No description available.

No description available.

Perhexiline maleate was first introduced for the prophylaxis of exertional angina in the 1970s but reports of adverse reactions, including potentially fatal hepatotoxicity, increasingly restricted its application. By 1988 Australia and New Zealand were the only countries permitting its use, limited to the treatment of refractory angina pectoris conditional upon the therapeutic monitoring of patients, due to recognition of the concentration dependent nature of its efficacy and toxicity. An understanding of the extreme interindividual variability in the pharmacokinetics of perhexiline due to metabolism by the polymorphic Cytochrome P450 2D6 (CYP2D6) has prompted a recent resurgence of its use in Australasia and Europe. Perhexiline is a chiral molecule and is administered as a racemic mixture. Prior to the publication of the papers that are the topic of this thesis the characterisation of the clinical pharmacology of the enantiomers of perhexiline had been limited to one pharmacokinetic study that suggested that the (+) enantiomer of perhexiline may display a smaller polymorphic effect in its metabolism than its optical antipode. The four publications that comprise this thesis describe a comprehensive investigation of the pharmacokinetics and metabolism of the enantiomers of perhexiline in extensive and poor metabolisers (EM and PM, respectively) of CYP2D6 in both an in vitro model and clinically. The aim was to determine if the CYP2D6 polymorphism affects the metabolism of (+)-perhexiline significantly less than (-)-perhexiline, such that the inherent variability observed in the pharmacokinetics of the racemic preparation used clinically might be overcome by administration of only (+)-perhexiline. Although both the in vitro and in vivo studies determined that the involvement of CYP2D6 was proportionately greater in the total clearance of (-)- than (+)-perhexiline, the empirical data also demonstrated that the role of CYP2D6 in the metabolism of (+)-perhexiline was simply too pre-eminent for a chiral preparation of this enantiomer to significantly reduce the difference in clearance observed between EM and PM. An unexpected finding was that the enantioselectivity observed in the clinical pharmacokinetics of perhexiline in EM was, in fact, significantly greater in PM. Whilst the enantioselectivity in EM was attributable to metabolism by CYP2D6, the mechanism responsible for this in PM could not be determined, but was postulated to involve enantioselective biliary excretion. Because PM are effectively exposed to greater concentrations of (+)-perhexiline and lower concentrations of (-)-perhexiline, when the relative pharmacodynamic activities of the individual enantiomers have been established therapeutic drug monitoring may be improved by the development of specific enantiomer target concentration ranges in plasma. What is certain is that perhexiline will remain an essential option in the armamentarium for the treatment of refractory angina pectoris and therapeutic drug monitoring will remain obligatory due to the inter- and intra-subject pharmacokinetic variability attributable to the respective polymorphic and saturable metabolism of both enantiomers by CYP2D6. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1346638 / Thesis (Ph.D.) - University of Adelaide, School of Medical Sciences, 2008

Perhexiline maleate was first introduced for the prophylaxis of exertional angina in the 1970s but reports of adverse reactions, including potentially fatal hepatotoxicity, increasingly restricted its application. By 1988 Australia and New Zealand were the only countries permitting its use, limited to the treatment of refractory angina pectoris conditional upon the therapeutic monitoring of patients, due to recognition of the concentration dependent nature of its efficacy and toxicity. An understanding of the extreme interindividual variability in the pharmacokinetics of perhexiline due to metabolism by the polymorphic Cytochrome P450 2D6 (CYP2D6) has prompted a recent resurgence of its use in Australasia and Europe. Perhexiline is a chiral molecule and is administered as a racemic mixture. Prior to the publication of the papers that are the topic of this thesis the characterisation of the clinical pharmacology of the enantiomers of perhexiline had been limited to one pharmacokinetic study that suggested that the (+) enantiomer of perhexiline may display a smaller polymorphic effect in its metabolism than its optical antipode. The four publications that comprise this thesis describe a comprehensive investigation of the pharmacokinetics and metabolism of the enantiomers of perhexiline in extensive and poor metabolisers (EM and PM, respectively) of CYP2D6 in both an in vitro model and clinically. The aim was to determine if the CYP2D6 polymorphism affects the metabolism of (+)-perhexiline significantly less than (-)-perhexiline, such that the inherent variability observed in the pharmacokinetics of the racemic preparation used clinically might be overcome by administration of only (+)-perhexiline. Although both the in vitro and in vivo studies determined that the involvement of CYP2D6 was proportionately greater in the total clearance of (-)- than (+)-perhexiline, the empirical data also demonstrated that the role of CYP2D6 in the metabolism of (+)-perhexiline was simply too pre-eminent for a chiral preparation of this enantiomer to significantly reduce the difference in clearance observed between EM and PM. An unexpected finding was that the enantioselectivity observed in the clinical pharmacokinetics of perhexiline in EM was, in fact, significantly greater in PM. Whilst the enantioselectivity in EM was attributable to metabolism by CYP2D6, the mechanism responsible for this in PM could not be determined, but was postulated to involve enantioselective biliary excretion. Because PM are effectively exposed to greater concentrations of (+)-perhexiline and lower concentrations of (-)-perhexiline, when the relative pharmacodynamic activities of the individual enantiomers have been established therapeutic drug monitoring may be improved by the development of specific enantiomer target concentration ranges in plasma. What is certain is that perhexiline will remain an essential option in the armamentarium for the treatment of refractory angina pectoris and therapeutic drug monitoring will remain obligatory due to the inter- and intra-subject pharmacokinetic variability attributable to the respective polymorphic and saturable metabolism of both enantiomers by CYP2D6. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1346638 / Thesis (Ph.D.) - University of Adelaide, School of Medical Sciences, 2008

No description available.

