Incorporation of N-heterocyclic cations into proteins with a highly directed chemical modification

N-Heterocyclic cations are incorporated into proteins using 5-(2-bromoethyl)phenanthridinium bromide, which selectively reacts with either cysteine or lysine residues, resulting in ethylphenanthridinium (Phen) or highly stable cyclised dihydro-imidazo-phenanthridinium (DIP) adducts respectively; these modifications have been found to manipulate the observed structure of lysozyme and bovine serum albumin by AFM.

N-Heterocyclic carbene coated metal nanoparticles

N-Heterocyclic carbene coated Au and Pd nanoparticles have been prepared by a ligand exchange reaction; although carbenes quantitatively displaced the thioether and phosphine ligands from the nanoparticle surface, the resultant nanoparticles spontaneously leached metal complexes and aggregated in solution. © 2009 The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.

Novel glucagon-like peptide-1 (GLP-1) analog (Val8)GLP-1 results in significant improvements of glucose tolerance and pancreatic β-cell function after 3-week daily administration in obese diabetic (ob/ob) mice

This study evaluates the antidiabetic potential of an enzyme-resistant analog, (Val8)GLP-1. The effects of daily administration of a novel dipeptidyl peptidase IV-resistant glucagon-like peptide-1 (GLP-1) analog, (Val8)GLP-1, on glucose tolerance and pancreatic β-cell function were examined in obese-diabetic (ob/ob) mice. Acute intraperitoneal administration of (Val8)GLP-1 (6.25-25 nmol/kg) with glucose increased the insulin response and reduced the glycemic excursion in a dose-dependent manner. The effects of (Val8)GLP-1 were greater and longer lasting than native GLP-1. Once-daily subcutaneous administration of (Val8)GLP-1 (25 nmol/kg) for 21 days reduced plasma glucose concentrations, increased plasma insulin, and reduced body weight more than native GLP-1 without a significant change in daily food intake. Furthermore, (Val8)GLP-1 improved glucose tolerance, reduced the glycemic excursion after feeding, increased the plasma insulin response to glucose and feeding, and improved insulin sensitivity. These effects were consistently greater with (Val8)GLP-1 than with native GLP-1, and both peptides retained or increased their acute efficacy compared with initial administration. (Val8)GLP-1 treatment increased average islet area 1.2-fold without changing the number of islets, resulting in an increased number of larger islets. These data demonstrate that (Val8)GLP-1 is more effective and longer acting than native GLP-1 in obese-diabetic ob/ob mice.

Analog of Favard's Theorem for Polynomials Connected with Difference Equation of 4-th Order

Orthonormal polynomials on the real line {pn (λ)} n=0 ... ∞ satisfy the recurrent relation of the form: λn−1 pn−1 (λ) + αn pn (λ) + λn pn+1 (λ) = λpn (λ), n = 0, 1, 2, . . . , where λn > 0, αn ∈ R, n = 0, 1, . . . ; λ−1 = p−1 = 0, λ ∈ C. In this paper we study systems of polynomials {pn (λ)} n=0 ... ∞ which satisfy the equation: αn−2 pn−2 (λ) + βn−1 pn−1 (λ) + γn pn (λ) + βn pn+1 (λ) + αn pn+2 (λ) = λ2 pn (λ), n = 0, 1, 2, . . . , where αn > 0, βn ∈ C, γn ∈ R, n = 0, 1, 2, . . ., α−1 = α−2 = β−1 = 0, p−1 = p−2 = 0, p0 (λ) = 1, p1 (λ) = cλ + b, c > 0, b ∈ C, λ ∈ C. It is shown that they are orthonormal on the real and the imaginary axes in the complex plane ...

A Fractional Analog of the Duhamel Principle

Mathematics Subject Classification: 35CXX, 26A33, 35S10

An Analog of the Tricomi Problem for a Mixed Type Equation with a Partial Fractional Derivative

Mathematics Subject Classification 2010: 35M10, 35R11, 26A33, 33C05, 33E12, 33C20.

Foraminiferal faunal estimates of paleotemperature: Circumventing the no-analog problem yields cool ice age tropics

The sensitivity of the tropics to climate change, particularly the amplitude of glacial-to-interglacial changes in sea surface temperature (SST), is one of the great controversies in paleoclimatology. Here we reassess faunal estimates of ice age SSTs, focusing on the problem of no-analog planktonic foraminiferal assemblages in the equatorial oceans that confounds both classical transfer function and modern analog methods. A new calibration strategy developed here, which uses past variability of species to define robust faunal assemblages, solves the no-analog problem and reveals ice age cooling of 5° to 6°C in the equatorial current systems of the Atlantic and eastern Pacific Oceans. Classical transfer functions underestimated temperature changes in some areas of the tropical oceans because core-top assemblages misrepresented the ice age faunal assemblages. Our finding is consistent with some geochemical estimates and model predictions of greater ice age cooling in the tropics than was inferred by Climate: Long-Range Investigation, Mapping, and Prediction (CLIMAP) [1981] and thus may help to resolve a long-standing controversy. Our new foraminiferal transfer function suggests that such cooling was limited to the equatorial current systems, however, and supports CLIMAP's inference of stability of the subtropical gyre centers.

