TY - JOUR
T1 - New approaches for the preparation of hydrophobic heparin derivatives
AU - Liu, Jian
AU - Pervin, Azra
AU - Gallo, Cindy M.
AU - Desai, Umesh R.
AU - Van Gorp, Cornelius L.
AU - Linhardt, Robert J.
N1 - Funding Information:
the form of a predoctoral fellowship. This work was supported in part through a grant (GM 38060) from the National Institutes of Health.
PY - 1994/7
Y1 - 1994/7
N2 - 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 (C2), 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.
AB - 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 (C2), 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.
UR - http://www.scopus.com/inward/record.url?scp=0028340370&partnerID=8YFLogxK
U2 - 10.1002/jps.2600830721
DO - 10.1002/jps.2600830721
M3 - Article
C2 - 7965660
AN - SCOPUS:0028340370
SN - 0022-3549
VL - 83
SP - 1034
EP - 1039
JO - Journal of Pharmaceutical Sciences
JF - Journal of Pharmaceutical Sciences
IS - 7
ER -