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J Org Chem. 2015 Dec 18;80(24):12265-79. doi: 10.1021/acs.joc.5b02172. Epub 2015 Dec 4.

Divergent Synthesis of Heparan Sulfate Oligosaccharides.

Author information

1
Department of Chemistry, Michigan State University , 578 S. Shaw Lane, East Lansing, Michigan 48824, United States.
2
Division of Medicinal Chemistry and Natural Products, UNC Eshelman School of Pharmacy, University of North Carolina , Chapel Hill, North Carolina 27599, United States.
3
Department of Chemistry, Beirut Arab University , P.O. Box 11-5020, Riad El Solh 11072809, Beirut, Lebanon.

Abstract

Heparan sulfates are implicated in a wide range of biological processes. A major challenge in deciphering their structure and activity relationship is the synthetic difficulties to access diverse heparan sulfate oligosaccharides with well-defined sulfation patterns. In order to expedite the synthesis, a divergent synthetic strategy was developed. By integrating chemical synthesis and two types of O-sulfo transferases, seven different hexasaccharides were obtained from a single hexasaccharide precursor. This approach combined the flexibility of chemical synthesis with the selectivity of enzyme-catalyzed sulfations, thus simplifying the overall synthetic operations. In an attempt to establish structure activity relationships of heparan sulfate binding with its receptor, the synthesized oligosaccharides were incorporated onto a glycan microarray, and their bindings with a growth factor FGF-2 were examined. The unique combination of chemical and enzymatic approaches expanded the capability of oligosaccharide synthesis. In addition, the well-defined heparan sulfate structures helped shine light on the fine substrate specificities of biosynthetic enzymes and confirm the potential sequence of enzymatic reactions in biosynthesis.

PMID:
26574650
PMCID:
PMC4685427
DOI:
10.1021/acs.joc.5b02172
[Indexed for MEDLINE]
Free PMC Article

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