title: Investigating Glycol-Split-Heparin-Derived Inhibitors of Heparanase: A Study of Synthetic Trisaccharides.
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, compound2is one order of magnitude more potent than1. Using molecular modeling techniques we have created a 3D model of1and2that 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 of1increases the conformational flexibility and shortens the distance between the two glucosamine motives, thus promoting interaction with heparanase. However, comparing the relative activities of2and roneparstat, we can conclude that the glycol-split motive is not the only determinant of the strong inhibitory effect of roneparstat.
authors.affiliation: Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, srl, via G. Colombo 81, 20133 Milano, Italy. niminghong@ronzoni.it.
authors.forename: Minghong
authors.initials: M
authors.lastname: Ni
authors.affiliation: Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, srl, via G. Colombo 81, 20133 Milano, Italy. elli@ronzoni.it.
authors.forename: Stefano
authors.initials: S
authors.lastname: Elli
authors.affiliation: Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, srl, via G. Colombo 81, 20133 Milano, Italy. naggi@ronzoni.it.
authors.forename: Annamaria
authors.initials: A
authors.lastname: Naggi
authors.affiliation: Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, srl, via G. Colombo 81, 20133 Milano, Italy. guerrini@ronzoni.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Guerrini
authors.affiliation: Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, srl, via G. Colombo 81, 20133 Milano, Italy. torri@ronzoni.it.
authors.forename: Giangiacomo
authors.initials: G
authors.lastname: Torri
authors.affiliation: Istituto di Ricerche Chimiche e Biochimiche G. Ronzoni, srl, via G. Colombo 81, 20133 Milano, Italy. petitou.ronzoni@orange.fr.
authors.forename: Maurice
authors.initials: M
authors.lastname: Petitou
mesh_terms: D002240:Carbohydrate Sequence; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005966:Glucuronidase / Q000037:antagonists & inhibitors*; D006018:Glycols / Q000737:chemistry*; D006493:Heparin / Q000737:chemistry*; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D014312:Trisaccharides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D000099175:Heparanase
chemical_list: D004791:Enzyme Inhibitors; D005966:Glucuronidase; D006018:Glycols; D006493:Heparin; D014312:Trisaccharides; D000099175:Heparanase
keywords: heparan sulfate; heparanase; heparin; oligosaccharide conformation; oligosaccharide synthesis; periodate oxidation