caa a22 4500 378866303 CHVBK 20180305123358.0 cr unu---uuuuu 161128e20030101xx s 000 0 eng 10.1351/pac200375020157 doi (NATIONALLICENCE)gruyter-10.1351/pac200375020157 Antiangiogenic heparin-derived heparan sulfate mimics [Elektronische Daten] [Benito Casu, A. Naggi] Heparan sulfate (HS) is a glycosaminoglycan (GAG) widely distributed as a proteoglycan on the cell surface and in the extracellular matrix of animal tissues. Among other important physiological functions, its polysaccharide chains mediate cell proliferation by binding growth factors [fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF)], which are released in active form through the action of the enzyme heparanase overexpressed by tumor cells. HS is constituted of alternating disaccharide sequences of variously sulfated uronic acid (d-glucuronic, GlcA, or l-iduronic, IdoA) and glucosamine (N-acetylated, GlcNAc, or N-sulfated, GlcNSO3). HS mimics can be obtained by chemical modification of heparin, a more highly sulfated GAG clinically used as an anticoagulant and antithrombotic drug. With the aim of obtaining antagonists of FGFs as potential inhibitors of tumor neo-vascularization (angiogenesis), arrays of short FGF-binding sequences have been obtained by generating sulfation gaps within the prevalent (IdoA2SO3-GlcNSO36SO3)n sequences of heparin, by controlled base-catalyzed removal of 2-O-sulfate groups of IdoA2SO3 residues.The C(2)-C(3) bond of all nonsulfated uronic acid residues have then been split with periodate, to generate flexible joints along the polysaccharide chain. The novel heparin derivative (poly-PST.sU), chiefly made up of the repeating tetrasaccharide units -GlcNSO36SO3- IdoA2SO3- GlcNSO36SO3- sU- (where sU is a glycol-split and reduced uronic acid residue) binds FGF2 as strongly as heparin. However, it is a poor inducer of formation of FGF2 dimers and of complexes with FGF receptors, required for triggering mitogenic signals. NMR and molecular modeling studies indicate that formation of these higher-order complexes is prevented by the unfavorable conformation induced by glycol-split residues. In a parallel study, partially N-acetylated heparins have been obtained that efficiently inhibit heparanase upon glycol-splitting. It is noteworthy that glycol-splitting involves inactivation of the active site for antithrombin, with consequent loss of anticoagulant activity. In contrast, poly-PST.sU and some of its analogs show potent antiangiogenic activity in in vivo models in which heparin is either proangiogenic or inactive. © 2013 Walter de Gruyter GmbH, Berlin/Boston Casu Benito G.Ronzoni Institute for Chemical and Biochemical Research, Milan, Italy aut Naggi A. G.Ronzoni Institute for Chemical and Biochemical Research, Milan, Italy aut Pure and Applied Chemistry De Gruyter 75/2-3(2003-01-01), 157-166 0033-4545 75:2-3<157 2003 75 pac https://doi.org/10.1351/pac200375020157 text/html Onlinezugriff via DOI 1 research article jats NATIONALLICENCE 856 40 https://doi.org/10.1351/pac200375020157 text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Casu Benito G.Ronzoni Institute for Chemical and Biochemical Research, Milan, Italy aut NATIONALLICENCE 700 1- Naggi A. G.Ronzoni Institute for Chemical and Biochemical Research, Milan, Italy aut NATIONALLICENCE 773 0- Pure and Applied Chemistry De Gruyter 75/2-3(2003-01-01), 157-166 0033-4545 75:2-3<157 2003 75 pac CC0 http://creativecommons.org/publicdomain/zero/1.0 nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-gruyter