Anticoagulant activity of functionalized dextrans. Structure analyses of carboxymethylated dextran and first Monte Carlo simulations

Krentsel, L. B.; Chaubet, Frédéric; Ребров, А. В.; Champion, J.; Ermakov, Igor; Bittoun, Patrick; Fermandjian, Serge; Litmanovich, A. D.; Platè, N. A.; Jozefonvicz, J.

doi:10.1016/s0144-8617(96)00173-7

Cited by 31 publications

(25 citation statements)

References 24 publications

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“…Results showed that reactions of carboxymethylation and sulfonation on hydroxyl functions preferentially occurred on the C-2 position. These results are in agreement with those showing that the OH on C-2 position displayed the higher rate coefficient of dextran carboxymethylation (15). The average molecular weight of each polymer (Table I) was determined by high performance size exclusion chromatography in 0.1 M NaNO 3 , using KB-804 and KB-805 aqueous gel filtration columns (Shodex, Japan) applied in series.…”

supporting

confidence: 88%

Human Plasmin Enzymatic Activity Is Inhibited by Chemically Modified Dextrans

Ledoux

Papy-García

Escartin

et al. 2000

Journal of Biological Chemistry

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Some synthetic dextran derivatives that mimic the action of heparin/heparan sulfate were shown to promote in vivo tissue repair when added alone to wounds. These biofunctional mimetics were therefore designated as "regenerating agents" in regard to their in vivo properties. In vitro, these biopolymers were able to protect various heparin-binding growth factors against proteolytic degradation as well as to inhibit the enzymatic activity of neutrophil elastase. In the present work, different dextran derivatives were tested for their capacity to inhibit the enzymatic activity of human plasmin. We show that dextran containing carboxymethyl, sulfate as well as benzylamide groups (RG1192 compound), was the most efficient inhibitor of plasmin amidolytic activity. The inhibition of plasmin by RG1192 can be classified as tight binding hyperbolic noncompetitive. One molecule of RG1192 bound 20 molecules of plasmin with a K i of 2.8 ؋ 10 ؊8 M. Analysis with an optical biosensor confirmed the high affinity of RG1192 for plasmin and revealed that this polymer equally binds plasminogen with a similar affinity (K d ‫؍‬ 3 ؋ 10 ؊8 M). Competitive experiments carried out with 6-aminohexanoic acid and kringle proteolytic fragments identified the lysine-binding site domains of plasmin as the RG1192 binding sites. In addition, RG1192 blocked the generation of plasmin from Glu-plasminogen and inhibited the plasmin-mediated proteolysis of fibronectin and laminin. Data from the present in vitro investigation thus indicated that specific dextran derivatives can contribute to the regulation of plasmin activity by impeding the plasmin generation, as a result of their binding to plasminogen and also by directly affecting the catalytic activity of the enzyme.

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supporting

confidence: 88%

Human Plasmin Enzymatic Activity Is Inhibited by Chemically Modified Dextrans

Ledoux

Papy-García

Escartin

et al. 2000

Journal of Biological Chemistry

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“…151 Although anti-coagulant activity could be introduced in these neutral polymers, the activity was small and the possibilities of enhancing it further are less. Similarly, neutral carbohydrate polymers including chitosan, 152,153 dextran, [154][155][156][157] galactomannan, 158 and fucan, 159,160 have been sulfated, yet the anticoagulant activity level in each of these polymers is small. …”

Section: S Y N T H E T I C M O D I F I E D H E P a R I N S A N D H mentioning

confidence: 99%

New antithrombin‐based anticoagulants

Desai

2003

Medicinal Research Reviews

131

115

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Clinically used anticoagulants are inhibitors of enzymes involved in the coagulation pathway, primarily thrombin and factor Xa. These agents can be either direct or indirect inhibitors of clotting enzymes. Heparin-based anticoagulants are indirect inhibitors that enhance the proteinase inhibitory activity of a natural anticoagulant, antithrombin. Despite its phenomenal success, current anticoagulation therapy suffers from the risk of serious bleeding. The need for safer and more effective antithrombotic agents clearly exists. The past decade has seen enormous effort directed toward discovering and/or designing new molecules with anticoagulant activity. These new molecules can be classified into (a). antithrombin and its mutants, (b). natural polysaccharides, (c). synthetic modified heparins and heparin-mimics, (d). synthetic oligosaccharides, and (e). synthetic non-sugar antithrombin activators. This review focuses on these efforts in designing or discovering new molecules that act through the antithrombin pathway of anticoagulation.

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“…Their activities are closely depending on the distribution of the substituents along the polymer chain 1,6) and the structure of CMD precursor strongly influences the distribution of B and S groups. In this respect, the correlations between individual CMDBS structures and their corresponding anticoagulant activities have been partially clarified by studying the distribution of CM groups, using 1D and 2D 1 H and 13 C NMR spectroscopy and Monte Carlo simulations 7) . The first and determining step in CMDBS synthesis is the carboxymethylation of dextran.…”

Section: Introductionmentioning

confidence: 99%

Carboxymethylation of dextran in aqueous alcohol as the first step of the preparation of derivatized dextrans

Huynh¹,

Chaubet

Jozefonvicz

1998

Angew. Makromol. Chem.

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Carboxymethyldextrans (CMD) with a degree of substitution of carboxymethyl groups DS > 0.9 are precursors for the synthesis of derivatized dextrans termed CMDBS, which present heparin‐like biological properties. Syntheses of CMD in water/organic solvent mixtures using monochloroacetic acid (MCA) and strong alkaline conditions allowed to obtain highly substituted CMD with good reproducibility and high yields. The influences of, respectively, individual concentrations of reactants, composition and temperature of reaction medium, and allowed reaction time have been examined. The most favorable conditions for dextran carboxymethylation were obtained with 3.8 M NaOH and a [MCA]/[dextran] ratio of 2.5, allowed to react at 60°C for 90 min, in a reaction medium consisting of a tert‐butanol/water (alternatively isopropanol/water) 85 : 15 (v/v) mixture. A DS of about 1.0 was obtained in one step, as compared to a DS less than 0.6 when using aqueous conditions. Improvements on overall CMD substitution levels (up to DS of 1.47) were achieved by merely repeating the reaction i. e. using the CMD products of the first reaction as substrate in the second.

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Anticoagulant activity of functionalized dextrans. Structure analyses of carboxymethylated dextran and first Monte Carlo simulations

Cited by 31 publications

References 24 publications

Human Plasmin Enzymatic Activity Is Inhibited by Chemically Modified Dextrans

Human Plasmin Enzymatic Activity Is Inhibited by Chemically Modified Dextrans

New antithrombin‐based anticoagulants

Carboxymethylation of dextran in aqueous alcohol as the first step of the preparation of derivatized dextrans

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