The conceptually simple process of linking carbohydrate units by glycosylation has proven to be one of the most difficult synthetic processes to control from a stereochemical perspective. In particular it is the stereocontrolled synthesis of 1,2-cis glycosyl linkages (e.g. α-glucosides, β-mannosides) which poses the most difficult challenge. The research presented in this thesis describes new ways in which stereocontrol in glycosylation reactions can be achieved. New methods of neighbouring group participation have been explored, utilising novel protecting groups at the 2-postion of a series of glycosyl donors. In particular the use of glucosyl donors bearing a 2-O-(2-(2,4,6- trimethoxyphenyl)thio)ethyl protecting group at the 2-hydroxyl, have shown exceptional α-selectivity especially when a completely armed donor was used. Work within this thesis also describes the use of chiral Brønsted acid catalysts in stereoselective glycosylation reactions. However the yields and stereoselectivity obtained were not very encouraging.

No description available.

<p> β-Lactones are present in a number of biologically interesting natural products. They also have inherent reactivity due to their strained ring system and act as important synthetic intermediates. In this current work, we focus on the development of an efficient stereoselective route for the synthesis of β-lactones. A Tandem Evans-type Aldol Lactonization (TEAL) method was developed and various di- and tri-substituted β-lactones were successfully synthesized in a one pot process, using the lithium enolates of N-acetyl- (2-8) and N-propionyl- (2-20) thiazolidine-2-thione and a variety of ketones with moderate to good yields. Substitution of these N-acyl thiazolidine-2-thiones with chiral N-acetyl and N-propionyl thiazolidine-2-thiones (2-41 and 2-42 respectively) produced β-lactones with good enantioselectivity (up to 83% e.e.) and also showed an improvement of diastereoselectivity indicating the potential of the developed method. </p> / Thesis / Master of Science (MSc)

