Scaffold hopping from pyridones to imidazo[1,2-a]pyridines. New positive allosteric modulators of metabotropic glutamate 2 receptor

Imidazo[1,2-a]pyridines were identified via their shape and electrostatic similarity as novel positive allosteric modulators of the metabotropic glutamate 2 receptor. The subsequent synthesis and SAR are described. Potent, selective and metabolically stable compounds were found representing a promising avenue for current further studies.     

Stereochemistry–activity relationship of orally active tetralin S1P agonist prodrugs

Modifying FTY720, an immunosuppressant modulator, led to a new series of well phosphorylated tetralin analogs as potent S1P1 receptor agonists. The stereochemistry effect of tetralin ring was probed, and (?)-(R)-2-amino-2-((S)-6-octyl-1,2,3,4-tetrahydronaphthalen-2-yl)propan-1-ol was identified as a good SphK2 substrate and potent S1P1 agonist with good oral bioavailability.     

Biological activity of modified and exchanged 2-amino-5-nitrothiazole amide analogues of nitazoxanide

Head group analogues of the antibacterial and antiparasitic drug nitazoxanide (NTZ) are presented. A library of 39 analogues was synthesized and assayed for their ability to suppress growth of Helicobacter pylori, Campylobacter jejuni, Clostridium difficile and inhibit NTZ target pyruvate:ferredoxin oxidoreductase (PFOR). Two head groups assayed recapitulated NTZ activity and possessed improved activity over their 2-amino-5-nitrothiazole counterparts, demonstrating that head group modification is a viable route for the synthesis of NTZ-related antibacterial analogues.     

Metabolic assessment of a novel chronic myelogenous leukemic cell line and an imatinib resistant subline by <Superscript>1</Superscript>H NMR spectroscopy

The goal of this study was to examine metabolic differences between a novel chronic myelogenous leukemic (CML) cell line, MyL, and a sub-clone, MyL-R, which displays enhanced resistance to the targeted Bcr-Abl tyrosine kinase inhibitor imatinib. ¹H nuclear magnetic resonance (NMR) spectroscopy was carried out on cell extracts and conditioned media from each cell type. Both principal component analysis (PCA) and specific metabolite identification and quantification were used to examine metabolic differences between the cell types. MyL cells showed enhanced glucose removal from the media compared to MyL-R cells with significant differences in production rates of the glycolytic end-products, lactate and alanine. Interestingly, the total intracellular creatine pool (creatine + phosphocreatine) was significantly elevated in MyL-R compared to MyL cells. We further demonstrated that the MyL-R cells converted the creatine to phosphocreatine using non-invasive monitoring of perfused alginate-encapsulated MyL-R and MyL cells by in vivo ³¹P NMR spectroscopy and subsequent HPLC analysis of extracts. Our data demonstrated a clear difference in the metabolite profiles of drug-resistant and sensitive cells, with the biggest difference being an elevation of creatine metabolites in the imatinib-resistant MyL-R cells.     

Computer aided selection of candidate vaccine antigens

Immunoinformatics is an emergent branch of informatics science that long ago pullulated from the tree of knowledge that is bioinformatics. It is a discipline which applies informatic techniques to problems of the immune system. To a great extent, immunoinformatics is typified by epitope prediction methods. It has found disappointingly limited use in the design and discovery of new vaccines, which is an area where proper computational support is generally lacking. Most extant vaccines are not based around isolated epitopes but rather correspond to chemically-treated or attenuated whole pathogens or correspond to individual proteins extract from whole pathogens or correspond to complex carbohydrate. In this chapter we attempt to review what progress there has been in an as-yet-underexplored area of immunoinformatics: the computational discovery of whole protein antigens. The effective development of antigen prediction methods would significantly reduce the laboratory resource required to identify pathogenic proteins as candidate subunit vaccines. We begin our review by placing antigen prediction firmly into context, exploring the role of reverse vaccinology in the design and discovery of vaccines. We also highlight several competing yet ultimately complementary methodological approaches: sub-cellular location prediction, identifying antigens using sequence similarity, and the use of sophisticated statistical approaches for predicting the probability of antigen characteristics. We end by exploring how a systems immunomics approach to the prediction of immunogenicity would prove helpful in the prediction of antigens.     

Physiological consequences of captive conditions in water voles (Arvicola terrestris)

Re-introductions of captive-bred animals are increasingly common in wildlife conservation and it is important that they fulfil their potential. To foster this goal we examined variations in stress levels in a captive-bred population of water voles Arvicola terrestris in response to housing conditions and radio-collaring, using weight loss and leukocyte coping capacity (LCC) as measures of relative stress, to investigate the impacts of housing conditions, handling and radio-collaring on this species. Thirty-eight water voles (22 males and 16 females) were used in the investigation, 25 housed in outdoor enclosures and 13 in laboratory cages. During the 6-week study, LCC, body weight and urine refractive index (URI, an indicator of hydration levels) were recorded once a week for each individual in weeks 1, 2, 4 and 6. After the first sample, radio-collars were attached to 20 individuals (10 males and 10 females) taken from both housing types. Throughout the experiment laboratory-cage housed voles weighed less, had lower LCC scores – indicating a reduced ability to combat infection – and had higher URIs than outdoor-enclosure voles. This suggests that the laboratory-cage voles were more stressed and dehydrated than the outdoor-enclosure voles. Weights and LCC scores of both housing groups decreased as the study progressed, suggesting that elements of the study, such as repeated handling, may have caused stress to both groups. Evidence suggested a short-term effect of radio-collaring on immuno-competence. We conclude that captive housing conditions, repeated manipulation and radio-collaring had demonstrable physiological effects on the water voles studied. We recommend that the effects of husbandry and tagging practices upon captive-bred mammals be closely studied as part of the quest to improve the success of the re-introductions to which they contribute.     

Balanced dispersal or source–sink–do both models describe wood mice in farmed landscapes?

Plant responses to browsing can affect root and shoot morphology, which is important to subsequent herbivory, nutrient acquisition and competition. This paper examines the above- and below-ground responses of three browse species, with different growth strategies, to simulated browsing damage at different times of year. Saplings were grown in pots in sand culture to enable whole sapling analysis. At winter dormancy or budburst, 50% of previous year's shoots (and associated leaves/buds) were clipped. Subsequent sapling growth and morphology was compared with that of unclipped control saplings. Treatment differences in growth parameters of each species were observed, including changes in branching patterns, shoot lengths, diameters and ratios, leaf sizes and end-of-season bud numbers. Some responses were damage-induced per se; others differed according to timing of damage. Compensatory growth by the two deciduous species ( Betula pendula , Sorbus aucuparia ) resulted in few biomass differences by the end of the year of damage as compared to controls, but both above- and below-ground growth of clipped Pinus sylvestris was poor, particularly those damaged at budburst, giving strong differences between control, dormant, and budburst clipped saplings.