Chemical Synthesis of Oligosaccharides Based on Heparin and Heparan Sulfate

Abstract

Heparin and heparan sulfate (HS) are complex polysaccharides that mediate and modulate the activity of numerous proteins. These proteins associate with the sugar's repeating disaccharide backbone, which is decorated with diverse sulfation patterns. Knowledge of the molecular details of these interactions may allow the development of new forms of diagnostic and therapeutic agents. Chemical syntheses of heparin-and HS-based oligosaccharides are vital in accessing the well-defined materials required by structure-activity relationship evaluations. These synthetic efforts, however, are confronted with several challenges such as access to the rare L-idose/L-iduronic acid derivatives, α-stereoselectivity in glucosaminylation, the manner of chain elongation, the selection and manipulation of protecting groups including the introduction of sulfonate groups at defined positions, and the efficient generation of compounds that are diverse enough to represent the natural heparin and HS chains. This review focuses on our achievements in addressing these concerns together with concise descriptions of the collective solutions that have been developed thus far. We also briefly highlight the results of biological assays involving our sugar constructs.

The stereoselectivities of tributyltin hydride-mediated reductions of 5-bromo-d-glucuronides tol-iduronides are dependent on the anomeric substituent: syntheses and DFT calculations

“…The 1 H and 13 C NMR spectra were in accord with the literature. 36 1 H NMR (500 MHz, CDCl 3 ): δ 5.79 (dd, 1H, J 1,2 = 2.6 Hz, J 1,F = 52.5 Hz, H-1), 5.53 (dd, 1H, J 2,3 = J 3,4 = 9.9 Hz, H-3), 5.21 (dd, 1H, J 4,5 = 9.9, H-4), 4.95 (ddd, J 2,F = 23.9 Hz, H-2), 4.44 (d, 1H, H-5), 3.74 (s, 3H, OCH 3 ), 2.08 (s, 3H, CH 3 ), 2.02 (s, 3H, CH 3 ), 2.02 (s, 3H, CH 3 ); 13 (12). To a solution of the bromide 14 (0.50 g, 1.3 mmol) in dry acetonitrile (20 mL) under a N 2 atmosphere was added silver fluoride (0.60 g, 4.8 mmol).…”

“…The synthesis of well-defined GAG oligosaccharides is thus of great interest for identifying therapeutically useful sequences and elucidating structure-activity relationships. [9][10][11][12] The main challenge in the synthesis of GAG oligosaccharides is the efficient preparation of IdoA building blocks since neither IdoA nor L-idose are commercially available or readily accessible from natural sources.…”

Formal synthesis of a disaccharide repeating unit (IdoA–GlcN) of heparin and heparan sulfate

“…1 It is a complex polysaccharide that has shown inuential biological activities by mediating the action of numerous proteins, such as growth factors, cytokines, chemokines, viral proteins, and coagulation factors. 2 It also mediates various physiologically important processes, such as viral and bacterial infection, angiogenesis, tumor metastasis, cell adhesion, and lipid metabolism. 3 Owing to wide range of biological applications, the heparan sulfate structural framework has attracted signicant interest in the development of new medicines.…”

New glucuronic acid donors for the modular synthesis of heparan sulfate oligosaccharides

“…In particular, glycosyl donors derived from uronic acid often perform poorly in glycosylations due to a low reactivity which is caused by the electron withdrawing carboxylic acid that destabilizes the oxacarbenium ion like transition state of glycosylations. [28][29][30] Therefore, it is common to employ a post-glycosylation oxidation approach in which an oligosaccharide is assembled followed by selective oxidation of the C-6 hydroxyl of glucosides or idosides to the corresponding carboxylic acid. Such an approach requires additional reaction steps of advanced intermediates, reducing the overall efficiency of the process.…”