BORGES, K. B. Análise estereosseletiva da tioridazina e seus principais metabólitos: um estudo cinético de biotransformação empregando fungos. 2006. 124f. Dissertação (Mestrado) Faculdade de Ciências Farmacêuticas de Ribeirão Preto Universidade de São Paulo, Ribeirão Preto, 2006. Atualmente, existe um grande interesse em estudar a biotransformação estereosseletiva de fármacos, incluindo os processos que reproduzem as vias de metabolização in vivo. Alguns desses estudos estão sendo realizados empregando microrganismos como, por exemplo, fungos. A cromatografia líquida de alta eficiência é umas das técnicas que pode ser empregada para a resolução, identificação e quantificação das espécies quirais formadas. A tioridazina (THD) é um fármaco quiral, com atividade antipsicótica utilizado para o tratamento da esquizofrenia. Possui como principais metabólitos a tioridazina-2-sulfóxido (THD-2-SO) e tioridazina-2-sulfona (THD-2-SO2), ambos com atividade antipsicótica, e a tioridazina-5-sulfóxido (THD-5-SO), que contribui para o efeito cardiotóxico do fármaco. Portanto, o presente trabalho tem por finalidade o desenvolvimento de um método de análise estereosseletiva da THD-2-SO e THD-5-SO em meio de cultura para avaliação do potencial de biotransformação da THD por alguns fungos. A melhor resolução dos estereoisômeros da THD-2-SO e THD-5-SO foi obtida utilizando a coluna CHIRALPAK® AS e fase móvel hexano : etanol : metanol (92:6:2, v/v/v) + 0,5% de dietilamina. A extração líquido líquido foi utilizada na preparação das amostras, tendo como solvente extrator o éter etílico. O método desenvolvido apresentou recuperação em torno de 100% para todos os compostos avaliados. Os coeficientes de variação e erros obtidos nos estudos de precisão e exatidão, intra e interensaios, foram inferiores a 10%. O método desenvolvido e validado foi empregado para avaliar o potencial de biotransformação da THD por 12 fungos endofíticos isolados de Tithonia diversifolia, Viguiera arenaria e Viguiera robusta e 1 fungo de solo (Penicillium waksmanii). Dentre os 13 fungos avaliados, quatro merecem destaque por apresentarem um potencial de biotransformação estereosseletivo mais evidenciado: Phomopsis sp. (TD2) apresentou maior mono-5-sulfoxidação para as formas (S)-(SE) e (R)-(FE) (9,3% e 5,8%, respectivamente);Glomerella cingulata (VA1) apresentou maior mono-5-sulfoxidação para as formas (S)-(SE) + (R)-(FE) (39,7%); Diaporthe phaseolorum (VR4) apresentou maior mono-2-sulfoxidação para as formas (S)-(SE) e (R)-(FE) (84,4% e 82,5%, respectivamente) e Aspergillus fumigatus (VR12) apresentou maior mono-2-sulfoxidação das formas (S)-(FE) (20,7%) e (R)-(SE) (34,4%). / BORGES, K. B. Stereoselective analysis of thioridazine and its major metabolites: a kinetic study of biotransformation by fungi. 2006. 124p. Dissertation (Masters degree) Faculdade de Ciências Farmacêuticas de Ribeirão Preto Universidade de São Paulo, Ribeirão Preto, 2006. The interest in stereoselective biotransformation of drugs including the processes that reproduce the in vivo metabolism has been increased. To study drug metabolism several models have been used. Among them, studies carried out using microorganisms, mainly fungi have been standing out. High-Performance Liquid Chromatography can be used for the resolution, identification and quantification of the chiral species formed. The thioridazine (THD) is a chiral drug used as antipsychotic for the treatment of schizophrenia. The main metabolites of THD are thioridazine-2-sulfoxide (THD-2-SO), thioridazine-2-sulfone (THD-2-SO2) and thioridazine-5-sulfoxide (THD-5-SO). The THD-2-SO and THD-2-SO2 possesss antipsychotic activity and THD-5-SO contributes to the cardiotoxicity of drug more than the parent compound. Therefore, the aim of the present work was to develop a method for the stereoselective analysis of THD-2-SO and THD-5-SO in culture medium to study biotransformation of THD by some fungi. The simultaneous determination of thioridazine-2-sulfoxide and thioridazine-5-sulfoxide was performed on a CHIRALPAK® AS column using a mobile phase constituted of hexane: ethanol: methanol (92:6:2, v/v/v) + 0.5% diethylamine. Diethyl ether was used as extraction solvent. Recoveries around 100% were obtained for all the evaluated species. The coefficients of variation and relative errors in precision and accuracy studies (within-day and between-day) were below 10%. The validated method was used to evaluate the biotransformation of THD by 12 endophytic fungi isolated from Tithonia diversifolia, Viguiera arenaria and Viguiera robusta and 1 fungus isolated from soil (Penicillium waksmanii). Among the 13 fungi evaluated, four of them deserve prominence for presenting an evidenced stereoselective biotransformation potential: Phomopsis sp. (TD2) presented greater mono-5-sulfoxidation to the forms (S)-(SE) e (R)-(FE) (9.3% and 5.8%, respectively); Glomerella cingulata (VA1) presented greater mono-5-sulfoxidation to the forms (S)-(SE) + (R)-(FE) (39.7%); Diaporthe phaseolorum (VR4) presented greater mono-2-sulfoxidation to the forms (S)-(SE) and (R)-(FE) (84.4% and 82.5%, respectively) and Aspergillus fumigatus (VR12) presented greater mono-2-sulfoxidation to the forms (S)-(FE) (20.7%) and (R)-(SE) (34.4%).

Polylactide (PLA) is a biodegradable and biocompatible alternative to traditional petrochemicalbased polymers. Synthesised by the ring-opening polymerisation of lactide (LA), the dehydrated form of lactic acid, PLA sits within a renewable cycle, and can be used in many commodity and biomedical applications. The intrinsic stereochemistry of LA can lead to a variety of polymer microstructures, and current industrially used initiators allow no control over this. Within this thesis a series of investigations into the use of amine tris(phenolate) metal complexes as stereoselective initiators for the ROP of LA are discussed. Chapter 1 introduces the field of ring-opening polymerisation (ROP) via a coordination insertion mechanism, presents previously reported initiators, and examines the influence of stereocomplexation on the physical properties of PLA chains. This introductory chapter also includes an in-depth review of recent developments in poly(phenolate) complexes of Group 4 and rare earth metals. Chapter 2 describes the synthesis of a series of isopropoxide and zwitterionic Group 4 complexes featuring the amine tris(phenolate) ligand motif, with emphasis on the effect of ligand variation on complex structure. The potential of the resulting complexes as initiators for the ROP of LA is also investigated, with in depth kinetic studies allowing for a proposed diastereoselective mechanism of stereocontrol. Chapter 3 details the synthesis of a series of borohydride and amide Group 4 amine tris(phenolate) complexes, and investigates their potential as initiators for the ROP of rac-LA. Chain-end analysis and kinetic studies are included, providing the basis for mechanistic discussions. Chapter 4 focuses on the synthesis of stereoblock PLA materials in a stereospecific manner, and co-block PLA-PEG materials by the reinitiation of short-chain macroinitiators. The effect of stereocomplexation on the thermal properties of these materials is investigated. Chapter 5 concerns the synthesis of a series of isopropanol and zwitterionic rare earth complexes featuring the amine tris(phenolate) ligand motif. The potential of these complexes as initiators for the ROP of rac-LA is also investigated, but only slight stereocontrol was observed in selected cases. Chapter 6 provides details of procedures employed in the synthesis of ligands, complexes and polymers within this thesis, as well as details of the analytical techniques used in their characterisation.