Glycosaminoglycans (GAGs) and proteoglycans are major components in the extracellular matrix and are involved in important processes such as cell-cell interactions, growth factor uptake and uptake of biomolecules. A key substrate in the biosynthesis of these macromolecules is the carbohydrate xylose, the substrate for the enzyme β4GalT7. It has been shown that a xylose with a naphthol aglycon can function either as a primer of GAGs or as an inhibitor depending on the modification of the carbohydrate. It is thus interesting to synthesize modified xylosides to investigate the biosynthesis of GAGs and how these affect cells. Since single modifications have previously been investigated, progression towards double modifications or other changes of the carbohydrate is natural.
To probe the active site of β4GalT7, several doubly modified naphthoxylosides were synthesized. The endo/exocyclic oxygen was also replaced with carbon or sulfur. Superficially simple compounds were shown to require complex synthetic routes. Despite many existing methods for synthesizing carbohydrates, double modifications of pentoses presented several challenges due to conformational, steric and stereoelectronic effects. Only two compounds showed any inhibition, revealing that the active site is stringent.  A profound effect in priming ability when replacing the oxygens for sulfur was observed, increasing the ability of the substrate by approximately 15 times due to a conformational change. These results may have a profound effect on the quest for better inhibitors.
- Willén D, Bengtsson D, Clementson S, Tykesson E, Manner S, Ellervik U. Synthesis of Double-Modified Xyloside Analogues for Probing the β4GalT7 Active Site. Journal of Organic Chemistry. 2018 feb 2;83(3):1259-1277.
- Thorsheim K, Willén D, Tykesson E, Ståhle J, Praly JP, Vidal S et al. Naphthyl Thio- and Carba-xylopyranosides for Exploration of the Active Site of β-1,4-Galactosyltransferase 7 (β4GalT7). Chemistry - A European Journal. 2017 dec 19;23(71):18057-18065.