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.
Highlights
Heparanase is an endo-β-D-glucuronidase that cleaves the glycosaminoglycan chains of heparan sulfate at specific sites, modulating the biological function of this proteoglycan expressed at the cell surface of most animal species [1]
Heparan sulfate and heparanase are involved in several pathological conditions, tumor development [2], and inflammation, diabetes, and atherosclerosis [3]
Heparanase degrades heparan sulfate through hydrolysis of the glycosidic linkage between selected glucuronic acid units and glucosamine [5,6,7]
Summary
Heparanase is an endo-β-D-glucuronidase that cleaves the glycosaminoglycan chains of heparan sulfate at specific sites, modulating the biological function of this proteoglycan expressed at the cell surface of most animal species [1]. Heparan sulfate glycosaminoglycan is a linear polysaccharide containing alternating units of uronic acids (D-glucuronic or L-iduronic) and glucosamine, both bearing various substituent groups at various positions [4]. Heparanase degrades heparan sulfate through hydrolysis of the glycosidic linkage between selected glucuronic acid units and glucosamine [5,6,7]. Among the known heparanase inhibitors roneparstat (SST0001, Sigma Tau Research) [11] and necuparanib (M 402, Momenta) [12], are the most advanced in clinical development Necuparanib is is aa low low molecular molecular weight weight heparin, heparin, resulting resulting from from depolymerization depolymerization of of heparin heparin and and necuparanib further periodate periodate oxidation oxidation and and borohydride borohydride reduction.
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