The Rise of Boron-Containing Compounds: Advancements in Synthesis, Medicinal Chemistry, and Emerging Pharmacology.

Boron-containing compounds (BCC) have emerged as important pharmacophores. To date, five BCC drugs (including boronic acids and boroles) have been approved by the FDA for the treatment of cancer, infections, and atopic dermatitis, while some natural BCC are included in dietary supplements. Boron's Lewis acidity facilitates a mechanism of action via formation of reversible covalent bonds within the active site of target proteins. Boron has also been employed in the development of fluorophores, such as BODIPY for imaging, and in carboranes that are potential neutron capture therapy agents as well as novel agents in diagnostics and therapy. The utility of natural and synthetic BCC has become multifaceted, and the breadth of their applications continues to expand. This review covers the many uses and targets of boron in medicinal chemistry.

Saccharomyces cerevisiae as a platform for assessing sphingolipid lipid kinase inhibitors.

Successful medicinal chemistry campaigns to discover and optimize sphingosine kinase inhibitors require a robust assay for screening chemical libraries and for determining rank order potencies. Existing assays for these enzymes are laborious, expensive and/or low throughput. The toxicity of excessive levels of phosphorylated sphingoid bases for the budding yeast, Saccharomyces cerevisiae, affords an assay wherein inhibitors added to the culture media rescue growth in a dose-dependent fashion. Herein, we describe our adaptation of a simple, inexpensive, and high throughput assay for assessing inhibitors of sphingosine kinase types 1 and 2 as well as ceramide kinase and for testing enzymatic activity of sphingosine kinase type 2 mutants. The assay was validated using recombinant enzymes and generally agrees with the rank order of potencies of existing inhibitors.

The effect of labetalol and nifedipine MR on blood pressure in women with chronic hypertension in pregnancy.

AIM: To compare the blood pressure (BP) lowering effects of labetalol and nifedipine modified release (MR) in hypertensive pregnant women. We also investigated the effect on the heart rate (HR) and determined the proportion of time spent in target. METHODS: This was an exploratory study. Women with chronic hypertension taking either labetalol or nifedipine were offered 24-h ambulatory blood pressure monitoring (ABPM). Sleep, wake and drug ingestion times were self-reported. An indirect response model was used to analyse the systolic BP (SBP), diastolic BP (DBP) and HR time-series; the effect of gestation and type of drug was evaluated. RESULTS: Forty-eight women were recruited: 24 in each group. There was no difference in clinical characteristics. In women taking nifedipine there was a positive association between the dose of nifedipine and pre-dose BP p = .002, this was not present in the labetalol group. There was a difference between the drug effects on both the SBP and DBP time-series (p = .014). In comparison to labetalol, there was less variation in day time BP in those women prescribed nifedipine. Women on labetalol spent a larger proportion of time with their DBP below target (<80 mmHg). The HR dynamics were qualitatively different, a stimulatory effect was found with nifedipine compared to an inhibitory effect with labetalol. CONCLUSION: There are significant and important differences between the BP lowering effects of nifedipine and labetalol. A large randomised control trial is required to investigate the relationship between BP variability and time in target on pregnancy outcomes.

Composition and concentration of hydrocarbons in sediment samples from the oil producing area of the East Shetland Basin, Scotland.

The East Shetland Basin is one of the areas that the Fisheries Research Services (FRS) has concentrated on to assess the possible impacts of oil exploration and production on the marine environment. A stratified random survey of the sediment was carried out in 2002. TOCs were low across the basin and were positively correlated with grain size. The total PAH concentrations (2- to 6-ring parent and alkylated PAHs, including the 16 US EPA PAHs) were less than 150 microg kg(-1) dry weight and their composition indicated a predominantly pyrolytic input to the basin in 2002. Minor unresolved complex mixtures in the n-alkane profiles indicated a slight petrogenic input but further examination of the biomarkers (hopanes and steranes) showed a mixed North Sea and Middle Eastern source. The Middle Eastern source is likely due to inputs from shipping activity, as it is widely used as bunker fuel. Grid surveys were carried out in 1986, 1988-89 and 1994 and areas were selected for which there was data for all the historic grid surveys and the 2002 stratified random survey. Although referring to only a small part of the East Shetland Basin, comparison with these historic surveys shows clearly that the concentrations of Forties crude oil equivalents and total PAH concentrations were highest in 1988-89 and by 2002 had returned to concentrations the same as or less than observed in the original survey in 1986.

The effects of oil exploration and production in the Fladen Ground: composition and concentration of hydrocarbons in sediment samples collected during 2001 and their comparison with sediment samples collected in 1989.

Due to the potentially accumulative nature of the Fladen Ground, an area of intense oil activity in the North Sea, a survey was carried out in 1989 to map the distribution of contamination in relation to these oil activities. All the sediments collected were screened by ultraviolet fluorescence (UVF) for polycyclic aromatic hydrocarbons (PAHs) and selected samples were analysed for n-alkanes (by GC-FID), PAHs and biomarkers (by GC-MSD). This survey was repeated in 2001, with all the 1989 sites being resampled. All of these sediments were analysed for UVF oil equivalents, PAHs, n-alkanes and biomarkers. The concentrations of these parameters decreased between 1989 and 2001, with average decreases ranging from 43% to 88%. In addition, no significant difference was found, for all the parameters, between near field (<5 km from an oil installation) and far field (>5 km from an oil installation) sites in 2001 indicating that the Fladen Ground is approaching a 'steady state' or background concentration for contamination.

