Modular Synthesis of Heparin Oligosaccharides.

Orgueira, Hernán A.; Bartolozzi, Alessandra; Schell, Peter; Litjens, Remy E. J. N.; Palmacci, Emma R.; Seeberger, Peter H.

doi:10.1002/chin.200318176

Cited by 31 publications

(51 citation statements)

References 1 publication

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“…Synthetic heparin-like glycosaminoglycans, Structures B-D, were synthesized in the laboratory of P. Seeberger (MIT, Cambridge, MA) [24]. Synthetic heparin-like glycosaminoglycans A and E were provided kindly by Sanofi-Synthelabo (Toulouse, France).…”

Section: Methodsmentioning

confidence: 99%

Competing fragmentation processes in tandem mass spectra of heparin-like glycosaminoglycans

Naggar

Costello

Zaia

2004

J. Am. Soc. Mass Spectrom.

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Heparin-like glycosaminoglycans (HLGAGs) are highly sulfated, linear carbohydrates attached to proteoglycan core proteins and expressed on cell surfaces and in basement membranes. These carbohydrates bind several families of growth factors and growth factor receptors and act as coreceptors for these molecules. Tandem mass spectrometry has the potential to increase our understanding of the biological significance of HLGAG expression by providing a facile means for sequencing these molecules without the need for time-consuming total purification. The challenge for tandem mass spectrometric analysis of HLGAGs is to produce abundant ions derived via glycosidic bond cleavages while minimizing the abundances of ions produced from elimination of the fragile sulfate groups. This work describes the competing fragmentation pathways that result from dissociation of high negative charge state ions generated from HLGAGs. Glycosidic bond cleavage ion formation competes with losses of equivalents of H 2 SO 4 , resulting in complex ion patterns. For the most highly sulfated structure examined, an octasulfated tetramer, an unusual loss of charge from the precursor ion was observed, accompanied by low abundance ions originating from subsequent backbone cleavages. These results demonstrate that fragmentation processes competing with glycosidic bond cleavages are more favored for highly sulfated HLGAG ions. In conclusion, reduction of charge-charge repulsions, such as is achieved by pairing the HLGAG ions with metal cations, is necessary in order to minimize the abundances of ions derived via fragmentation processes that compete with glycosidic bond cleavages. Sequence determination, including localization of sulfate groups on HLGAGs, is of significant interest, as their biological activities are believed to be expressed through patterns of sulfation and uronic acid epimerization [4,5].HLGAGs have traditionally proven difficult to analyze using mass spectrometry. Efforts to analyze these molecules using fast atom bombardment MS resulted in the observation of losses of SO 3 and NaSO 3 from the precursor ion, in addition to glycosidic bond cleavage ions [6 -10]. The poor sensitivity, relative to that achieved for peptides of comparable size, and lack of an intact precursor ion meant that tandem MS was not a viable analysis option when FAB ionization was employed. Although HLGAGs produce weak signals by matrix-assisted laser desorption/ionization (MALDI), much more abundant ions are detected from complexes between these molecules and a basic peptide [11][12][13]. In conjunction with enzymatic and/or chemical degradation, this MALDI sample preparation technique has been effectively used to sequence highly purified HLGAGs [14 -17]. Because the ions are detected in the positive mode, however, the charge is carried by the basic peptide and tandem MS of the HLGAG is not possible.Because HLGAGs and other sulfated carbohydrates produce abundant negative ions using electrospray ionization (ESI) without requiring basic peptide complexation [18...

