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Abstract
Heparan sulfate (HS) is a linear, polysaccharide belonging to the glycosaminoglycan family. It comprises of a repeating disaccharide unit of 14 linked uronic acid (either -L-iduronic acid or -D-glucuronic acid) and -D-glucosamine unit and can be sulfated at various positions. HS interacts with a number of proteins such as growth factors, morphogens, enzymes and chemokines and these HS-protein complexes mediate several biological processes. The 3-O-sulfation on the glucosamine sugar unit is an important modification in forming structural domains for heparan sulfate to enable its biological functions. Seven different 3-O-sulfotransferase isoforms in the human genome are involved in the biosynthesis. However, in spite of this, 3-O-sulfate remains a rare modification thus making the availability of 3-O-sulfated oligosaccharides is very limited. Access to structurally defined oligosaccharides is critical for the successful development of HS structure-activity relationships. Therefore, novel synthetic strategy was designed to access various 3-O-sulfated heparan sulfate oligosaccharides. Our previously reported modular synthetic strategy has been extended to accommodate 3-O-sulfate moiety by introducing a Nap protecting group at the 3-OH of glucosamine sugar residue. Selective removal of this Nap group facilitates incorporation of the 3-O-sulfate group at this position. This strategy was first utilized to obtain a synthetic 3-O-sulfated tetrasaccharide. Upon lyase degradation, this was able to generate 3-O-sulfate containing 4-5 unsaturated disaccharides, which are important diagnostic standards for mucopolysaccharidoses. Next, this strategy was further extended to chemically synthesize 4-5 unsaturated oligosaccharides. These efforts demonstrated the successful synthesis of 4-5 unsaturated hexasaccharides with an internal 3-O-sulfate moiety. Finally, this approach allowed us to generate an unprecedented library of hexasaccharides providing access to all possible structural combinations that may surround the 3-O-sulfate. Using the discussed methodologies, we set a premise for generating newer synthetic strategies for the construction of complex GAG oligosaccharides.