Preclinical evaluation of a prostate-targeted gene-directed enzyme prodrug therapy delivered by ovine atadenovirus.

Gene-directed enzyme prodrug therapy (GDEPT) based on the Escherichia coli enzyme, purine nucleoside phosphorylase (PNP), provides a novel strategy for treating slowly growing tumors like prostate cancer (CaP). PNP converts systemically administered prodrug, fludarabine phosphate, to a toxic metabolite, 2-fluoroadenine, that kills PNP-expressing and nearby cells by inhibiting DNA, RNA and protein synthesis. Reporter gene expression directed by a hybrid prostate-directed promoter and enhancer, PSMEPb, was assayed after plasmid transfection or viral transduction of prostate and non-CaP cell lines. Androgen-sensitive (AS) LNCaP-LN3 and androgen-independent (AI) PC3 human CaP xenografts in nude mice were injected intratumorally with an ovine atadenovirus vector, OAdV623, that carries the PNP gene under PSMEPb, formulated with cationic lipid for enhanced infectivity. Fludarabine phosphate was then given intraperitoneally for 5 days at 75 mg/m2/day. PNP expression was evaluated by enzymic conversion of its substrate using reverse phase HPLC. OAdV623 showed excellent in vitro transcriptional specificity for CaP cells. In vivo, expression of PNP persisted for > 6 days after OAdV623 injection and a single treatment provided 100% increase in tumor doubling time and > 50% inhibition of tumor growth for both LNCaP-LN3 and PC3 lines, with increased tumor necrosis and apoptosis and decreased tumor cell proliferation. OAdV623 significantly suppressed the growth of AS and AI human CaP xenografts in mice.

Analysis of sediments from Shetland Island voes for polycyclic aromatic hydrocarbons, steranes and triterpanes.

A few days after the grounding of the oil tanker Braer on 5 January 1993, an Exclusion Zone was designated by Order under the Food and Environment Protection Act 1985, prohibiting the harvesting of farmed or wild shellfish within the Zone to prevent contaminated products reaching the market place. The order was progressively lifted for species that were found to be free of petrogenic taint and for which the polycyclic aromatic hydrocarbon (PAH) levels were within the range for reference samples. This Order, however, still remains in place for mussels (Mytilus edulis) as the PAH levels are higher than in reference mussels. To investigate the possible source of PAHs found in these mussels, sediments were collected from three reference and three Zone sites and their hydrocarbon compositions studied using the n-alkane composition and concentration, PAH composition and concentration and the sterane and triterpane composition. The reference site at Olna Firth was found to have the highest levels of 2-6-ring parent and branched PAHs, the highest concentration in one of the pooled sediments being 4,530 ng g(-1) dry weight. Values in the other two reference sites (Vaila Sound and Mangaster Voe) ranged from 248.7 to 902.2 ng g(-1) dry weight. PAH concentrations at the Zone sites (Sandsound Voe, Stromness Voe and Punds Voe) ranged from 641.0 to 2,766 ng g(-1) dry weight. The PAH data were normalised to the percentage of organic carbon and log-transformed prior to being analysed using principal component analysis. The mean total PAH concentrations for Zone sites were found not to be significantly different from the reference sites. The PAH concentration ratios were consistent with the main source of PAHs being pyrolysis. However, there was a petrogenic contribution, suggested by the presence of alkylated PAHs, with Punds Voe having the largest petrogenic hydrocarbon content. This was supported by the triterpane profiles and the presence of a UCM in the aliphatic chromatograms from Punds Voe sediments.

Induction of opioid receptor-mediated macrophage chemotactic activity after neonatal brain injury.

Macrophages have a prominent role in the injury response of the brain, yet the molecular mechanisms that control their invasion to the site of neuronal degeneration is unknown. After removal of the posterior cortex at birth, there is massive and specific targeting of nonresident macrophages to axotomized neurons in the lateral thalamus. The present study has identified an injury-induced, brain-derived chemotactic factor (BDCF) capable of eliciting chemotactic responses from resident peritoneal macrophages and brain macrophages. Conditioned media collected from tissue slices containing the axotomized central nervous system neurons exhibit BDCF activity. Initial experiments indicated that BDCF is a small peptide and, thus, we used specific pharmacologic reagents to characterize further BDCF activity. Naloxone, a pan opioid receptor antagonist, completely blocks BDCF activity. Although both kappa and mu opioid receptor antagonists failed to modify BDCF-induced macrophage chemotaxis, two specific delta receptor antagonists blocked BDCF. Analysis of BDCF by reverse phase HPLC and RIA revealed peak chemotactic activity in fractions consistent with the presence of an opioid peptide. The results suggest that cells in the brain respond to neuronal injury by producing and releasing opioids that can initiate a specific macrophage response.

High dose of antacid (Mylanta II) reduces bioavailability of ranitidine.

To investigate the effect of antacid on the bioavailability and disposition of ranitidine six healthy volunteers were studied on two occasions one week apart. In the first study the received ranitidine 150 mg with 60 ml water, and in the second study they received ranitidine 150 mg plus 30 ml of an aluminium/magnesium hydroxide mixture (Mylanta II) and 30 ml water. Giving antacid reduced both the maximum plasma ranitidine concentration and the area under the curve by one-third; elimination of the drug was not changed. Thus giving a high dose of antacid significantly diminished the bioavailability of ranitidine.