Semi-synthetic heparin derivatives: chemical modifications of heparin beyond chain length, sulfate substitution pattern and N-sulfo/N-acetyl groups.
The glycosaminoglycan heparin is a polyanionic polysaccharide most recognized for its anticoagulant activity. Heparin binds to cationic regions in hundreds of prokaryotic and eukaryotic proteins, termed heparin-binding proteins. The endogenous ligand for many of these heparin-binding proteins is a structurally similar glycosaminoglycan, heparan sulfate (HS). Chemical and biosynthetic modifications of heparin and HS have been employed to discern specific sequences and charge-substitution patterns required for these polysaccharides to bind specific proteins, with the goal of understanding structural requirements for protein binding well enough to elucidate the function of the saccharide-protein interactions and/or to develop new or improved heparin-based pharmaceuticals. The most common modifications to heparin structure have been alteration of sulfate substitution patterns, carboxyl reduction, replacement N-sulfo groups with N-acetyl groups, and chain fragmentation. However, an accumulation of reports over the past 50 years describe semi-synthetic heparin derivatives obtained by incorporating aliphatic, aryl, and heteroaryl moieties into the heparin structure. A primary goal in many of these reports has been to identify heparin-derived structures as new or improved heparin-based therapeutics. Presented here is a perspective on the introduction of non-anionic structural motifs into heparin structure, with a focus on such modifications as a strategy to generate novel reduced-charge heparin-based bind-and-block antagonists of HS-protein interactions. The chemical methods employed to synthesize such derivatives, as well as other unique heparin conjugates, are reviewed.
Fernández
Cristina
C
Division of Medicinal and Natural Products Chemistry, University of Iowa, Iowa City, IA 52242, USA.
Hattan
Christopher M
CM
Kerns
Robert J
RJ
D000215:Acylation; D000478:Alkylation; D000577:Amides / Q000138:chemical synthesis; D002240:Carbohydrate Sequence; D004952:Esters / Q000138:chemical synthesis; D006493:Heparin / Q000819:agonists / Q000031:analogs & derivatives* / Q000737:chemistry; D006494:Heparin Antagonists / Q000138:chemical synthesis; D006497:Heparan Sulfate / Q000031:analogs & derivatives / Q000737:chemistry; D008969:Molecular Sequence Data
D000577:Amides; D004952:Esters; D006493:Heparin; D006494:Heparin Antagonists; D006497:Heparan Sulfate