The use of hydroamination in the attempted synthesis of ant alkaloid 223H (xenovenine).

Thesis (M.Sc.)-University of KwaZulu-Natal, Pietermaritzburg, 2008.The ability to construct C-N bonds is of great importance to organic chemists as exemplified by the vast number of natural products, pharmaceutical agents and fine chemicals that contain such linkages. An atom efficient C-N bond forming reaction namely hydroamination has attracted much interest to date due to its ability in forming amine, imine and enamine functionality. The scope of this project involved the attempted synthesis of a biologically active and nitrogen containing pyrrolizidine alkaloid isolated from cryptic thief ants and poison dart frogs namely 223H (xenovenine). The method of hydroamination was utilized as the pivotal ring forming step and was established as being a valuable synthetic tool towards the construction of 223H (xenovenine). The stereoselective synthesis resulted in the successful formation of ethyl (3R)-5-heptyl-3-methyl-2,3-dihydro-lH-pyrrolizine-7-carboxylate 74, a novel, and structurally analogous precursor to 223H (xenovenine) over 10 synthetic steps from (S)-pyroglutamic acid. The following research also resulted in the synthesis of two other novel compounds namely ethyl 3-[(2R)-2-methyl-5-thioxotetrahydro-lH-pyrrol-l-yl]propanoate 86 and ethyl 3-{(5R)-2-[(E)-2-ethoxy-2-oxoethylidene]-5-methyltetrahydro-lH-pyrrol-l-yl}propanoate 87. A catalytic hydroamination study on the conversion of C-propargyl vinylogous amides into pyrroles demonstrated that transition metal salts of groups 11 and 12 serve as effective hydroamination catalysts. The oxide, acetate, chloride and nitrate derivatives of group 11 and 12 metals namely Cu(II), Ag(I), Zn(II), Cd(II) and Hg(II) were employed as potential hydroamination catalysts in the oxidation states provided. The Zn(II) catalyst series with the exception ZnO provided the greatest hydroamination yields under mild reaction conditions owing to their high Lewis acidities however the Ag(I) and Hg(II) catalyst series also provided excellent yields of product under more forcing reaction conditions

Synthesis and anti-norovirus activity of pyranobenzopyrone compounds

During the last decade, noroviruses have gained media attention as the cause of large scale outbreaks of gastroenteritis on cruise ships, dormitories, nursing homes, etc. Although noroviruses do not multiply in food or water, they can cause large outbreaks because approximately 10–100 virions are sufficient to cause illness in a healthy adult. Recently, it was shown that the activity of acyl-coenzyme A:cholesterol acyltransferase-1 (ACAT1) enzyme may be important in norovirus infection. In search of anti-noroviral agents based on the inhibition of ACAT1, we synthesized and evaluated the inhibitory activities of a class of pyranobenzopyrone molecules containing amino, pyridine, substituted quinolines, or 7,8-benzoquinoline nucleus. Three of the sixteen evaluated compounds possess ED[subscript]5[subscript]0 values in the low micrometer range. 2-Quinolylmethyl derivative 3A and 4-quinolylmethyl derivative 4A showed ED[subscript]5[subscript]0 values of 3.4 and 2.4 [mu]M and TD[subscript]5[subscript]0 values of >200 and 96.4 [mu]M, respectively. The identified active compounds are suitable for further modification for the development of anti-norovirus agents

Inhibition of long chain fatty acyl-CoA synthetase (ACSL) and ischemia reperfusion injury

Various triacsin C analogs, containing different alkenyl chains and carboxylic acid bioisoteres including 4-aminobenzoic acid, isothiazolidine dioxide, hydroxylamine, hydroxytriazene, and oxadiazolidine dione, were synthesized and their inhibitions of long chain fatty acyl-CoA synthetase (ACSL) were examined. Two methods, a cell-based assay of ACSL activity and an in situ [¹⁴C]-palmitate incorporation into extractable lipids were used to study the inhibition. Using an in vivo leukocyte recruitment inhibition protocol, the translocation of one or more cell adhesion molecules from the cytoplasm to the plasma membrane on either the endothelium or leukocyte or both was inhibited by inhibitors 1, 9, and triacsin C. The results suggest that inhibition of ACSL may attenuate the vascular inflammatory component associated with ischemia reperfusion injury and lead to a decrease of infarct expansion

Syntheses of 3-[(Alkylamino)methylene]-6-methyl-1Hpyridine-2,4-diones, Fluorescence Probes 3-Substituted 7-Methyl-6H-pyrano[3,2-c]pyridine-2,5-diones, and Tetrahydro-6H-2,10-dioxa-9-azaanthracen-1-ones

