Synthesis and biology of oligoethylene glycol linked naphthoxylosides.

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Synthesis and biology of oligoethylene glycol linked naphthoxylosides. / Thorsheim, Karin; Persson, Andrea; Johnsson, Richard; Löfgren, Johanna; Mani, Katrin; Ellervik, Ulf.

I: Bioorganic & Medicinal Chemistry, Vol. 21, Nr. 11, 2013, s. 3310-3317.

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Thorsheim, Karin ; Persson, Andrea ; Johnsson, Richard ; Löfgren, Johanna ; Mani, Katrin ; Ellervik, Ulf. / Synthesis and biology of oligoethylene glycol linked naphthoxylosides. I: Bioorganic & Medicinal Chemistry. 2013 ; Vol. 21, Nr. 11. s. 3310-3317.

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TY - JOUR

T1 - Synthesis and biology of oligoethylene glycol linked naphthoxylosides.

AU - Thorsheim, Karin

AU - Persson, Andrea

AU - Johnsson, Richard

AU - Löfgren, Johanna

AU - Mani, Katrin

AU - Ellervik, Ulf

PY - 2013

Y1 - 2013

N2 - Proteoglycans (PGs) are important macromolecules in mammalian cells, consisting of a core protein substituted with carbohydrate chains, known as glycosaminoglycans (GAGs). Simple xylosides carrying hydrophobic aglycons can enter cells and act as primers for GAG chain synthesis, independent of the core protein. Previously it has been shown that aromatic aglycons can be separated from the sugar residue by short linkers without affecting the GAG priming ability. To further investigate the effects of the xylose-aglycon distance on the GAG priming ability, we have synthesized xyloside derivatives with 2-naphthyl and 2-(6-hydroxynaphthyl) moieties connected to xylose, directly, via a methylene bridge, or with oligoethylene glycol linkers of three different lengths. The GAG priming ability and the antiproliferative activity of the xylosides, as well as the composition of the xyloside-primed GAG chains were investigated in a matched pair of human breast fibroblasts and human breast carcinoma cells. An increase of the xylose-aglycon distance from 0.24 to 0.37nm resulted in an increased GAG priming ability in both cell lines. Further increase of the xylose-aglycon distance did not result in any pronounced effects. We speculate that by increasing the xylose-aglycon distance, and thereby the surface area of the xyloside, to a certain level would make it more accessible for enzymes involved in the GAG synthesis. The compositions of the primed GAG chains varied with different xylosides, independent of the xylose-aglycon distance, probably due to various affinities for enzymes and/or different cellular uptake. Furthermore, no correlations between the antiproliferative activities, the xylose-aglycon distances, and the amounts or compositions of the GAG chains were detected suggesting involvement of other factors such as fine structure of the GAG chains, effects on endogenous PG synthesis, or other unknown factors for the antiproliferative activity.

AB - Proteoglycans (PGs) are important macromolecules in mammalian cells, consisting of a core protein substituted with carbohydrate chains, known as glycosaminoglycans (GAGs). Simple xylosides carrying hydrophobic aglycons can enter cells and act as primers for GAG chain synthesis, independent of the core protein. Previously it has been shown that aromatic aglycons can be separated from the sugar residue by short linkers without affecting the GAG priming ability. To further investigate the effects of the xylose-aglycon distance on the GAG priming ability, we have synthesized xyloside derivatives with 2-naphthyl and 2-(6-hydroxynaphthyl) moieties connected to xylose, directly, via a methylene bridge, or with oligoethylene glycol linkers of three different lengths. The GAG priming ability and the antiproliferative activity of the xylosides, as well as the composition of the xyloside-primed GAG chains were investigated in a matched pair of human breast fibroblasts and human breast carcinoma cells. An increase of the xylose-aglycon distance from 0.24 to 0.37nm resulted in an increased GAG priming ability in both cell lines. Further increase of the xylose-aglycon distance did not result in any pronounced effects. We speculate that by increasing the xylose-aglycon distance, and thereby the surface area of the xyloside, to a certain level would make it more accessible for enzymes involved in the GAG synthesis. The compositions of the primed GAG chains varied with different xylosides, independent of the xylose-aglycon distance, probably due to various affinities for enzymes and/or different cellular uptake. Furthermore, no correlations between the antiproliferative activities, the xylose-aglycon distances, and the amounts or compositions of the GAG chains were detected suggesting involvement of other factors such as fine structure of the GAG chains, effects on endogenous PG synthesis, or other unknown factors for the antiproliferative activity.

U2 - 10.1016/j.bmc.2013.02.062

DO - 10.1016/j.bmc.2013.02.062

M3 - Article

VL - 21

SP - 3310

EP - 3317

JO - Bioorganic and Medicinal Chemistry

T2 - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 11

ER -