Design and Synthesis of Fondaparinux and its Analogs

Abstract

Heparin is a linear polysaccharide comprised of alternating α (1,4)-D-glucosamine (GlcN) and β (1-4) glucuronic acid (GlcA) or α(1,4)-L-iduronic acid (IdoA) units. It is used as an anticoagulant to treat arterial thrombosis. There are three approved heparin based anticoagulant drugs for clinical use: unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and pentasaccharide fondaparinux. UFH, which is derived from animal sources such as porcine intestine or bovine lung, has a rapid anticoagulant effect to treat acute thrombotic events but can cause heparin-induced thrombocytopenia and osteoporosis. LMWH, which is prepared by chemically or enzymatically degrading UFH, has a longer half-life and can be administered subcutaneously. However, its anticoagulant effect is only partially neutralized by protamine, which may result in bleeding risks. Fondaparinux, a pure synthetic pentasaccharide, has better antithrombotic efficacy and biosafety than UFH and LMWH but lacks an effective neutralizable agent, limiting its clinical use. Moreover, fondaparinux also possesses anti-inflammatory activity. Therefore, there is an immediate need to improve its bioavailability and reduce its anti-inflammatory activity and neutralization of the drug. To address this issue, we propose incorporating different protection/deprotection strategies to synthesize well-defined fondaparinux (FA) analogues with an amine linker. The synthetic FA will then be conjugated to different proteins through bioconjugation techniques, and the drug loading will be optimized. Finally, the chemically prepared fondaparinux conjugates will be tested for its anti-FXa, neutralizable, and anti-inflammatory activity.