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This thesis is largely concerned with the study of a cytochrome P-450 enzyme mimic consisting of an Iron porphyrin and iodosylbenzene. Chapter 1 consists of a review of the work that has been published on the above and other related metalloporphyrin biomimetic systems. The contents bear witness to the relatively recent interest in these particular enzyme mimics. A kinetic investigation forms the substance of the second chapter. The effect of structural and electronic changes on the iron porphyrin catalyst and the iodosylbenzene oxidant are measured in terms of their effect on the rate of cyclohexene oxidation. Other variables, such as the structure of the substrate and the nature of the solvent system, lead to a proposed mechanism. In Chapter 3 the iron porphyrin system is applied to 15,16-dihydrocyclopenta[a] phenanthren-17-one and its carcinogenic 11-methyl homologue. An attempt is made to selectively oxidise the terminal rings of the cyclopenta[a] phenanthrenes by Incorporating sterically bulky groups around the periphery of the iron porphyrin. The chemically active K-region remained the target for the majority of the iron porphyrins used, however some porphyrin substituents played an active role in encouraging the approach of the cyclopenta[a] phenanthrene substrate. Chemical modelling studies of the active site of the iron porphyrins and the question of steric hindrance as it relates to the approach of the cyclopenta[a] phenanthrenes are reported in Chapter 4.

M.Sc. (Botany) / Please refer to full text to view abstract

Class of 2005 Abstract / Objective: The purpose of this study was to retrospectively determine if individuals within the SAVAHCS home-based patient population with a diagnosis of diabetes mellitus are receiving an angiotensin-converting-enzyme inhibitor (ACE-I) based on recent evidence supporting its use in these patients. Research Design: A retrospective, chart review of 41 patients with a diagnosis of diabetes mellitus from November 1, 2004 to December 31, 2005. Methodology: This was a retrospective, chart review of all patients within the SAVAHCS home-based population with an active diagnosis of diabetes mellitus. Once the patients were identified, their clinical profiles were extracted from the VISTA computer system. The patients had data regarding age, gender, diabetes type, diagnoses of heart disease and hypertension, type of ACE- Inhibitor prescribed, blood pressure, HgbA1c, and height and weight in order to calculate body mass index (BMI). The patients were classified as either having or not having ACE-Inhibitor therapy. Results: The total number of diabetic patients currently receiving an ACE-Inhibitor was 24 (58.5%). This was significantly lower than the value of 80% predetermined (p=0.0352). Thirty-one patients were also found to have a diagnosis of hypertension (75.6%), with 18 of these patients having a prescription for an ACE-Inhibitor (43.9%). Four patients (9.8%) who were not currently on an ACE- Inhibitor had a documented history of cough induced by the use of these drugs. Clinical Relationships: ACE-Inhibitors are drug agents used to treat hypertension. They have also been shown to be of significant clinical value in diabetic patients, in both renal protective effects as well as to reduce cardiovascular risk, the most common cause of morbidity and mortality in diabetic patients.

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Secondary N-nitrosamines: diphenylnitrosamine (DPhNA), dimethylnitrosamine (DMNA), diethylnitrosamine (DENA), dipropylnitrosamine (DPNA), dibutylnitrosamine (DBNA), diethanolnitrosamine (DEtNA), methylnitrosoglycine (MNGly), nitrosopyrrolidine (NPyr), nitrosomorpholine (NMor) and nitrosopiperidine (NPip) were synthesised and their interaction with acetylcholinesterase (AChE) was investigated. Analyses of kinetic results show that DMNA (Ki=34.78 μM); DENA (Ki=54.24 μM); DPNA(Ki=60.36 μM); DBNA(Ki=95.54 μM); DEtNA(Ki=43.68 μM)MNGly (Ki=30.18 μM); NPip (Ki=123 μM); NPyr (Ki=66.07 μM), NMor (Ki=73.93 μM) and DPhNA (Ki=20.32 μM) are competitive and reversible inhibitors of acetylcholinesterase, with respect to the substrate, acetylthiocholine chloride, ATChCl. With time they act as irreversible covalent inhibitors with dipropy1nitrosamine producing 72% inactivation after 60 minutes. Scatchard analyses of f1uorometric titrations, (Kd=0.75mM-4.09mM); gel chromatography (Kd=O. 80mM-4. 60mM) and equilibrium dia1ysis (Kd=O. 71mM- 4.21mM) for MNG1y, DMNA, DEtNA, DENA, DPNA, NPyr, DSNA, NMor and NPip show that these compounds have weaker affinity for the enzyme, as compared to the much tightly binding aromatic DPhNA, Kd values (0.65mM, 0.68mM and 0.68mM) for fluorometric experiments, gel chromatography and equilibrium dialysis respectively. In all cases, the number of binding sites of acetylcholinesterase averaged to four.