Synthesis of heterocyclic compounds of medicinal relevance

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.

Studies in asymmetric and heterocyclic synthesis: I. chiral ketones II. Quinolones III. Trifluoromethylated pyrones

This thesis is split into three sections based on three different areas of research. In the first section, investigations into the α-alkylation of ketones using a novel chiral auxiliary is reported. This chiral auxiliary was synthesised containing a pyrrolidine ring in the chiral arm and was applied in the preparation of α-alkylated ketones which were obtained in up to 92% ee and up to 63% yield over two steps. Both 3-pentanone and propiophenone based ketones were used in the investigation with a variety of both alkyl and benzyl based electrophiles. The novel chiral auxiliary was also successful when applied to Michael and aldol reactions. A diamine precursor en route to the chiral auxiliary was also applied as an organocatalyst in a Michael reaction, with the product obtained in excellent enantioselectivity. In the second section, investigations into potential anti-quorum sensing molecules are reported. The bacteria Pseudomonas aeruginosa is an antibiotic-resistant pathogen that demonstrates cooperative behaviours and communicates using small chemical molecules in a process termed quorum sensing. A variety of C-3 analogues of the quorum sensing molecules used by P. aeruginosa were synthesised. Expanding upon previous research within the group, investigations were carried out into alternative protecting group strategies of 2-heptyl-4-(1H)- quinolone with the aim of improving the yields of products of cross-coupling reactions. In the third section, investigations into fluorination and trifluoromethylation of 2-pyrones, pyridones and quinolones is reported. The incorporation of a fluorine atom or a trifluoromethyl group into a molecule is important in pharmaceutical drug discovery programmes as it can lead to increased lipophilicity and bioavailability, however late-stage incorporation is rarely reported. Both direct fluorination and trifluoromethylation were attempted. Eight trifluoromethylated 2-pyrones, five trifluoromethylated 2-pyridones and a trifluoromethylated 2-quinolone were obtained in a late-stage synthesis from their respective iodinated precursors using methyl fluorosulfonyldifluoroacetate as a trifluoromethylating reagent.

The Synthesis of Novel N-Heterocyclic Scaffolds and Diazirine-Based Molecular Tags

N-Heterocycles are ubiquitous in biologically active natural products and pharmaceuticals. Yet, new syntheses and modifications of N-heterocycles are continually of interest for the purposes of expanding chemical space, finding quicker synthetic routes, better pharmaceuticals, and even new handles for molecular labeling. There are several iterations of molecular labeling; the decision of where to place the label is as important as of which visualization technique to emphasize.

Piperidine and indole are two of the most widely distributed N-heterocycles and thus were targeted for synthesis, functionalization, and labeling. The major functionalization of these scaffolds should include a nitrogen atom, while the inclusion of other groups will expand the utility of the method. Towards this goal, ease of synthesis and elimination of step-wise transformations are of the utmost concern. Here, the concept of electrophilic amination can be utilized as a way of introducing complex secondary and tertiary amines with minimal operations.

Molecular tags should be on or adjacent to an N-heterocycle as they are normally the motifs implicated at the binding site of enzymes and receptors. The labeling techniques should be useful to a chemical biologist, but should also in theory be useful to the medical community. The two types of labeling that are of interest to a chemist and a physician would be positron emission tomography (PET) and magnetic resonance imaging (MRI).

Coincidentally, the 3-positions of both piperidine and indole are historically difficult to access and modify. However, using electrophilic amination techniques, 3-functionalized piperidines can be synthesized in good yields from unsaturated amines. In the same manner, 3-labeled piperidines can be obtained; the piperidines can either be labeled with an azide for biochemical research or an 18F for PET imaging research. The novel electrophiles, N-benzenesulfonyloxyamides, can be reacted with indole in one of two ways: 3-amidation or 1-amidomethylation, depending on the exact reaction conditions. Lastly, a novel, hyperpolarizable 15N2-labeled diazirine has been developed as an exogenous and versatile tag for use in magnetic resonance imaging.

Synthesis of heterocyclic compounds of medicinal relevance

Mémoire numérisé par la Direction des bibliothèques de l'Université de Montréal.