De par leurs propriétés biologiques et leur structure remarquables, les C-aryl glycosides<br />ont suscité l'intérêt de nombreuses équipes de recherche. La création de la liaison Cglycosidique<br />de façon régio- et stéréocontrôlée constitue la principale difficulté de la synthèse<br />de ces composés.<br />L'objectif de ce travail est la mise au point d'une synthèse de C-aryl glycosides par voie<br />intramoléculaire. Nous avons développé une méthode de C-arylation intramoléculaire efficace<br />et stéréocontrôlée basée sur l'activation d'un glycoside de pentényle. Cette méthode a été<br />appliquée à la synthèse de dérivés de la Bergénine et a conduit à des produits de cyclisation<br />inattendus en série mannopyranose.<br />Pour généraliser la méthode, nous avons exploré plusieurs liens temporaires entre<br />l'aglycone et la copule glucidique : les agrafes de type arylsilyle nous ont permis de mettre au<br />point la première méthode de synthèse d'αlpha-C-aryl glucosides avec un stéréocontrôle total et de<br />bons rendements.

A total synthesis of the complex C-aryl glycoside isokidamycin was achieved during an effort to construct the natural product kidamycin, a member of the pluramycin family of antitumor antibiotics. The angolosamine carbohydrate was appended, along with annelation of a benzene ring by the implementation of the Martin group's silicon tether-directed, intramolecular aryne-furan cycloaddition strategy. The vancosamine-derived carbohydrate was then installed by an O -> C-glycoside rearrangement. A novel protocol for the carbonylative cross-coupling of ortho-disubstituted aryl iodides with aryl boronic acids and alkynyl zinc reagents was also discovered during efforts to introduce the pyranone ring of kidamycin. The reaction proved general, as a variety of electron-rich and electron-poor aryl iodides, boronic acids, and alkynyl-zinc reagents participated in the cross-coupling. / text

The cryopreservation of cells and tissues requires the addition of a cryoprotectant in order to prevent cellular damage caused by ice. Unfortunately, common cryoprotectants such as DMSO and glycerol exhibit significant toxicity which makes their use unfeasible for many clinical procedures. Our laboratory is interested in the development of alternative, non-toxic cryoprotectants which possess ice recrystallization inhibition (IRI) activity. Potent IRI activity has recently been discovered in certain small molecules, but the structural features required for this process are unclear. Herein we report the development of a library of O-aryl glycosides in order to probe the importance of electron density and hydrophobic moieties for IRI activity. It was found that the degree of electron density at the anomeric oxygen does not correlate with IRI ability in para-substituted aryl glycosides, nor does changing the position of the aryl substituent impart a predictable effect on activity. However, the addition of hydrophobic alkyl or acyl chains was beneficial for IRI activity; generally, increasing chain length was found to correlate with increasing activity. In some instances, an optimal alkyl chain length was identified, after which continued lengthening results in a loss of potency. We conclude from this study that a certain extent of hydrophobic character is beneficial for the IRI activity of aryl glycosides, and that a balance between hydrophobicity and hydrophilicity is required for optimum IRI ability. It is hoped that these findings will aid future efforts towards the rational design of novel cryoprotectants.

