A highly efficient one-pot methodology is described for the synthesis of heparin and heparan sulfate oligosaccharides utilizing thioglycosides with well-defined reactivity as building blocks. L-Idopyranosyl and D-glucopyranosyl thioglycosides 5 and 10 were used as donors due to low reactivity of uronic acids as the glycosyl donors in the one-pot synthesis. The formation of uronic acids by a selective oxidation at C-6 was performed after assembly of the oligosaccharides. The efficiency of this programmable strategy with the flexibility for sulfate incorporation was demonstrated in the representative synthesis of disaccharides 17, 18, tetrasaccharide 23, and pentasaccharide 26.
Sucrose octasulfate (SOS) is believed to stimulate fibroblast growth factor (FGF) signaling by binding and stabilizing FGFs. In this report, we show that SOS induces FGF-dependent dimerization of FGF receptors (FGFRs). The crystal structure of the dimeric FGF2-FGFR1-SOS complex at 2.6-Å resolution reveals a symmetric assemblage of two 1:1:1 FGF2-FGFR1-SOS ternary complexes. Within each ternary complex SOS binds to FGF and FGFR and thereby increases FGF-FGFR affinity. SOS also interacts with the adjoining FGFR and thereby promotes protein-protein interactions that stabilize dimerization. This structural finding is supported by the inability of selectively desulfated SOS molecules to promote receptor dimerization. Thus, we propose that SOS potentiates FGF signaling by imitating the dual role of heparin in increasing FGF-FGFR affinity and promoting receptor dimerization. Hence, the dimeric FGF-FGFR-SOS structure substantiates the recently proposed "two-end" model, by which heparin induces FGF-FGFR dimerization. Moreover, the FGF-FGFR-SOS structure provides an attractive template for the development of easily synthesized SOS-related heparin agonists and antagonists that may hold therapeutic potential.Fibroblast growth factors (FGFs; FGF1 to FGF22) regulate a wide array of physiological processes including embryogenesis, cell growth, differentiation, angiogenesis, tissue repair, and wound healing (30). The diverse activities of FGFs are mediated by four receptor tyrosine kinases (FGFR1 to FGFR4), each composed of an extracellular ligand-binding portion consisting of three immunoglobulin-like domains (D1 to D3), a single transmembrane helix, and a cytoplasmic portion with protein tyrosine kinase activity (18).Receptor dimerization is an obligatory event in FGF signaling and requires heparin or heparan sulfate proteoglycans (28). Two contrasting mechanisms for FGF receptor (FGFR) dimerization have emerged from the recent crystal structures of FGF-FGFR-heparin complexes. In the "two-end" model, deduced from the FGF2-FGFR1-heparin crystal structure, two 1:1:1 FGF-FGFR-heparin ternary complexes form a symmetric dimer (40). Each FGF binds to both receptors, and there is a direct contact between the two FGFRs. Within each ternary complex, heparin interacts extensively with FGF and FGFR, thereby enhancing FGF-FGFR affinity. Heparin also binds to the FGFR across the twofold dimer and thereby fortifies the interactions of FGF and FGFR from one ternary complex with FGFR in the other ternary complex. Thus, heparin fulfils an adapter role in receptor dimerization.In the model derived from the FGF1-FGFR2-heparin structure (33), a single heparin oligosaccharide bridges two FGF molecules into a dimer that in turn brings two receptor chains together. Heparin makes a different set of contacts with the two ligands and binds to one receptor only, resulting in the distinctive asymmetry of the dimer. Unlike the configuration in the two-end model, each FGF contacts a single FGFR and there is no direct FGFR-FGFR contact. The total lack of p...
N-(phenylthio)-epsilon-caprolactam (1) has been applied as a new promoter for the activation of thioglycosides. This proceeds by the reaction of 1 with trifluoromethansulfonic anhydride, which subsequently activates the thioglycoside for glycosidic bond formation. Notably, the reaction proceeds efficiently at room temperature and is adaptable to our reactivity-based one-pot oligosaccharide synthesis. [reaction: see text]
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.