Development of specific inhibitors for heparin-binding proteins based on the cobra cardiotoxin structure: an effective synthetic strategy for rationally modified heparin-like disaccharides and a trisaccharide

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DOIResolve DOI: http://doi.org/10.1016/j.carres.2004.11.029
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TypeArticle
Journal titleCarbohydrate Research
Volume340
Issue3
Pages355372; # of pages: 18
Subject1,3-Diaxial interactions; Cobra cardiotoxin; Glycosylations; Heparin-like oligosaccharides; l-Iduronic acid building blocks
AbstractRecently, a new heparin disaccharide-binding site on the convex side of cobra cardiotoxin (CTX) was identified by NMR spectroscopy and molecular modeling. To further characterize this site two heparin-like disaccharides were synthesized for binding studies with CTX, and a trisaccharide was synthesized for testing the sequence of the disaccharide binding to CTX. Thus six differentially protected monosaccharide building blocks (three l-iduronic acids and three d-glucosamines) were prepared. These include a l-iduronic acid elongation building block namely methyl 2-O-acetyl-4-O-levulinoyl-3-O-pivaloyl-[alpha]-l-idopyranosyluronate trichloroacetimidate for which a single-crystal X-ray structure was determined to have Mr?=?576.79, a?=?9.3098(11)?A [alpha]?=?90?, b?=?10.3967(12)?A [beta]?=?90?, c?=?28.026(3)?A [gamma]?=?90?, V?=?2712.7(6)?A3, P212121, Z?=?4, [mu]?=?0.71073?A, and R?=?0.0378 for 7586 observed reflections. It shows that the molecular structure of the donor is in the 1C4 conformation with significant 1,3-diaxial interactions between O-1 and O-3 as well as O-2 and O-4. The disaccharides and trisaccharide vary in the degree and position of O- and N-sulfation. The pivaloyl group was used as permanent protecting group of hydroxyl. The levulinoyl group was used as the temporary protecting group to protect the hydroxyl for elongation.
Publication date
AffiliationNational Research Council Canada; NRC Institute for Biological Sciences; NRC Steacie Institute for Molecular Sciences
Peer reviewedNo
NPARC number12327325
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Record identifier925385f3-5f4f-4f94-8072-2a2516fcbd69
Record created2009-09-10
Record modified2016-05-09
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