Design, synthesis and biological evaluation of heparan sulfate fragments analogs (or derivatives) as human endosulfatatases inhibitors

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1st EuroCarb Young Researcher (ECYR) Workshop

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Mini symposium: Glycobiology at the LUMC and beyond

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Design, synthesis and biological evaluation of heparan sulfate fragments analogs (or derivatives) as human endosulfatatases inhibitors

Pauline Quellier 1 , Jérôme Hénault 1 , Maxime Mock-Joubert 1 , Aurélien Alix 1 , Romain Vivès 2 , David Bonnaffé 1 , Christine Le Narvor 1

1 Paris Saclay - ICMMO, Orsay, France, 2 IBS, Grenoble, France

Heparan Sulfate proteoglycans (HSPGs) interact with many proteins, especially growth factors or cytokines via specific sulfation patterns. They can be remodeled in the pericellular space by a novel class of extracellular enzymes, the Endosulfatases (HSulf 1 and 2), which selectively remove the 6-O-sulfate groups from glucosamine residues within the HSPGs chains [1-2]. HSulfs expression/production is deregulated in many human cancers including breast, lung, ovarian and hepatocarcinoma [3-4]. Thus, this family of enzymes represents an interesting therapeutic target.

Most of sulfatases require a post-translational modification of a cysteine residue to a catalytically formylglycine residue to be active [5]. One of the most efficient classes of sulfatases inhibitors are sulfamate compounds. For Endosulfatases, very few molecules have been reported as inhibitors and no selectivity towards Endosulfatases was found with the most potent one [6].

In order to increase the selectivity and to obtain an efficient inhibitor, we designed heparan sulfate fragments library bearing a 6-O-sulfamate at the non-reducing end (see figure 1). The synthesis and biological evaluation of these analogs will be presented.

Figure 1 : Heparan sulfate fragments library bearing a 6-O-sulfamate

A. Seffouh, et al, FASEB J. 2013, 23, 2431-2439, R. R. Vivès, et al, Front. Oncol. 2014, 3, 331, 1-11.

M. Buono et al, Cell. Mol. Life Sci. 2010, 67, 769-780.

S. Rosen et al, Expert. Opin. Ther. Targets. 2010, 14, 935-949, X. Zheng et al, Genes Chromosom. Cancer 2013, 52, 225–236.

X. Zheng et al, Genes Chromosom. Cancer 2013, 52, 225–236.

M. Schmid et al, Cell 1995, 82, 271-278.

M. Schelwies, et al, ChemBioChem 2010, 11, 2393–2397, T. Reuillon et al, Chem. Sci., 2016,7, 2821-2826.

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