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Physical organic chemistry (anomeric effects, acetal openings and aromatic substitution)


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Xylose is an unusual structural component in mammalian cells. So far, it has only been found as the linker between protein and carbohydrate in proteoglycans. Proteoglycans are widely expressed in tissues with important roles in cell development, differentiation, migration, adhesion and proliferation. The proteoglycans are composed of glycosaminoglycan (GAG) chains covalently attached to a core protein. It is still unclear what determines the type of carbohydrate chain that is built on the core protein. [1]
GAG chains
Proteoglycans are composed of glycosamino-glycan chains linked to a core protein by the highly unusual carbohydrate xylose.

Biosynthesis of GAG chains can also take place independently of core protein synthesis by using xylosides as primers. [2] Xylosides with suitable hydrophobic aglycon can thus penetrate cell membranes and initiate GAG synthesis. The composition of the GAG assembled on the xyloside primer depends on the structure of the aglycon.
We have previously reported that the GAG-priming 2-(6-hydroxynaphthyl)-β-D-xylopyranoside selectively inhibits growth of tumor cells in vitro as well as in vivo. Treatment with this xyloside at a pharmacologically relevant dose reduced the average tumor load by up to 97% in SCID mice. [3]
Mechanism
New anti-tumor mechanism a) Xylosides, such as XylNapOH can enter both normal cells (blue) and tumor cells (pink). b) The xylosides serve as primers for the synthesis of soluble GAG chains. Short and medium length GAG chains are secreted from both cell types. c) The short GAG chains produced from T24 cells (pink) are taken up and transported to the nuclei of both cell types and induce apoptosis. The GAG chains from normal HFL-1 cells (blue) are not taken up or transported to the cell nuclei of either cell type. d) In vivo, the short antiproliferative carbohydrate chains secreted from the tumor cells form a gradient around the tumor (pink). The GAG chains will be rapidly taken up by neighbouring cells (i.e. mainly cancer cells), which explains the tumor selective effect. [4]



References

[1] Schwartz, N. B. Trends Glycosci. Glycotechnol. 1995, 7, 429-445.
[2] Okayama, M.; Kimata, K.; Suzuki, S. J. Biochem. 1973, 74, 1069-1073.
[3] Mani, K.; Belting, M.; Ellervik, U.; Falk, N.; Svensson, G.; Sandgren, S.; Cheng, F.; Fransson, L.-Å. Glycobiology 2004, 14, 387-397. 
[4] Nilsson, U.; Johnsson, R.; Fransson, L.-Å.; Ellervik, U.; Mani, K. Cancer Res., 2010, 70, 3771-3779