Derivatives - Heparin

Shaw JP, Johnson Z, Borlat F, et al. The X-ray structure of RANTES heparin-derived disaccharides allows the rational design of chemokine inhibitors. Structure (Cambridge) 2004 12 2081-93. 

De Kort, M., Buijsman, R.C., and van Boeckel, C.A. 2005. Synthetic heparin derivatives as new anticoagulant drugs. Drug Discovery Today 10(11), 769-779. 

L. M. Mallis, H. M. Wang, D. Loganathan, and R. J. Linhardt. Sequence Analysis of Highly Sulfated, Heparin-Derived Oligosaccharides Using Fast Atom Bombardment Mass Spectrometry. Anal. Chem., 61(1989) 1453-1458. 

The binding of cations to heparin derivatives was also investigated by NOE and T2 relaxation analysis.21,22 The detailed effect of the presence of different cations was analysed, by differentiating the sulphation pattern of the several GAGs under analysis. NMR along with other techniques allowed concluding that the sequence alone does not define the conformation and flexibility for this class of molecules. Indeed, the associated cations must also be considered. Interestingly, the presence of particular cations... 

Probably, one of the most valuable advances in this field has dealt with the first chemoenzymatic synthesis of the stable isotope-enriched heparin from a uniformly double labelled 13C, 15N /V-acetylheparosan from E. coli K5. Heteronuclear, multidimensional nuclear magnetic resonance spectroscopy was employed to analyze the chemical composition and solution conformation of N-acety 1 hcparosan, the precursors, and heparin. Isotopic enrichment was found to provide well-resolved 13C spectra with the high sensitivity required for conformational studies of these biomolecules. Stable isotope-labelled heparin was indistinguishable from heparin derived from animal tissues and might be employed as a novel tool for studying the interaction of heparin with different receptors.30... 

Chemical Class Heparin derivative, depolymerized low-molecular-weight heparin Clinical Pharmacology ... 

FIGURE 12.4 Structures of the complexes between different SPs and AT. (A) Ternary complex between AT, thrombin, and an heparin derivative (PDB ID 1TB6) (B) AT bounded to the synthetic pentasaccharide (PDB ID 1E03) (C) final structure from a 5-ns MD of AT complexed to a SF decasaccharide with pyranose rings (D) final structure from a 5-ns MD of AT complexed to a SG decasaccharide with pyranose rings. For (B)-(D), two orientations of the complexes are presented. Data from Becker et al. (2007). 

A similar approach was used in Ref. 103) to obtain the fat-soluble derivatives of heparin by its copolymerization with butyl methacrylate or vinyllaurate and to get high-molecular products with a molecular mass of over 200000 by homopolymerization of the unsaturated heparin derivative. The products were used as thromboresistant... 

Chemical modification of the unfiactionated heparin, such as desul tion, deamination and coupling with various agents have resulted in products of non-anticoagulant nature with selective actions on enzymes and cellular receptors. Thioxyloside derivatives have also been reported to produce oral antithrombotic actions in animal models. However, relatively larger dosages are needed to produce these effects. These heparin derivatives are currently tested for such indications as sepsis, viral infections and the treatment of proliferative disorders. 

Heparin-induced thrombocytopenia (HIT), characterised by arterial thromboemboli and haemorrhage, occurs in about 2-3% of patients who receive standard heparin for a week or more (less in patients on LMW heparins). It is due to an autoantibody directed against heparin in association with platelet factor 4, causing platelet activation, and occurs most commonly with heparin derived from bovine lung. HIT should be suspected in any patient in whom the platelet count falls by 50% or more after starting heparin, and usually occurs 5 or more days after starting therapy (or sooner if the patient has previously been exposed to heparin). Up to 30% of patients may require amputation or may die. 

Heparin antagonism. Heparin effects wear off so rapidly that an antagonist is seldom required except after extracorporeal perfusion for heart surgery. Protamine, a protein obtained from fish sperm, reverses the anticoagulant action of heparin, when antagonism is needed. It is as strongly basic as heparin is acidic, which explains its immediate action. Protamine sulphate, 1 mg by slow i.v. injection, neutralises about 100 units of heparin derived from mucosa (mucous) or 80 units of heparin from lung ... 

The reverse of sulfation is desulfation, which can be effected under mild enzymic conditions [96]. Similarly, enzymic depolymerization, closely guarded by trade secrets, is routinely used in the production of heparin-derived dmgs. 

The effect of the substitution on S( H), 6( C) NMR chemical shifts and /hc couplings in heparin derivatives containing various sulfation patterns has been studied by Yates et al. They have observed that the /hc couplings at the glycosidic linkage positions varied between free-amino and A-sulfated compounds, by up to 9 Hz, indicating that an overall conformational change takes place upon sulfonation of the compounds. 

Barzu, T., Lormeau, J.-C., Petitou, M., Michelson, S., Choay, J. (1989). Heparin-derived oligosaccharides affinity for acidic fibroblast growth factor and effect on its growth-promoting activity for human endothelial cells. J. Cell. Physiol. 140, 538-548. 

Heparin derivatives, 48, 200 Heptonic acid, D-glyeero-v-gulo, 21, 83 —, 2-deoxy-D-gluco-, lactone, 22 Heptonic acids, 3-amino-3-deoxy-, 66 Heptopyranosides, methyl, hydrolysis of, 29... 

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