Sustainable approaches to novel heterocyclic scaffolds for medicinal chemistry

This thesis investigates new methods for the environmentally sustainable synthesis of heterocyclic scaffolds for application in medicinal chemistry. Chapter I introduces general principles of sustainability in synthetic organic chemistry. This includes the characterization and application of sustainable solvents and the use of biomass feedstocks in synthesis. Chapter II explores the synthesis of substituted isoindolinones via a ruthenium-catalyzed alkyne cyclotrimerization. The introduction details the synthesis and medicinal application of isoindolinones and describes previous research involving alkyne cyclotrimerizations. Following this, the development of a regioselective alkyne cyclotrimerization reaction in a sustainable solvent is reported. The optimized alkyne cyclotrimerization conditions are then used to synthesize a selection of isoindolinone products. Chapter III describes the application of a kinetically-controlled furan-Diels–Alder reaction to the synthesis of heterocyclic scaffolds, including the endo-cantharimide. The study and application of furan-Diels–Alder reactions are introduced. Following this, the Diels–Alder reaction of a 3-alkoxyfuran under sustainable reaction conditions is explored experimentally and applied to the diastereoselective synthesis of endo-cantharimides. The potential application of endo-cantharimides in medicinal chemistry is discussed with the aid of biological testing and the Diels–Alder reactions of 3-alkoxyfurans is probed with the aid of computational calculations. Chapter IV concerns the cyclization of reducing sugars to prepare chiral tetrahydrofurans. The role of tetrahydrofurans in medicinal chemistry, the synthesis of tetrahydrofurans from sugar derivatives and the application of hydrazones in synthetic chemistry are introduced. Following this the development of a hydrazone-mediated cyclization of L-arabinose under sustainable reaction conditions is reported. The optimized conditions are applied to prepare tetrahydrofurans from other sugars. The manipulation of the tetrahydrofuran products is also explored. Chapter V draws some general conclusions from the thesis and describes potential future directions for the research. Chapter VI contains the details of experimental procedures and compound characterization for the results discussed in Chapters II–IV

Sustainable Synthesis of Chiral Tetrahydrofurans through the Selective Dehydration of Pentoses

L-Arabinose is an abundant resource available as a waste product of the sugar beet industry. Through use of a hydrazone-based strategy, L-arabinose was selectively dehydrated to form a chiral tetrahydrofuran on a multi-gram scale without the need for protecting groups. This approach was extended to other biomass-derived reducing sugars and the mechanism of the key cyclization investigated. This methodology was applied to the synthesis of a range of functionalized chiral tetrahydrofurans, as well as a formal synthesis of 3R-3-hydroxymuscarine

Item response theory evaluation of the biomedical scale of the Pain Attitudes and Beliefs Scale.

OBJECTIVES: The assessment of health care professionals' attitudes and beliefs towards musculoskeletal pain is essential because they are key determinants of their clinical practice behaviour. The Pain Attitudes and Beliefs Scale (PABS) biomedical scale evaluates the degree of health professionals' biomedical orientation towards musculoskeletal pain and was never assessed using item response theory (IRT). This study aimed at assessing the psychometric performance of the 10-item biomedical scale of the PABS scale using IRT. METHODS: Two cross-sectional samples (BeBack, n = 1016; DABS; n = 958) of health care professionals working in the UK were analysed. Mokken scale analysis (nonparametric IRT) and common factor analysis were used to assess dimensionality of the instrument. Parametric IRT was used to assess model fit, item parameters, and local reliability (measurement precision). RESULTS: Results were largely similar in the two samples and the scale was found to be unidimensional. The graded response model showed adequate fit, covering a broad range of the measured construct in terms of item difficulty. Item 3 showed some misfit but only in the DABS sample. Some items (i.e. 7, 8 and 9) displayed remarkably higher discrimination parameters than others (4, 5 and 10). The scale showed satisfactory measurement precision (reliability > 0.70) between theta values -2 and +3. DISCUSSION: The 10-item biomedical scale of the PABS displayed adequate psychometric performance in two large samples of health care professionals, and it is suggested to assess group-level professionals degree of biomedical orientation towards musculoskeletal pain

Derivation and validation of a simple, accurate and robust prediction rule for risk of mortality in patients with Clostridium difficile infection.

Published onlineJournal ArticleResearch Support, Non-U.S. Gov'tBACKGROUND: Clostridium difficile infection poses a significant healthcare burden. However, the derivation of a simple, evidence based prediction rule to assist patient management has not yet been described. METHOD: Univariate, multivariate and decision tree procedures were used to deduce a prediction rule from over 186 variables; retrospectively collated from clinical data for 213 patients. The resulting prediction rule was validated on independent data from a cohort of 158 patients described by Bhangu et al. (Colorectal Disease, 12(3):241-246, 2010). RESULTS: Serum albumin levels (g/L) (P = 0.001), respiratory rate (resps /min) (P = 0.002), C-reactive protein (mg/L) (P = 0.034) and white cell count (mcL) (P = 0.049) were predictors of all-cause mortality. Threshold levels of serum albumin ≤ 24.5 g/L, C- reactive protein >228 mg/L, respiratory rate >17 resps/min and white cell count >12 × 10(3) mcL were associated with an increased risk of all-cause mortality. A simple four variable prediction rule was devised based on these threshold levels and when tested on the initial data, yield an area under the curve score of 0.754 (P < 0.001) using receiver operating characteristics. The prediction rule was then evaluated using independent data, and yield an area under the curve score of 0.653 (P = 0.001). CONCLUSIONS: Four easily measurable clinical variables can be used to assess the risk of mortality of patients with Clostridium difficile infection and remains robust with respect to independent data.This work was funded by University of Exeter, Systems Biology Initiative, a small grants fund from the RD&E NHS Trust and The National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula (PenCLAHRC). This article presents independent research funded by the National Institute for Health Research (NIHR) Collaboration for Leadership in Applied Health Research and Care (CLAHRC) for the South West Peninsula. The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health in England

