Antiangiogenic heparin-derived heparan sulfate mimics
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| 024 | 7 | 0 | |a 10.1351/pac200375020157 |2 doi |
| 035 | |a (NATIONALLICENCE)gruyter-10.1351/pac200375020157 | ||
| 245 | 0 | 0 | |a Antiangiogenic heparin-derived heparan sulfate mimics |h [Elektronische Daten] |c [Benito Casu, A. Naggi] |
| 520 | 3 | |a 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. | |
| 540 | |a © 2013 Walter de Gruyter GmbH, Berlin/Boston | ||
| 700 | 1 | |a Casu |D Benito |u G.Ronzoni Institute for Chemical and Biochemical Research, Milan, Italy |4 aut | |
| 700 | 1 | |a Naggi |D A. |u G.Ronzoni Institute for Chemical and Biochemical Research, Milan, Italy |4 aut | |
| 773 | 0 | |t Pure and Applied Chemistry |d De Gruyter |g 75/2-3(2003-01-01), 157-166 |x 0033-4545 |q 75:2-3<157 |1 2003 |2 75 |o pac | |
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| 950 | |B NATIONALLICENCE |P 856 |E 40 |u https://doi.org/10.1351/pac200375020157 |q text/html |z Onlinezugriff via DOI | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Casu |D Benito |u G.Ronzoni Institute for Chemical and Biochemical Research, Milan, Italy |4 aut | ||
| 950 | |B NATIONALLICENCE |P 700 |E 1- |a Naggi |D A. |u G.Ronzoni Institute for Chemical and Biochemical Research, Milan, Italy |4 aut | ||
| 950 | |B NATIONALLICENCE |P 773 |E 0- |t Pure and Applied Chemistry |d De Gruyter |g 75/2-3(2003-01-01), 157-166 |x 0033-4545 |q 75:2-3<157 |1 2003 |2 75 |o pac | ||
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