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Naphthoxylosides Investigations into glycosaminoglycan biosynthesis

by Jacobsson, Mårten, PhD

Abstract (Summary)
Glycosaminoglycans (GAGs) are members of a family of polysaccharide structures consisting mostly of repeating disaccharide units. Most GAGs are attached to specific serine residues in proteins to form proteoglycans (PGs). GAGs and PGs show a large and diverse number of biological functions ranging from cell cycle regulation and control of formation of blood vessels to modification of tissue transparency and lubrication in joints. Glycosaminoglycan biosynthesis is initiated by the formation of a linker tetrasaccharide common to most glycosaminoglycans. Addition of the fifth monosaccharide then determines whether dermatan sulphate/chondroitin sulphate or heparin sulphate/heparin is synthesised. Since the GAGs are attached to a protein, it is complicated to study their structure and biosynthesis. Therefore lipophilic compounds carrying a xylose residue are used as artificial primers. Xylosides carrying naphthalenic aglycon proved to be efficient primers of heparan sulphate and due to possible implications in anti-cancer therapy, further explorations into the so called naphthoxylosides were initiated. The present thesis discusses my efforts towards a systematic investigation into the effects of aglycon structure on the antiproliferative and glycosaminoglycan priming properties of naphthoxylosides. Varying the substitution pattern on the naphthalene framework of hydroxynaphthyl ?-D-xylosides confirmed previous indications that the aglycon structure is important for the biological activity of xylosides. Also, for healthy human lung fibroblasts a clear correlation between xyloside lipophilicity and toxicity, indicative of a passive uptake dependency, was found. However, for several compounds this correlation was absent in transformed cells, indicating the presence of a different mechanism of uptake or toxicity in these cells. Further, increased levels of apoptosis was shown in transformed cells treated with a hydroxynaphthyl ?-D-xylopyranoside with tumour-selective antiproliferative properties. Substitution of the oxygen atoms attached to the naphthalene moiety for sulphur increased the diversity of naphthoxylosides available for study. The toxicity and glycosaminoglycan priming properties of these reinforced the complexity of the structure-activity relationship. Also, as part of the synthesis of sulphur-containing xylosides, the mechanism for the acid-catalysed nucleophilic aromatic substitution of phenolic hydroxyls in non-polar solvents was investigated. Kinetic studies indicated a mechanism involving a change in the rate-determining step depending on reaction temperature. Theoretical studies allowed a mechanism involving an unusual concerted step with a highly ordered eight-membered ring to be proposed.
Bibliographical Information:

Advisor:

School:Lunds universitet

School Location:Sweden

Source Type:Doctoral Dissertation

Keywords:NATURAL SCIENCES; Chemistry; proteoglycan; Organisk kemi; Organic chemistry; nucleophilic aromatic substitution; thioether; glycosaminoglycan; xylosides; naphthoxylosides

ISBN:978-91-7422-153-4

Date of Publication:01/01/2007

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