Highly Regioselective Synthesis of Substituted Isoindolinones via Ruthenium-Catalyzed Alkyne Cyclotrimerizations

Cyclooctadiene)(pentamethylcyclopentadiene)ruthenium chloride [Cp*RuCl(cod)] has been used to catalyze the regioselective cyclization of amide-tethered diynes with monosubstituted alkynes to give polysubstituted isoindolinones. Notably, the presence of a trimethylsilyl group on the diyne generally led to complete control over the regioselectivity of the alkyne cyclotrimerization. The cyclization reaction worked well in a sustainable non-chlorinated solvent and was tolerant of moisture. The optimized conditions were effective with a diverse range of alkynes and diynes. The 7-silylisoindolinone products could be halogenated, protodesilylated or ring opened to access a range of usefully functionalized products

Gold catalysed synthesis of 3-alkoxyfurans at room temperature

Synthetically important 3-alkoxyfurans can be prepared efficiently via treatment of acetal-containing propargylic alcohols (obtained from the addition of 3,3-diethoxypropyne to aldehydes) with 2 mol% gold catalyst in an alcohol solvent at room temperature. The resulting furans show useful reactivity in a variety of subsequent transformations

Incidence of Primary Mitochondrial Disease in Children Younger Than 2 Years Presenting With Acute Liver Failure

Background: Mitochondrial liver disease (MLD), and in particular mitochondrial DNA (mtDNA) depletion syndrome (MDS) is an important cause of acute liver failure (ALF) in infancy. Early and accurate diagnosis is important because liver transplantation (LT) is often contraindicated. It is unclear which methods are the best to diagnose MLD in the setting of ALF. Objective: The aim of the study was to determine the incidence of MLD in children younger than 2 years with ALF and the utility of routine investigations to detect MLD. Methods: Thirty-nine consecutive infants with ALF were admitted to a single unit from 2009 to 2011. All were extensively investigated using an established protocol. Genes implicated in mitochondrial DNA depletion syndrome were sequenced in all cases and tissue mtDNA copy number measured where available. Results: Five infants (17%) had genetically proven MLD: DGUOK (n ¼ 2), POLG (n ¼ 2), and MPV17 (1). Four of these died, whereas 1 recovered. Two had normal muscle mtDNA copy number and 3 had normal muscle respiratory chain enzymes. An additional 8 children had low hepatic mtDNA copy number but pathogenic mutations were not detected. One of these developed fatal multisystemic disease after LT, whereas 5 who survived remain well without evidence of multisystemic disease up to 6 years later. Magnetic resonance spectroscopy did not distinguish between those with and without MLD. Conclusions: Low liver mtDNA copy number may be a secondary phenomenon in ALF. Screening for mtDNA maintenance gene mutations may be the most efficient way to confirm MLD in ALF in the first 2 years of life

Irreversible endo-selective diels-alder reactions of substituted alkoxyfurans: a general synthesis of endo-cantharimides

The [4+2] cycloaddition of 3-alkoxyfurans with N-substituted maleimides provides the first general route for preparing endo-cantharimides. Unlike the corresponding reaction with 3H furans, the reaction can tolerate a broad range of 2-substitued furans including alkyl, aromatic, and heteroaromatic groups. The cycloaddition products were converted into a range of cantharimide products with promising lead-like properties for medicinal chemistry programs. Furthermore, the electron-rich furans are shown to react with a variety of alternative dienophiles to generate 7-oxabicyclo[2.2.1]heptane derivatives under mild conditions. DFT calculations have been performed to rationalize the activation effect of the 3-alkoxy group on a furan Diels-Alder reaction

The writing on the wall: the concealed communities of the East Yorkshire horselads

This paper examines the graffiti found within late nineteenth and early-twentieth century farm buildings in the Wolds of East Yorkshire. It suggests that the graffiti were created by a group of young men at the bottom of the social hierarchy - the horselads – and was one of the ways in which they constructed a distinctive sense of communal identity, at a particular stage in their lives. Whilst it tells us much about changing agricultural regimes and social structures, it also informs us about experiences and attitudes often hidden from official histories and biographies. In this way, the graffiti are argued to inform our understanding, not only of a concealed community, but also about their hidden histor

The intestinal expulsion of the roundworm Ascaris suum is associated with eosinophils, intra-epithelial T cells and decreased intestinal transit time

Ascaris lumbricoides remains the most common endoparasite in humans, yet there is still very little information available about the immunological principles of protection, especially those directed against larval stages. Due to the natural host-parasite relationship, pigs infected with A. suum make an excellent model to study the mechanisms of protection against this nematode. In pigs, a self-cure reaction eliminates most larvae from the small intestine between 14 and 21 days post infection. In this study, we investigated the mucosal immune response leading to the expulsion of A. suum and the contribution of the hepato-tracheal migration. Self-cure was independent of previous passage through the liver or lungs, as infection with lung stage larvae did not impair self-cure. When animals were infected with 14-day-old intestinal larvae, the larvae were being driven distally in the small intestine around 7 days post infection but by 18 days post infection they re-inhabited the proximal part of the small intestine, indicating that more developed larvae can counter the expulsion mechanism. Self-cure was consistently associated with eosinophilia and intra-epithelial T cells in the jejunum. Furthermore, we identified increased gut movement as a possible mechanism of self-cure as the small intestinal transit time was markedly decreased at the time of expulsion of the worms. Taken together, these results shed new light on the mechanisms of self-cure that occur during A. suum infections