Publication Date:
2011-10-29
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3425363/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3425363/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Xu, Yongmei -- Masuko, Sayaka -- Takieddin, Majde -- Xu, Haoming -- Liu, Renpeng -- Jing, Juliana -- Mousa, Shaker A -- Linhardt, Robert J -- Liu, Jian -- AI074775/AI/NIAID NIH HHS/ -- AI50050/AI/NIAID NIH HHS/ -- GM38060/GM/NIGMS NIH HHS/ -- HL094463/HL/NHLBI NIH HHS/ -- HL096972/HL/NHLBI NIH HHS/ -- HL62244/HL/NHLBI NIH HHS/ -- R01 AI050050/AI/NIAID NIH HHS/ -- R01 GM038060/GM/NIGMS NIH HHS/ -- R01 HL062244/HL/NHLBI NIH HHS/ -- R01 HL094463/HL/NHLBI NIH HHS/ -- R01 HL096972/HL/NHLBI NIH HHS/ -- R21 AI074775/AI/NIAID NIH HHS/ -- New York, N.Y. -- Science. 2011 Oct 28;334(6055):498-501. doi: 10.1126/science.1207478.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Medicinal Chemistry and Natural Products, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22034431" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Anticoagulants/*chemical synthesis/chemistry/pharmacokinetics/pharmacology
;
Antithrombins/chemistry/metabolism
;
Binding Sites
;
Chemical Processes
;
Glycosyltransferases/metabolism
;
Heparin, Low-Molecular-Weight/*chemical
;
synthesis/chemistry/pharmacokinetics/pharmacology
;
Molecular Structure
;
Molecular Weight
;
N-Acetylglucosaminyltransferases/metabolism
;
Oligosaccharides/chemistry
;
Polysaccharides/chemistry/pharmacokinetics/pharmacology
;
Rabbits
;
Racemases and Epimerases/metabolism
;
Spectrometry, Mass, Electrospray Ionization
;
Substrate Specificity
;
Sulfotransferases/metabolism
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
,
Chemistry and Pharmacology
,
Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink