Oligosaccharides corresponding to the regular sequence of heparin: chemical synthesis and interaction with FGF-2

It has been proposed that oligosaccharides corresponding to the so-called regular region of heparin/heparan sulfate (HS) bind to fibroblast growth factor-2 (FGF-2). In order to explore the molecular basis of FGF/HS interaction, we describe here the chemical synthesis of a tetra and a hexasaccharide, prepared as methyl glycosides, corresponding to the regular sequence of heparin. The strategy relies on the efficient preparation of three building blocks: a seeding block, an elongating block and a capping block. The hexasaccharide inhibited the binding of FGF-2 on its receptor on human aorta vascular smooth muscle cells with an IC50 value (16±1.2 μg/mL) close to that of standard heparin (14.8±0.5 μg/mL) whereas the tetrasaccharide was much less potent (IC50=127±10.5 μg/mL). The hexasaccharide and heparin, inhibited in a dose-dependent manner FGF-2 (30 nM) induced proliferation (IC50=23.7±1.6 and 30.1±1.3 μg/mL, respectively). Under the same experimental conditions, the tetrasaccharide only slightly inhibited the mitogenic effect of FGF-2 (IC50>100 μg/mL).