Various condensation and ring-closing reactions were used for the syntheses of 3-[(alkylamino)methylene]-6-methylpyridine-2,4(1H,3H)-diones, bicyclic pyridinones, and tricyclic morpholinopyrones. For instance, 3-[(dialkylamino)methylene]-6-methylpyridine-2,4(1H,3H)-diones were synthesized from the condensation of dialkylamines and 3-formyl-4-hydroxy-6-methylpyridin-2(1H)-one. 3-Formyl-4-hydroxy-6-methylpyridin-2(1H)-one, derived from 3-formyl-4-hydroxy-6-methylpyridin-2(1H)-one, was used to construct a number of bicyclic pyridinones via a one-pot Knoevenagal and intramolecular lactonization reaction. Tricyclic morpholinopyrones were assembled from a dialkylation reaction involving a dinucleophile, 3-amino-4-hydroxy-6-methyl-2H-pyran-2-one, and a dielectrophile, trans-3,6-dibromocyclohexene. Depending on the reaction conditions, isomers of the tricyclic molecules can be selectively produced, and their chemical structures were unequivocally determined using single-crystal X-ray analyses and 2D COSY spectroscopy. The fluorescently active bicyclic pyridinone compounds show longer absorption (368–430 nm; maximum) and emission wavelengths (450–467 nm) than those of 7-amino-4-methylcoumarin (AMC; λ[subscript abs,max] = 350 nm; λ[subscript em] = 430 nm) suggesting these molecules, such as 3-(2-aminoacetyl)-7-methyl-2H-pyrano[3,2-c]pyridine-2,5(6H)-dione, can be employed as fluorescence activity based probes for tracing biological pathways

Genome-Wide Population-Based Association Study of Extremely Overweight Young Adults – The GOYA Study

Background: Thirty-two common variants associated with body mass index (BMI) have been identified in genome-wide association studies, explaining ~1.45% of BMI variation in general population cohorts. We performed a genome-wide association study in a sample of young adults enriched for extremely overweight individuals. We aimed to identify new loci associated with BMI and to ascertain whether using an extreme sampling design would identify the variants known to be associated with BMI in general populations. Methodology/Principal Findings: From two large Danish cohorts we selected all extremely overweight young men and women (n = 2,633), and equal numbers of population-based controls (n = 2,740, drawn randomly from the same populations as the extremes, representing ~212,000 individuals). We followed up novel (at the time of the study) association signals (

Enhanced implementation of low back pain guidelines in general practice: study protocol of a cluster randomised controlled trial

Evidence-based clinical practice guidelines may improve treatment quality, but the uptake of guideline recommendations is often incomplete and slow. Recently new low back pain guidelines are being launched in Denmark. The guidelines are considered to reduce personal and public costs. The aim of this study is to evaluate whether a complex, multifaceted implementation strategy of the low back pain guidelines will reduce secondary care referral and improve patient outcomes compared to the usual simple implementation strategy.Methods/design: In a two-armed cluster randomised trial, 100 general practices (clusters) and 2,700 patients aged 18 to 65 years from the North Denmark region will be included. Practices are randomly allocated 1:1 to a simple or a complex implementation strategy. Intervention practices will receive a complex implementation strategy, including guideline facilitator visits, stratification tools, and quality reports on low back pain treatment. Primary outcome is referral to secondary care. Secondary outcomes are pain, physical function, health-related quality of life, patient satisfaction with care and treatment outcome, employment status, and sick leave. Primary and secondary outcomes pertain to the patient level. Assessments of outcomes are blinded and follow the intention-to-treat principle. Additionally, a process assessment will evaluate the degree to which the intervention elements will be delivered as planned, as well as measure changes in beliefs and behaviours among general practitioners and patients

On the mechanisms governing gas penetration into a tokamak plasma during a massive gas injection

A new 1D radial fluid code, IMAGINE, is used to simulate the penetration of gas into a tokamak plasma during a massive gas injection (MGI). The main result is that the gas is in general strongly braked as it reaches the plasma, due to mechanisms related to charge exchange and (to a smaller extent) recombination. As a result, only a fraction of the gas penetrates into the plasma. Also, a shock wave is created in the gas which propagates away from the plasma, braking and compressing the incoming gas. Simulation results are quantitatively consistent, at least in terms of orders of magnitude, with experimental data for a D 2 MGI into a JET Ohmic plasma. Simulations of MGI into the background plasma surrounding a runaway electron beam show that if the background electron density is too high, the gas may not penetrate, suggesting a possible explanation for the recent results of Reux et al in JET (2015 Nucl. Fusion 55 093013)