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Molecules 2016, 21(11), 1602; doi:10.3390/molecules21111602

Investigating Glycol-Split-Heparin-Derived Inhibitors of Heparanase: A Study of Synthetic Trisaccharides

Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, srl, via G. Colombo 81, 20133 Milano, Italy
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Academic Editor: Derek J. McPhee
Received: 25 October 2016 / Revised: 16 November 2016 / Accepted: 18 November 2016 / Published: 23 November 2016
(This article belongs to the Collection Advances in Carbohydrate Chemistry)
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Abstract

Heparanase is the only known endoglycosidase able to cleave heparan sulfate. Roneparstat and necuparanib, heparanase inhibitors obtained from heparin and currently being tested in man as a potential drugs against cancer, contain in their structure glycol-split uronic acid moieties probably responsible for their strong inhibitory activity. We describe here the total chemical synthesis of the trisaccharide GlcNS6S-GlcA-1,6anGlcNS (1) and its glycol-split (gs) counterpart GlcNS6S-gsGlcA-1,6anGlcNS (2) from glucose. As expected, in a heparanase inhibition assay, compound 2 is one order of magnitude more potent than 1. Using molecular modeling techniques we have created a 3D model of 1 and 2 that has been validated by NOESY NMR experiments. The pure synthetic oligosaccharides have allowed the first in depth study of the conformation of a glycol-split glucuronic acid. Introducing a glycol-split unit in the structure of 1 increases the conformational flexibility and shortens the distance between the two glucosamine motives, thus promoting interaction with heparanase. However, comparing the relative activities of 2 and roneparstat, we can conclude that the glycol-split motive is not the only determinant of the strong inhibitory effect of roneparstat. View Full-Text
Keywords: heparanase; heparin; heparan sulfate; periodate oxidation; oligosaccharide synthesis; oligosaccharide conformation heparanase; heparin; heparan sulfate; periodate oxidation; oligosaccharide synthesis; oligosaccharide conformation
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Ni, M.; Elli, S.; Naggi, A.; Guerrini, M.; Torri, G.; Petitou, M. Investigating Glycol-Split-Heparin-Derived Inhibitors of Heparanase: A Study of Synthetic Trisaccharides. Molecules 2016, 21, 1602.

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