The activation of fibroblast growth factors by heparin: Synthesis, structure, and biological activity of heparin-like oligosaccharides

An effective strategy has been designed for the synthesis of oligosaccharid es of different sizes structurally related to the regular, region of hepari n; this is illustrated by the preparation of "hexasaccharide 1 and octasacc haride 2. This synthetic strategy provides the oligosaccharide sequence con taining a D-glucosamine unit at the nonreducing end that is not available e ither by enzymatic or chemical degradation of heparin. It may permit, after slight modifications, the preparation of oligosaccharide fragments with di fferent charge distribution as well. NMR spectroscopy and molecular dynamic s simulations have shown that the overall structure of 1 in solution is a s table right-hand helix with four residues per turn. Hexasaccharide 1 and, m ost likely, octasaccharide 2 are, therefore, chemically well-defined struct ural models of naturally, occurring heparin-like oligosaccharides for Use i n binding and biological activity studies. Both compounds 1 and 2 induce th e mitogenic activity of acid fibroblast growth factor (FGF1), with the half -maximum activating concentration of 2 being equivalent to that of heparin. Sedimentation equilibrium analysis with compound 2 suggests that heparin-i nduced FGF1 dimerization is not an absolute requirement for biological acti vity.