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 b y transdermal or oral routes would be of great pharmaceutical interest . For such applications, the functional groups within heparin's antith rombin III binding site, responsible for its anticoagulant activity, c annot be modified. Chemistry is described in which lipophilic substitu ents were attached to the reducing termini of heparin chains. Substitu ents Introduced at this position had a minimal effect on the antithrom bin III binding sites found in heparin's interior. These derivatives, with enhanced hydrophobicities, were prepared using two distinctly dif ferent approaches. First, octyl isocyanate and octadecyl isocyanate we re coupled to the core peptide of peptidoglycan heparin to form octyl- and octadecyl-peptidoglycan heparin. These octyl- and octadecyl-pepti doglycan heparins were then purified by hydrophobic interaction chroma tography on phenyl-Sepharose CL-4B, demonstrating their enhanced hydro phobicities. Second, the lipophilic acyl hydrazides of various long ch ain fatty acids were coupled to heparin's reducing end. Caprylic(C-8) capric (C-10), lauric (C-12), and stearic (C-18) hydrazide derivatives of heparin were prepared using this approach. Only the stearyl hydraz ide derivative of heparin showed a measurable increase in lipophilicit y. This result demonstrated that a single small linear C-8, C-10 or C- 12 aliphatic chain was ineffective in enhancing the hydrophobicity of the highly negative, polyanionic heparin molecule. Two lipophilic chai ns, lauryl (C-12) and stearyl (C-18), were then coupled to a single he parin chain, resulting in a heparin derivative having enhanced hydroph obicity. All the heparin derivatives prepared in this study maintained some of their anticoagulant activity.