Cryopreservation of human red blood cells (RBCs) extends the storage time from 42 days (hypothermic storage limit) to a maximum of 10 years. While this reduces the possibility of RBC shortages in emergency situations, this preservation method is currently limited to individuals with rare blood phenotypes, patients who require autologous blood transfusions, and military applications. Furthermore, cryopreservation is associated with a high degree of cellular damage, which can subsequently reduce the viability of cells post-thaw. The cellular damage incurred upon cryopreservation is primarily attributed to the process of ice recrystallization. To reduce the degree of cellular damage, cryoprotective agents (CPAs) are used. Currently, 10 % dimethyl sulphoxide (DMSO) and 40 % glycerol are used for the cryopreservation of hematopoietic stem cells (HSCs) and human RBCs respectively. Unfortunately, these CPAs do not provide protection against ice recrystallization. The biological antifreezes (BAs) consisting of antifreeze proteins (AFPs) and antifreeze glycoproteins (AFGPs) were identified as the first inhibitors of ice recrystallization. Consequently, the Ben laboratory is interested in synthesizing small molecule carbohydrate-based inhibitors of ice recrystallization that can be used as an alternative to glycerol or DMSO for the cryopreservation of various cell types. Therefore, this thesis focuses on elucidating important structural features of carbohydrate-based derivatives that are responsible for IRI activity. The first part of this study examines the importance of the anomeric oxygen atom of aryl glycosides for IRI activity. Our laboratory previously demonstrated that the O-linked aryl glycosides are effective inhibitors of ice recrystallization. However, the influence of stereoelectronic effects at the C1 position of aryl glycosides on IRI activity has not been investigated. As a result, N- and S-linked aryl glycosides were synthesized in this study and their IRI activities were compared to that of the O-linked aryl glycosides. These results suggest that a stronger exo-anomeric effect exhibited by the C1 nitrogen derivatives reduces the IRI activity of aryl glycosides. The second part of this study focuses on the synthesis of AFGP disaccharide analogs. While the β-(1,3) glycosidic linkage found in native AFGP-8 was previously assessed for its influence on IRI activity, an extensive structure-function analysis of AFGP disaccharide analogs has not yet been performed. As a result, an AFGP disaccharide analog was designed whereby a para-methoxyphenyl (PMP) substituent was incorporated. This was done to assess whether the PMP substituent could enhance the lack of IRI activity exhibited previously with AFGP disaccharide analogs. Although the synthesis of this disaccharide target was not completed, a number of advantageous developments have been made regarding the glycosylation of N-acetyl-D-glycosamine derivatives. In addition, the PMP-GlcNAc intermediate encountered in disaccharide synthesis was assessed for its IRI activity, confirming that the acetamido (NHAc) function is not required for IRI activity.

The cryopreservation of cells and tissues requires the addition of a cryoprotectant in order to prevent cellular damage caused by ice. Unfortunately, common cryoprotectants such as DMSO and glycerol exhibit significant toxicity which makes their use unfeasible for many clinical procedures. Our laboratory is interested in the development of alternative, non-toxic cryoprotectants which possess ice recrystallization inhibition (IRI) activity. Potent IRI activity has recently been discovered in certain small molecules, but the structural features required for this process are unclear. Herein we report the development of a library of O-aryl glycosides in order to probe the importance of electron density and hydrophobic moieties for IRI activity. It was found that the degree of electron density at the anomeric oxygen does not correlate with IRI ability in para-substituted aryl glycosides, nor does changing the position of the aryl substituent impart a predictable effect on activity. However, the addition of hydrophobic alkyl or acyl chains was beneficial for IRI activity; generally, increasing chain length was found to correlate with increasing activity. In some instances, an optimal alkyl chain length was identified, after which continued lengthening results in a loss of potency. We conclude from this study that a certain extent of hydrophobic character is beneficial for the IRI activity of aryl glycosides, and that a balance between hydrophobicity and hydrophilicity is required for optimum IRI ability. It is hoped that these findings will aid future efforts towards the rational design of novel cryoprotectants.

La protéine tyrosine phosphatase 1B (PTP 1B) et la glycogène phosphorylase (GP) sont des nouveaux cibles thérapeutiques pour le traitement du diabète (type II) et l'obésité. Dans l'objective de trouver des inhibiteurs actives et sélectives de ces enzymes, des aryl C glycosides tels que les C glycosyl 1,4 naphthaquinones, les 6 O benzoyl C glycosyl benzoquinone /naphthaquinones, les dérivés quinone d'acides glycuroniques et d'amides carboxylés ainsi que les inhibiteurs bidentates C glycosyl quinones ont été conçus et synthétisés. En tout, 178 composés ont été préparés. Le mécanisme et les facteurs d'influence de la réaction de C aryl glycosylation ont également été étudiés. Les essais préliminaires montrent que certaines molécules présentent des activités biologiques très intéressantes. Des études biologiques plus approfondies seront réalisées par la suite.