Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1998-05-06
2000-02-22
Lee, Howard C.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536118, 536122, 536123, 5361231, C08B 3700
Patent
active
06028191&
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to obtaining sulphated polysaccharides of low molecular weight by depolymerization of fucans extracted from Phaeophyceae.
The fucans sulfates are sulphated polysaccharides, present in the cell walls of shoots of brown algae. For simplicity the term "fucan" will be used to describe the fucan sulfates. The crude fucan extracted from shoots by acid extraction is formed of a heterogeneous population of molecules of high average molecular weight (100,000 to 800,000 g/mol), which are principally polymers of .alpha.-1,2-L-fucose-4-sulphate. However, the fucans also contain a not inconsiderable proportion of other components, in particular of chains of uronic acids, and of neutral sugars such as D-xylose, and of D-galactose, and of D-mannose.
The fucans have different properties which make particularly interesting their use as a source of novel therapeutic active principles. It has thus been shown that they have anticoagulant, antithrombotic [T. NISHINO and T. NAGUMO, Carbohydr. Res. 229, p. 355-362, (1992); Application EP 0403 377; S. COLLIEC et al., Thromb. Res. 64, pp. 143-154 (1991); S. SOEDA et al., Thromb. Res. 72, pp. 247-256 (1993)], antiviral [M. BABA et al., J. AIDS, 3, pp. 493-492, (1990)], antiangiogenic [R. HAHNENBERGER and A. M. JACKOBSON, Glycoconjugate J., 8, 350-353 (1991)] and anti-complementary [C. BLONDIN et al., Molecular Immunology, 31, pp. 247-253, (1994)] activity. It has likewise been observed that they are able to act as modulators of cell adhesion [C. G. GLABE et al., J. Cell Sci., 61, pp. 475-490, (1983)], of the release of growth factors [D. A. BELFORT et al., J. Cell. Physiol. 157, pp. 184-189, (1993)], of the proliferation of tumour cells [M. ELLOUALI et al., Anticancer Research, 13, pp. 2011-2020 (1993); D. R. COOMBE et al., Int. J. Cancer, 39, pp. 82-90, (1987)] and block the spermatozoid/ovule interactions between different species [M. C. MAHONY et al., Contraception, 48, pp. 277-289, (1993); M. C. MAHONY et al., Contraception, 44, pp. 657-665, (1991)].
Despite their potential interest, and although some of their properties (for example their anticoagulant activity) have been known for a long time, the crude fucans have not been used in therapeutics because of their high molecular weight and their heterogeneity, which cause poor solubility, which makes the characterization of the active preparations and their reproducible obtainment very difficult.
During the above studies, the team of inventors perfected a method for the controlled lysis of crude fucan by acid hydrolysis (Application EP 0403 377), followed by fractionation by gel filtration, which allows polysaccharide fractions of molecular weight lower than or equal to 20,000 g/mol to be obtained. These fractions retain the properties of the crude fucan, such as the anticoagulant activity and the anti-complementary activity.
However, acid hydrolysis followed by fractionation only allows fractions of low molecular weight to be obtained in a moderate yield (.ltoreq.10% of the crude starting fucan); in addition, the characterization of the fractions obtained by acid hydrolysis reveals a great heterogeneity of the polysaccharides in weight as in chemical composition.
Moreover, it has been shown that it was possible to obtain polysaccharide fractions of low molecular weight and of constant composition starting from heparin or from dermatan sulphate by employing a free-radical depolymerization reaction [VOLPI et al., J. Chromatogr. B Biomed. Appl. 622, pp. 13-20, (1993); Anal. Biochem. 200, pp. 100-107, (1992)]. The reaction proceeds by the formation of free radicals, originating from the reaction of a metallic ion (Cu.sup.2+ or Fe.sup.3+) with hydrogen peroxide [G. VAN DEDEM and J. I. NIELSEN, Pharmeuropa, 3, 202-218, (1990)]. These free radicals are very reactive and capable, at neutral pH, of degrading the polysaccharides more effectively than acid hydrolysis.
The inventors tried to carry out the free-radical depolymerization of a high molecular weight fraction (HMWF) of fucan by the action of hydroge
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Boisson-Vidal Catherine
Chaubet Frederic
Colliec Jouault Sylvia
Durand Patrick
Jozefonvicz Jacqueline
Centre National de la Recherche Scientifique "CNRS"
Institut Francais de Recherche Pour L'Exploitation de la Mer (If
Lee Howard C.
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