Rachel Hevey
University of Calgary
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Publication
Featured researches published by Rachel Hevey.
Future Medicinal Chemistry | 2012
Rachel Hevey; Chang-Chun Ling
Cancer cells can often be distinguished from healthy cells by the expression of unique carbohydrate sequences decorating the cell surface as a result of aberrant glycosyltransferase activity occurring within the cell; these unusual carbohydrates can be used as valuable immunological targets in modern vaccine designs to raise carbohydrate-specific antibodies. Many tumor antigens (e.g., GM2, Le(y), globo H, sialyl Tn and TF) have been identified to date in a variety of cancers. Unfortunately, carbohydrates alone evoke poor immunogenicity, owing to their lack of ability in inducing T-cell-dependent immune responses. In order to enhance their immunogenicity and promote long-lasting immune responses, carbohydrates are often chemically modified to link to an immunogenic protein or peptide fragment for eliciting T-cell-dependent responses. This review will present a summary of efforts and advancements made to date on creating carbohydrate-based anticancer vaccines, and will include novel approaches to overcoming the poor immunogenicity of carbohydrate-based vaccines.
Journal of Organic Chemistry | 2012
Rachel Hevey; Alizée Morland; Chang-Chun Ling
A practical method to obtain orthogonally protected D-idopyranose from D-galactose has been developed, which is the first method to enable synthesis of the challenging β-D-idopyranoside linkage. The method relies on a key double inversion at O-2 and O-3 in an easily prepared D-galactose derivative, which proceeds regio- and stereoselectively through a 2,3-anhydrotalopyranoside; reaction using a selection of alkoxides affords exclusively the 3-O-alkylidopyranoside, which can be used to generate an orthogonally protected monosaccharide. The process is scalable and requires minimal purification, so it could be used to produce building blocks to aid in the synthesis of various β-idopyranose-containing oligosaccharide targets to further probe their biological functions.
Carbohydrate Research | 2011
Jianhao Feng; Rachel Hevey; Chang-Chun Ling
The total chemical synthesis of a Forssman antigen analog is described. The pentasaccharide contains a functionalized tether which should facilitate future conjugation with immunogenic proteins. We found that the total synthesis can be efficiently achieved by following a convergent 2+3 strategy, and using N-Troc protected GalNAc thioglycoside as a donor.
Carbohydrate Research | 2013
Rachel Hevey; Xining Chen; Chang-Chun Ling
The recently reported conversion of 2,3-di-O-sulfonyl-D-galactopyranosides to D-idopyranosides has provided an efficient route to obtaining orthogonally-protected idopyranoside building blocks with a β-1,2-cis glycosidic linkage. In an effort to expand the scope of this process and better understand the regio- and stereoselectivity observed in the key di-inversion step of the method, a small library of 4,6-O-acetal protected galactopyranosides has been synthesized and used as substrates in the process, together with a number of substrates that lack the acetal functionality. The results suggest that although the substituent at the acetal center does not contribute to the observed selectivity of the process, the acetal group is indeed required for efficient conversion by reducing the conformational flexibility of the substrate, resulting in enhanced reaction rates at both the O-transsulfonylation and epoxide ring-opening steps.
Carbohydrate Research | 2017
Rachel Hevey; Chang-Chun Ling
β-D-Idopyranosides are interesting sugars because of their unusual conformational flexibility in the pyranosyl ring, and also their β-1,2-cis-anomeric configuration. Here we report our studies of the regioselective opening of 4,6-O-benzylidene-protected β-D-idopyranosides under reducing conditions, and the subsequent 6-homologation via Swern oxidation and Wittig olefination to afford a 6,7-dideoxy-β-D-ido-hept-6-enopyranoside. This olefination product was found to adopt predominantly 1C4 conformation in solution by NMR experiments, which places the vinyl group at a more sterically hindered axial position and creates difficulty in subsequent hydroborations.
Beilstein Journal of Organic Chemistry | 2017
Christoph P. Sager; Deniz Eris; Martin Smiesko; Rachel Hevey; Beat Ernst
In general, carbohydrate–lectin interactions are characterized by high specificity but also low affinity. The main reason for the low affinities are desolvation costs, due to the numerous hydroxy groups present on the ligand, together with the typically polar surface of the binding sites. Nonetheless, nature has evolved strategies to overcome this hurdle, most prominently in relation to carbohydrate–lectin interactions of the innate immune system but also in bacterial adhesion, a process key for the bacterium’s survival. In an effort to better understand the particular characteristics, which contribute to a successful carbohydrate recognition domain, the mannose-binding sites of six C-type lectins and of three bacterial adhesins were analyzed. One important finding is that the high enthalpic penalties caused by desolvation can only be compensated for by the number and quality of hydrogen bonds formed by each of the polar hydroxy groups engaged in the binding process. In addition, since mammalian mannose-binding sites are in general flat and solvent exposed, the half-lives of carbohydrate–lectin complexes are rather short since water molecules can easily access and displace the ligand from the binding site. In contrast, the bacterial lectin FimH benefits from a deep mannose-binding site, leading to a substantial improvement in the off-rate. Together with both a catch-bond mechanism (i.e., improvement of affinity under shear stress) and multivalency, two methods commonly utilized by pathogens, the affinity of the carbohydrate–FimH interaction can be further improved. Including those just described, the various approaches explored by nature to optimize selectivity and affinity of carbohydrate–lectin interactions offer interesting therapeutic perspectives for the development of carbohydrate-based drugs.
Chemistry: A European Journal | 2018
Priska Frei; Rachel Hevey; Beat Ernst
Dynamic combinatorial chemistry (DCC) has repeatedly proven to be an effective approach to generate directed ligand libraries for macromolecular targets. In the absence of an external stimulus, a dynamic library forms from reversibly reacting building blocks and reaches a stable thermodynamic equilibrium. However, upon addition of a macromolecular host which can bind and stabilize certain components of the library, the equilibrium composition changes and induces an evolution-like selection and enrichment of high-affinity ligands. A valuable application of this so-called target-directed DCC (tdDCC) is the identification of potent ligands for pharmacologically relevant targets. Over time, the term tdDCC has been applied to describe a number of different experimental setups, leading to some ambiguity concerning its definition. This article systematically classifies known procedures for tdDCC and related approaches, with a special focus on the methods used for analysis and evaluation of experiments.
Journal of Organic Chemistry | 2017
Pengfei Zhang; Rachel Hevey; Chang-Chun Ling
The 6-deoxy-β-d-ido-heptopyranoside related to the capsular polysaccharides of C. jejuni HS:4 is very remarkable, owing to the unique, multifaceted structural features that have been combined into one molecule, which include (1) the rare ido-configuration, (2) the unusual 7-carbon backbone, and (3) the challenging β-(1→2)-cis-anomeric configuration. Two distinct strategies toward the total synthesis of this interesting target are reported. The first involved establishment of the β-d-idopyranosyl configuration from β-d-galactopyranosides, prior to a C-6-homologation extending the d-hexose to the desired 6-deoxy-d-heptose. However, this approach encountered difficulties due to the significantly reduced reactivity of the 6-position of the β-d-idopyranosides, so instead a second strategy was employed, which involved first carrying out a 6-homologation on the less flexible d-galactopyranose, followed by a very successful conversion to the desired β-d-ido-configuration found in the target heptopyranoside (2). This report is the first successful synthesis of the 6-deoxy-β-d-ido-heptopyranoside, which could possess interesting immunological properties.
Future Medicinal Chemistry | 2012
Rachel Hevey; Chang-Chun Ling
Organic and Biomolecular Chemistry | 2013
Rachel Hevey; Chang-Chun Ling