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Section: Methodsmentioning

confidence: 99%

Competing fragmentation processes in tandem mass spectra of heparin-like glycosaminoglycans

Naggar

Costello

Zaia

2004

J. Am. Soc. Mass Spectrom.

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“…Among the most active areas of investigation are studies of glycosaminoglycans and their derivatives in developing improved anti-coagulants such as new heparins (Orgueira et al, 2003). The N-acetyl glucosamine containing oligo-and polysaccharides are an important class of glycosaminoglycans, some of which have been developed for medical uses such as the inhibition of surgical adhesions, the relief of joint pain due to osteoarthritis, and the control of bleeding.…”

Section: Introductionmentioning

confidence: 99%

Comparison of structural and hemostatic properties of the poly‐N‐acetyl glucosamine Syvek Patch with products containing chitosan

Fischer¹,

Connolly²,

Thatte³

et al. 2004

Microscopy Res & Technique

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Polysaccharides are becoming increasingly developed as therapeutics and medical products, as the new field of Glycomics expands. Glycosaminoglycans that contain N-acetyl glucosamine constituents have been the focus of research leading to medical devices. A new hemostatic bandage, the Syvek Patch, has been introduced in the recent past for the control of bleeding at vascular access sites in interventional cardiology and radiology procedures. This product consists of poly-N-acetyl glucosamine (pGlcNAc) isolated in a unique fiber crystalline structural form from the large-scale culture and processing of a marine diatom. The Syvek pGlcNAc fiber material has chemical, physical, and biological properties that result in its favorable performance as a hemostat. Two new products, the Clo-Sur PAD and ChitoSeal, have recently become available also as patch hemostats. These two products both use chitosan, another N-acetyl glucosamine containing glycosaminoglycan, as their active ingredient. Structural, chemical, and biological comparisons of Syvek pGlcNAc and chitosan reveal a number of important differences. Syvek pGlcNAc fibers contain approximately 50 fully acetylated, high molecular weight pGlcNAc molecules in a crystalline, three-dimensional beta structure array, and are insoluble. Chitosan is a low molecular weight mixed amorphous cationic polymer with no regular structure as a solid, and is water-soluble taking on a random coil configuration when in solution. These structural dissimilarities result in differences in the hemostatic properties of the two materials. Syvek pGlcNAc is able to significantly reduce the in vitro fibrin clot formation time of platelet-rich plasma samples and has the ability to cause aggregation of red blood cells in vitro. Chitosan is no better than gauze or other controls in these in vitro assays. The Syvek Patch is able to control the bleeding and cause hemostasis in a coagulopathic swine spleen-bleeding animal model 100% of the time, whereas Clo-Sur PAD was completely unsuccessful (0%) and ChitoSeal (25%) was worse than a gauze pad control (50%) in the same model. Syvek pGlcNAc fibers have structural and chemical properties that provide a unique basis for their ability to interact with blood components to cause hemostasis. Chitosan does not have the same properties and capabilities.

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“…It enhances the ability of antithrombin to inactivate thrombin and factor Xa, which are enzymes that promote coagulation. A number of carbohydrate-based drugs have been developed as alternative anti-thrombotic agents and these have been prepared via chemical (Orgueira et al 2003) and enzymatic (Kuberan et al 2003) methods. For example, Table 8 portrays low-molecular-weight heparinbased drugs that have been approved for the treatment of thrombosis and Table 9 displays further drugs that are undergoing clinical trials.…”

Section: Carbohydrate-based Anti-thrombotic Agentsmentioning

confidence: 99%

Carbohydrate-based therapeutics

Osborn

Evans

Gemmell

et al. 2004

Journal of Pharmacy and Pharmacology

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In recent years there has been a resurgence of interest in the biological roles of carbohydrates and as a result it is now known that carbohydrates are involved in a vast array of disease processes. This review summarises progress in the development of carbohydrate-based therapeutics that involve: inhibition of carbohydrate-lectin interactions; immunisation, using monoclonal antibodies for carbohydrate antigens; inhibition of enzymes that synthesise disease-associated carbohydrates; replacement of carbohydrate-processing enzymes; targeting of drugs to specific disease cells via carbohydrate-lectin interactions; carbohydrate based anti-thrombotic agents.

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Modular Synthesis of Heparin Oligosaccharides.

Cited by 31 publications

References 1 publication

Competing fragmentation processes in tandem mass spectra of heparin-like glycosaminoglycans

Competing fragmentation processes in tandem mass spectra of heparin-like glycosaminoglycans

Comparison of structural and hemostatic properties of the poly‐N‐acetyl glucosamine Syvek Patch with products containing chitosan

Carbohydrate-based therapeutics

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