Class of 2008 Abstract / Objectives: : The purpose of this paper is to provide greater understanding of ACE inhibitor cough and appropriate treatment options. Methods: A Medline search of key terms from 1975-2008 was conducted and all types of published material were included in this review. The articles were evaluated for relevance and appropriateness for inclusion in this review. Subjects considered appropriate included ACE inhibitor cough treatment, mechanism of action, incidence and prevalence, genetics, cough characteristics, onset and resolution of cough, and others. Whenever possible, original studies were obtained but several reviews were also used. Results: ACE inhibitor cough is typically a dry, non-productive, persistent but benign cough reportedly occurring in anywhere from 0.5%-50% of patients receiving ACE inhibitors, though most studies indicate less than 20%. The mechanism is not completely understood but seems to be related to a complicated mechanism involving pathways caused by ACE inhibition and including bradykinin, C fibers, and prostaglandins. Several treatment options have been successful in resolving or relieving cough, including NSAIDs, baclofen, cromolyn and others. Results, however, are inconsistent. Anti-tussive agents, switching to a different ACE inhibitor, or lowering the dose of the current ACE inhibitor do not seem to be effective. Conclusions: In spite of its benign nature, ACE inhibitor cough is usually bothersome enough to discontinue the medication and therefore can not be ignored. Several treatments have appeared effective, all of which carry the risk of drug interactions and additional side effects, and alternative therapy such as angiotensin receptor blockers seem to be reasonable in indicated patients.

IDE (Insulin-Degrading Enzyme) est une métalloenzyme impliquée dans la dégradation de plusieurs peptides physiologiques. Des études lient la maladie d’Alzheimer et le diabète de type II à IDE. En effet, parmi ses substrats, l’enzyme compte le peptide Béta-amyloïde (A-Béta) responsable des plaques séniles de la maladie d'Alzheimer et l’insuline régulant la glycémie. En 2006, l’équipe du Pr. Tang a élucidé la structure cristallographique d'IDE qui a révélée que les substrats se lient à deux sites de l'enzyme : le site catalytique et un exosite. Grâce au criblage d'une chimiothèque, un composé a été découvert modulant de façon substrat-dépendante l'activité d'IDE. Ce composé a été cristallisé dans l’enzyme: il peut se lier aux deux sites importants pour l’hydrolyse des substrats: le site catalytique et l'exosite. Ce mode de liaison est cohérent avec la modulation substrat-dépendante observée. 80 analogues ont été synthétisés pour améliorer l’activité et la perméation cellulaire. La modulation substrat-dépendante de la protéase permet d’envisager l’obtention d’outils chimiques pour l’étude de la fonction de cette enzyme et ouvre de nouvelles perspectives dans des pathologies où des substrats d’IDE seraient impliqués. En parallèle, une réaction de Click Chemistry in situ a été effectuée et a permis l'identification de 32 ligands parmi 180 composés potentiels. 12 ont été resynthétisés et ont montré une activité inhibitrice de l'enzyme. Ces composés possèdent une fonction hydroxamate et se lient donc au site catalytique inhibant l'enzyme quelque soit son substrat. La co-cristallisation d'un des composés avec l'enzyme a confirmé ce mode de liaison. / Insulin-Degrading Enzyme (IDE) is a zinc metalloprotease implicated in the clearance of numerous physiological peptides, in particular beta-amyloid (A[Béta]) peptide and insulin, respectively implicated in Alzheimer’s disease and Diabetes.Tang et al. elucidated the X-ray structure of the human IDE and found that substrates have two anchoring sites : the catalytic site at the zinc and an exosite which are both key features for the binding and hydrolysis.In our laboratory, we have screened a 2080-compound library on the enzyme and found a 5 µM hit inhibitor of A[Béta] hydrolysis. X-ray analysis of ligand-enzyme complexes, revealed that unexpectedly these compounds are either ligands of the catalytically site or the exosite of IDE.Consistently with their peculiar binding mode, these compounds behave as inhibitors or activators of the enzyme in a substrate-dependent manner.We made several chemical modulations on the hit structure and synthesized about 80 analogues to increase both potency and cell permeation.The mode of action of our compounds opens new avenues for the study of the function of IDE and for the design of therapeutic interventions.In the mean time, an in situ Click Chemistry experiment led to the identification of 32 ligands over 180 potential compounds. 12 compounds were resynthesised and showed inhibitory activities on the enzyme for all substrats. Co-crystallisation confirmed the binding to the catalytical site thanks to a hydroxamate function.

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