side-chain of the products to the respective carboxaldehyde derivatives.     

Preparation of TiO2 anatase nanocrystals by TiCl4 hydrolysis with additive H2SO4

A new methodology was developed to synthesize uniform titania anatase nanocrystals by the hydrolysis of titanium chloride in sulfuric acid aqueous solutions at 0-90°C. The samples were characterized by Raman spectroscopy, UV-visible spectroscopy, transmission electron microscopy (TEM), electron diffraction (ED), and an Energy dispersive X-ray spectroscopy (EDS). The effects of the reaction temperature, mole ratio of SO(4)(2-) to Ti(4+), and the calcinations temperature on the particle size and crystal phase were investigated. Depending on the acidity, the hydrolysis temperature, and the calcination temperature, rhombic anatase nanocrystals sizes in the range of 10 nm to 50 nm were obtained. In the additive of sulfuric acid, Raman spectra and electron diffraction confirmed that the nanoparticles are composed of anatase TiO(2). No other titania phases, such as rutile or brookite, were detected.     

The metabolism of acetamidothiazoles in the rat. 2-Acetamido-, 2-acetamido-4-methyl- and 2-acetamido-4-phenyl-thiazole

The metabolism of some anti-inflammatory acetamidothiazoles was studied in the rat. The main metabolites were the corresponding acetylthiohydantoic acids, produced by fission of the thiazole ring. Minor metabolites arising from oxidation of the methyl or phenyl substituents were also identified. The structures of metabolites were established spectroscopically (u.v., i.r., n.m.r. and mass spectroscopy) and by identification with authentic specimens. The excretion of the original compounds and of metabolites, labelled with (14)C is also reported.     

Partial trisomy 4q due to familial 2/4 translocation

Summary The case of a 5-year-old boy with partial trisomy for the long arm of chromosome No. 4 is described. The pattern of abnormal development in this and in 12 previously reported cases is similar, but the phenotype is not as characteristic as that associated with some other types of chromosomal imbalance. The most consistent features are: growth and mental retardation, small head with narrow forehead, short philtrum, relatively large ears with incomplete differentiation of the pinnae, cryptorchidism, oedema of the hands and/or feet, and renal anomalies. Abnormal development of the thumb was present in 4 of 13 cases. Eleven of the 13 families had balanced translocation carriers whose future offspring would be at increased risk for a mental retardation syndrome.     

Synthesis of 4-deoxy-4-fluoro analogues of 2-acetamido-2-deoxy-D-glucose and 2-acetamido-2-deoxy-D-galactose and their effects on cellular glycosaminoglycan biosynthesis

4-Deoxy-4-fluoro analogues of 2-acetamido-2-deoxy-D-glucose and 2-acetamido-2-deoxy-D-galactose were synthesized and evaluated as inhibitors of hepatic glycosaminoglycan biosynthesis. 2-Acetamido-1,3,6-tri-O-acetyl-2,4-dideoxy-4-fluoro-D-glucopyranose (16) exhibited a reduction of [3H]GlcN and [35S]SO4 incorporation into hepatocyte cellular glycosaminoglycans to 12 and 18%, respectively, of the control cells, at 1.0 mM. Similarly, 2-acetamido-1,3,6-tri-O-acetyl-2,4-dideoxy-4-fluoro-D-galactopyranose (31) exhibited a reduction of [3H]GlcN and [35S]SO4 incorporation to 1 and 9%, respectively, of the control cells, at 1.0 mM. Unlike 16, 31 exhibited a reduction of [14C]Leu incorporation into cellular protein to 57% of control cells, at 1.0 mM.     

Bone mineral density in patients with apolipoprotein E type 2/2 and 4/4 genotype

The peak bone mass and the rate of bone loss are in part genetically determined. It has been suggested that bone mineral density (BMD) may be related to allelic variation in the apolipoprotein E (ApoE) gene locus. ApoE is important in the receptor-mediated clearance of chylomicron particles from the plasma, Apo E4 having the highest and Apo E2 the lowest receptor affinity. Chylomicrons are the main carrier of vitamin K in the plasma; vitamin K plays an important role in the carboxylation of osteocalcin. We have tested the hypothesis that persons with E4 variant would have lower BMD and increased bone turnover than those with E2 variant. A total of 18 ApoE 2/2 and ApoE 4/4 homozygotes were selected from 873 patients who were examined for the ApoE genotype. BMD in lumbar vertebral, femoral neck and distal forearm was measured and plasma concentrations of osteocalcin and C-terminal fragments of collagen (CTx) were determined. BMD values (expressed as T-score) at the three specified sites were -0.12+/-1.72, -0.52+/-1.32 and -0.52+/-0.81 in ApoE 2/2 group and -0.24+/-1.22, 0.00+/-0.84 and -0.17+/-1.07 in the ApoE 4/4 group. Plasma osteocalcin and CTx were within normal limits in both groups. In conclusion, we did not observe any association of ApoE genotype with BMD and biochemical markers of bone metabolism in ApoE 2/2 and ApoE 4/4 homozygotes.