Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1991-06-18
1994-01-25
Carson, Nancy S.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 41, 536 55, 536 551, 536 552, 514 25, 514 54, 514 62, C07H 506, C07H 1504, A61K 3173
Patent
active
052817024
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to ganglioside derivatives, their use as therapeutic agents, methods for the preparation of said derivatives, and pharmaceutical compounds containing them. In particular this invention relates to N-deacylated derivatives of monosialo-gangliosides useful as inhibitors of phospholipases A.sub.2, and of superoxide production, as antiproliferative and immunosuppressant agents and in the treatment of autoimmune diseases
BACKGROUND OF THE INVENTION
The gangliosides are a class of naturally occurring glycosphingolipids comprising an oligosaccharide moiety to which may be attached one or more sialic acid groups, and a ceramide portion which contains a sphingosine or sphinganine chain and an acyl moiety derived from a fatty acid. Gangliosides have been found in the brain, spleen, liver, kidneys and blood of mammals and also in chicken eggs (see Ledeen, J. Supramolecular Structure, 8:1-17 (1978) Cell Surface Carbohydrates and Biological Recognition 437-453 for a general review of the gangliosides).
According to the nomenclature proposed by Svennerholm (J. Neurochem., 10, 613, 1963) the various gangliosides are designated by the letter G followed by one of four letters, M, D, T or Q depending on whether the ganglioside is a mono-, di-, tri or tetra-sialo-ganglioside. Thus for example the ganglioside GM.sub.1 is a mono-sialoganglioside with the following structure: ##STR3## wherein R.sup.a is --CH.sub.3 or --C.sub.3 H.sub.7. GM.sub.1 isolated from natural sources is generally a mixture of molecules wherein R.sup.a is --CH.sub.3 and those wherein R.sup.a is --C.sub.3 H.sub.7 that is having a carbon chain length of 18 or 20 C-atoms. It will be appreciated that the molecule may be in the erythro or threo configuration with respect to the double bond in the sphingosine chain, but the naturally occurring form is the erythro configuration. Naturally occurring GM.sub.1 also contains a small proportion of molecules having a fully saturated sphinganine chain in place of the sphingosine moiety. In addition there is some variation in the length of the fatty acyl chain, with that derived from stearic acid (C.sub.18) being the major component; other fatty acyl components include those derived from myristic (C.sub.14) arachidic (C.sub.20) and lignoceric (C.sub.24) acids. (Sonnino et a]., Journal of Lipid Research, Vol 26, 1985 p248; and Gazzotti et a]., Journal of Neuroscience Research 12:179-192, 1984). GM.sub.2 has a similar structure but lacks the galactose moiety (IV) of the above structure and GM.sub.3 lacks both the galactose and N-acetyl-galactosamine (III) moieties. The numbering of the hexopyranoside moieties (I) to (IV) and the designation of the sialic acid group (A) are the designations proposed by Sillerud et al., Biochemistry 1982, 21, 1260-1271, and Koerner et al., Biochemistry 1983, 22, 2676-2687 and will be followed hereinafter.
A closely related class of sphingolipids is the lysosphingolipids, also known as lysogangliosides, which lack the fatty acyl moiety of the corresponding ganglioside. It has been reported that lysogangliosides are potent inhibitors of protein kinase C activity and phorbol-diester binding, suggesting they have a role in neurological disorders (Hannun and Bell, Science Vol 235 p670-674). Neuenhofer et al, Biochemistry, (1985) 24 p525-532, describes the synthesis of various lysogangliosides by deacylation of gangliosides GM.sub.21, GM.sub.1 and GD.sub.1a, to remove both the fatty acyl moiety and the acetyl group present on the sialic acid residue, followed by reacylation of the sialic acid. The paper also indicates that traces of the completely deacylated GM.sub.1 and GD.sub.1a were revealed by FAB mass analysis. No biological activity is ascribed to these compounds.
Sonnino et al. (Journal of Lipid Research, Vol 26, 1985 p248) describe the preparation of various derivatives of GM.sub.1 in which the naturally occurring fatty acyl moiety is replaced with a different fatty acyl moiety. The synthesis of these compounds also proceeds via the lysoganglioside derivati
REFERENCES:
Nores et al; Carbohydrate Research 179:393-410 (1988).
Song et al; Biochemistry 28:4194-4200 (1989).
Manev et al; Journal of Pharmacology and Experimental Therapeutics 252(1):419-427 (Jan. 1990).
Chemical Abstracts, vol. 113, No. 1, abstract 151b, Dyatlovitskaya et al, Derivatives of ganglioside GM3 and their immounomodullating effects, Jul. 2, 1980.
Isolation of Cholera Toxin by Affinity Chromatography on Porous Silica Beads with Covalently Coupled Galgliodise GM1, Taylot & Tardy, Institute Merieux, pp. 471-478 (1980).
Synthesis of Lysogangliodides, Neuenhofer, et al., Biochemistry, 24, pp. 525-532 (1985).
Chemical Abstracts, 113, No. 1, p14 (1990).
Preparation of GM1 ganglioside molecular species having homogeneous fatty acid and long chain base moieties, Sonnino et al., J. of Lipid Research, 26, pp. 248-257 (1985).
Bioorganic Chemistry, Dyatlovitskaya et al., 16, 402 (1990) in Russian (translation attached).
Holmgren et al, Medical Biology, 52 229, (1974).
Taketomi and Kawamura, J. Biochem., 68 475 (1970).
Cavallo Giovanni
Tubaro Ezio
Carson Nancy S.
Wellcome Foundation Limited
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