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Disubstituted naphthyl β-D-xylopyranosides: Synthesis, GAG priming, and histone acetyltransferase (HAT) inhibition

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Abstract

Xylosides are a group of compounds that can induce glycosaminoglycan (GAG) chain synthesis independently of a proteoglycan core protein. We have previously shown that the xyloside 2-(6-hydroxynaphthyl)β-D-xylopyranoside has a tumor-selective growth inhibitory effect both in vitro and in vivo, and that the effect in vitro was correlated to a reduction in histone H3 acetylation. In addition, GAG chains have previously been reported to inhibit histone acetyltransferases (HAT). To investigate if xylosides, or the corresponding xyloside-primed GAG chains, can be used as HAT inhibitors, we have synthesized a series of naphthoxylosides carrying structural motifs similar to the aromatic moieties of the known HAT inhibitors garcinol and curcumin, and studied their biological activities. Here, we show that the disubstituted naphthoxylosides induced GAG chain synthesis, and that the ones with at least one free phenolic group exhibited moderate HAT inhibition in vitro, without affecting histone H3 acetylation in cell culture. The xyloside-primed GAG chains, on the other hand, had no effect on HAT activity, possibly explaining why the effect of the xylosides on histone H3 acetylation was absent in cell culture as the xylosides were recruited for GAG chain synthesis. Further investigations are required to find xylosides that are effective HAT inhibitors or xylosides producing GAG chains with HAT inhibitory effects.

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Abbreviations

AA:

Anacardic acid

β4GalT7:

β-1,4-galactosyltransferase 7

CCD-1095Sk:

Human breast fibroblasts

CS:

Chondroitin sulfate

DS:

Dermatan sulfate

GAG:

Glycosaminoglycan

HCC70:

Human breast carcinoma cells

HDAC:

Histone deacetylase

HS:

Heparan sulfate

HAT:

Histone acetyltransferase

KAT:

Lysine acetyltransferase

PCAF:

p300/CBP-associated factor

PG:

Proteoglycan

pgsA-745:

Xylosyltransferase-deficient Chinese hamster ovarian cells

p300:

E1A binding protein p300

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Acknowledgments

This work was supported by grants from the Alfred Österlund Foundation, the Crafoord Foundation, the Evy and Gunnar Sandberg Foundation, the Foundation of the Hedda and John Forssman Fund, Greta and John Kock, the Lars Hiertas Memorial Foundation, Lund University, the Magnus Bergwall Foundation, the Medical Faculty of Lund University, the Royal Physiographic Society in Lund, the Swedish Cancer Society, the Swedish Heart-Lung Foundation, the Swedish Medical Research Council, the Swedish Research Council, and the Åhlén Foundation.

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Authors and Affiliations

  1. Center for Analysis and Synthesis, Center for Chemistry and Chemical Engineering, Lund University, P.O. Box 124, 221 00, Lund, SE, Sweden

    Karin Thorsheim, Anna Siegbahn & Ulf Ellervik

  2. Department of Experimental Medical Science, Lund University, BMC, 221 84, Lund, SE, Sweden

    Andrea Persson, Emil Tykesson, Gunilla Westergren-Thorsson & Katrin Mani

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  1. Karin Thorsheim
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  2. Andrea Persson
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  7. Ulf Ellervik
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Correspondence to Ulf Ellervik.

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Karin Thorsheim and Andrea Persson contributed equally to this manuscript.

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Thorsheim, K., Persson, A., Siegbahn, A. et al. Disubstituted naphthyl β-D-xylopyranosides: Synthesis, GAG priming, and histone acetyltransferase (HAT) inhibition. Glycoconj J 33, 245–257 (2016). https://doi.org/10.1007/s10719-016-9662-6

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