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Naphthoxylosides Investigations into glycosaminoglycan biosynthesis

Jacobsson, Mårten LU (2007)
Abstract (Swedish)
Popular Abstract in Swedish

Många av cellernas reglerings-, kommunikations- och interaktionssystem styrs av kolhydrater. Dessa kolhydrater sitter ofta bundna på proteiner och bildar då så kallade makromolekyler. En sådan grupp av makromolekyler kallas för glykosaminoglykaner. I de flesta medlemmar av denna grupp sitter långa kolhydratkedjor fast på proteinet via sockret xylos, även känt som björksocker.



För att studera strukturen på kolhydratkedjorna, utan den försvårande närvaron av proteindelen, kan xylos-molekyler bundna till feta strukturer användas. Dessa molekyler, som kallas för xylosider, kan ta sig in i celler och där agera som startpunkt för biosyntesen av glykosaminoglykankedjor.

... (More)
Popular Abstract in Swedish

Många av cellernas reglerings-, kommunikations- och interaktionssystem styrs av kolhydrater. Dessa kolhydrater sitter ofta bundna på proteiner och bildar då så kallade makromolekyler. En sådan grupp av makromolekyler kallas för glykosaminoglykaner. I de flesta medlemmar av denna grupp sitter långa kolhydratkedjor fast på proteinet via sockret xylos, även känt som björksocker.



För att studera strukturen på kolhydratkedjorna, utan den försvårande närvaron av proteindelen, kan xylos-molekyler bundna till feta strukturer användas. Dessa molekyler, som kallas för xylosider, kan ta sig in i celler och där agera som startpunkt för biosyntesen av glykosaminoglykankedjor.



Det har visat sig att xylosider inte bara agerar som startpunkt för denna biosyntes ? de kan även ha egna intressanta egenskaper. Till exempel kan xylosider där xylos sitter bundet till naftalen, så kallade naftoxylosider, öka proportionen av heparan sulfat som är en sorts glykosaminoglykan. Vissa sådana strukturer visade sig även ha en tillväxthämmande effekt på celler, och var mer giftiga mot vissa former av mänskliga cancerceller än mot friska celler.



Denna avhandling diskuterar min systematiska undersökning av hur en naftoxylosids kemiska struktur påverkar vilken sorts kolhydratkedjor som byggs på xylos av cellernas maskineri samt till vilken grad det sker. Effekten av strukturen på molekylernas toxicitet och selektivitet undersöks också och påvisar tydligt den komplexitet som ligger bakom de mekanismer som gör naftoxylosider giftiga.



En spännande framtid för forskning om naftoxylosider utlovas då studien visar att en av naftoxylosiderna som uppvisar selektivitet mot cancerceller verkar genom att få cellerna att begå självmord, något som är mycket attraktivt för presumtiva anticancerläkemedel. (Less)
Abstract
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Associate Professor Elofsson, Mikael, Umeå University
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Organisk kemi, proteoglycan, Organic chemistry, nucleophilic aromatic substitution, thioether, glycosaminoglycan, xylosides, naphthoxylosides
pages
129 pages
publisher
Organic Chemistry, Lund University
defense location
Lecture hall K:C Chemical Center Getingevägen 60 Lund Sweden
defense date
2007-05-25 09:30
ISBN
978-91-7422-153-4
language
English
LU publication?
yes
id
7e855d96-2cc1-4628-8912-56f1819535f3 (old id 548597)
date added to LUP
2007-10-09 11:16:59
date last changed
2016-09-19 08:45:07
@misc{7e855d96-2cc1-4628-8912-56f1819535f3,
  abstract     = {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.<br/><br>
<br/><br>
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.<br/><br>
<br/><br>
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.<br/><br>
<br/><br>
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.<br/><br>
<br/><br>
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.<br/><br>
<br/><br>
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.},
  author       = {Jacobsson, Mårten},
  isbn         = {978-91-7422-153-4},
  keyword      = {Organisk kemi,proteoglycan,Organic chemistry,nucleophilic aromatic substitution,thioether,glycosaminoglycan,xylosides,naphthoxylosides},
  language     = {eng},
  pages        = {129},
  publisher    = {ARRAY(0xaf289b8)},
  title        = {Naphthoxylosides Investigations into glycosaminoglycan biosynthesis},
  year         = {2007},
}