New approaches for the preparation of hydrophobic heparin derivatives.
A heparin derivative sufficiently lipophilic to be bound to plastics, forming blood-compatible supports, or to be used as an anticoagulant by transdermal or oral routes would be of great pharmaceutical interest. For such applications, the functional groups within heparin's antithrombin III binding site, responsible for its anticoagulant activity, cannot be modified. Chemistry is described in which lipophilic substituents were attached to the reducing termini of heparin chains. Substituents introduced at this position had a minimal effect on the antithrombin III binding sites found in heparin's interior. These derivatives, with enhanced hydrophobicities, were prepared using two distinctly different approaches. First, octyl isocyanate and octadecyl isocyanate were coupled to the core peptide of peptidoglycan heparin to form octyl- and octadecyl-peptidoglycan heparin. These octyl- and octadecyl-peptidoglycan heparins were then purified by hydrophobic interaction chromatography on phenyl-Sepharose CL-4B, demonstrating their enhanced hydrophobicities. Second, the lipophilic acyl hydrazides of various long chain fatty acids were coupled to heparin's reducing end. Caprylic (C8), capric (C10), lauric (C12), and stearic (C18) hydrazide derivatives of heparin were prepared using this approach. Only the stearyl hydrazide derivative of heparin showed a measurable increase in lipophilicity. This result demonstrated that a single small linear C8, C10, or C12 aliphatic chain was ineffective in enhancing the hydrophobicity of the highly negative, polyanionic heparin molecule. Two lipophilic chains, lauryl (C12) and stearyl (C18), were then coupled to a single heparin chain, resulting in a heparin derivative having enhanced hydrophobicity. All the heparin derivatives prepared in this study maintained some of their anticoagulant activity.
Division of Medicinal and Natural Products Chemistry, College of Pharmacy, University of Iowa, Iowa City 52242.
J
J
Liu
A
A
Pervin
C M
CM
Gallo
U R
UR
Desai
C L
CL
Van Gorp
R J
RJ
Linhardt
D000990:Antithrombin III / Q000378:metabolism; D001665:Binding Sites; D002240:Carbohydrate Sequence; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006493:Heparin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D006834:Hydrazines / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010457:Peptidoglycan / Q000737:chemistry
D006834:Hydrazines; D010457:Peptidoglycan; D000990:Antithrombin III; D006493:Heparin