Chemoenzymatic synthesis of homogeneous ultralow molecular weight heparins.
Ultralow molecular weight (ULMW) heparins are sulfated glycans that are clinically used to treat thrombotic disorders. ULMW heparins range from 1500 to 3000 daltons, 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 homogeneous 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 pharmacokinetic 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.
Division of Medicinal Chemistry and Natural Products, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
Yongmei
Y
Xu
Sayaka
S
Masuko
Majde
M
Takieddin
Haoming
H
Xu
Renpeng
R
Liu
Juliana
J
Jing
Shaker A
SA
Mousa
Robert J
RJ
Linhardt
Jian
J
Liu
D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000991:Antithrombins / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D055598:Chemical Phenomena; D000077425:Fondaparinux; D016695:Glycosyltransferases / Q000378:metabolism; D006495:Heparin, Low-Molecular-Weight / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D015394:Molecular Structure; D008970:Molecular Weight; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism; D009844:Oligosaccharides / Q000737:chemistry; D011134:Polysaccharides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D011817:Rabbits; D019998:Racemases and Epimerases / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D013379:Substrate Specificity; D015238:Sulfotransferases / Q000378:metabolism
D000925:Anticoagulants; D000991:Antithrombins; D006495:Heparin, Low-Molecular-Weight; D009844:Oligosaccharides; D011134:Polysaccharides; D016695:Glycosyltransferases; D017351:N-Acetylglucosaminyltransferases; C450833:heparosan synthase; C037649:N-acetyllactosaminide beta-1,6-N-acetylglucosaminyltransferase; D015238:Sulfotransferases; D019998:Racemases and Epimerases; D000077425:Fondaparinux