Glycosylation of fluoroquinolones through direct and oxygenated polymethylene linkages as a sugar-mediated active transport system for antimicrobials.

We report herein the synthesis and biological testing of several glycosylated derivatives of some fluoroquinolone antibiotics. In particular, we have prepared several glycosylated derivatives of ciprofloxacin (2) in which the carbohydrate units are linked to the free secondary amine of the piperazine unit by: (a) no linker (e.g., a glycosylamine), (b) a beta-oxyethyl linker, and (c) a gamma-oxypropyl linker. Both glucose and galactose were used as carbohydrates so that six compounds of this type were prepared, e.g., no linker 4a,b, oxyethyl linker 5a,b, and oxypropyl linker 6a,b. In addition the aryl glycosides of glucose and galactose (7a,b) were prepared from the active 1-(4-hydroxyphenyl)fluoroquinolone (3.) The syntheses of the glycosylamines 4a,b involved the direct condensation of glucose and galactose with the hydrochloride salt of ciprofloxacin (2). For the oxyalkyl-linked compounds, we first prepared the peracetylated omega-bromoalkyl glycopyranosides 14a,b and 15a,b and then coupled them to the allyl ester of ciprofloxacin (11) to give, after saponification to remove all of the esters, the desired fluoroquinolone carbohydrates 5a,b and 6a,b. The final series was prepared from 2,4,5-trifluorobenzoyl chloride (22) which gave 3 in four precedented steps. Coupling of 3 with the peracetylated glucosyl and galactosyl halides 12a,b and 26 afforded, after saponification, the desired aryl glycosides 7a,b. Six of these derivatives of ciprofloxacin-4a,b, 5a,b, and 6a,b-were subjected to microbiological screening. Of the six, compound 6a showed the highest activity. Since 6a would give the hydroxypropyl-substituted ciprofloxacin on hydrolysis and its activity is approximately 4-8 times less than that of ciprofloxacin (2), this implies that compound 6a is probably being actively transported. Thus preliminary results suggest that some of the compounds are stable in culture conditions and may be differentially transported by multiple resistant organisms. In some cases, the addition of a linker and a carbohydrate to ciprofloxacin lessens, but does not eliminate, antimicrobial activity.

Meta-analysis: vitamin D and non-alcoholic fatty liver disease.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent condition. Emerging evidence suggests that vitamin D may play a role in the pathogenesis of NAFLD. AIM: To review systematically the association between vitamin D levels, measured as serum 25-hydroxy vitamin D [25(OH)D], and NAFLD. METHODS: We used PubMed and EMBASE databases to identify all studies that assessed the association between vitamin D and NAFLD up until 22 April 2013, without language restrictions. We included studies that compared vitamin D levels between NAFLD cases and controls and also those that compared the odds of vitamin D deficiency by NAFLD status. Pooled standardised differences and odds ratios were calculated using an inverse variance method. RESULTS: Seventeen cross-sectional and case-control studies have evaluated the association between vitamin D and NAFLD. NAFLD was diagnosed using biopsy (4 studies), ultrasound or CT (10 studies) and liver enzymes (3 studies). Nine studies provided data for a quantitative meta-analysis. Compared to controls, NAFLD patients had 0.36 ng/mL (95% CI: 0.32, 0.40 ng/mL) lower levels of 25(OH)D and were 1.26 times more likely to be vitamin D deficient (OR 1.26, 95% CI: 1.17, 1.35). CONCLUSIONS: NAFLD patients have decreased serum 25(OH)D concentrations, suggesting that vitamin D may play a role in the development of NAFLD. The directionality of this association cannot be determined from cross-sectional studies. Demonstration of a causal role of hypovitaminosis D in NAFLD development in future studies could have important therapeutic implications.

Stimulus-secretion coupling in rat parietal cells is affected by extracellular magnesium.

We investigated the effects of extracellular magnesium on stimulus-secretion coupling in isolated rat parietal cells. A high concentration of extracellular magnesium (10 mM) decreased basal and carbachol-stimulated calcium levels, whereas low magnesium levels (0.2 mM) had the opposite effect. The calcium-triggered acid secretion was influenced in the same manner. Basal and carbachol-stimulated acid secretion could be enhanced by incubation in a buffer of low magnesium concentration, whereas a high magnesium concentration totally suppressed the carbachol-induced acid secretion. These results demonstrate that magnesium plays a modulative role in calcium-dependent stimulus-secretion coupling in rat parietal cells.