S25: Chemoenzymatic synthesis of homogeneous ultra-low molecular weight heparins

Ultra-low molecular weight (ULMW) heparins are sulfated glycans that are clinically used to treat thrombotic disorders. ULMW heparins range from 1500 to 3000 Da, corresponding from 5 to 10 saccharide units. The commercial drug Arixtra^® (fondaparinux sodium) is a structurally homogeneous ULMW heparin pentasaccharide that is synthesized through a lengthy chemical process.  Here, we report 10 and 12-step chemoenzymatic syntheses of two structurally homogenous ULMW heparins (MW = 1778.5 and 1816.5) in 45% and 37% overall yield respectively, starting from a simple disaccharide. These ULMW heparins display excellent in vitro anticoagulant activity and comparable pharmacodymamic properties to Arixtra^® as demonstrated in a rabbit model. The chemoenzymatic approach is scalable, and shows promise for a more efficient route to synthesize this important class of medicinal agent.