Fluorine-substituted ganglioside GM3 derivative and intermediate

Details Fluorine-substituted ganglioside GM3 derivative and intermediate Fluorine-substituted ganglioside GM3 derivative and intermediate

1997-08-13

1998-08-04

Fonda, Kathleen K.

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

536 184, 514 25, C07H 1504, C07H 1510, A61K 3170

Patent

active

057895619

DESCRIPTION:

BRIEF SUMMARY
This is the U.S. national stage entry under 35 U.S.C. 371 of PCT/JP96/03624, filed Dec. 12, 1996.


FIELD OF THE INVENTION

The present invention relates to a ganglioside GM3 derivative in which a hydroxyl group at the C-7 position of sialic acid is replaced by a fluorine atom and which contributes to various biological phenomena as a biologically active glycolipid, and intermediates therefor.


DESCRIPTION OF THE PRIOR ART

Ganglioside is a collective name of sphingoglucolipids having a sialic acid moiety, and an amphipathic molecule comprising a hydrophilic saccharide chain and a hydrophobic ceramide moiety. Depending on their structures, in particular, kinds of the saccharide structures, they have abbreviations such as GM1, GM2, GM3, GM4, GD2, GD3, GT2, GT3, GT1b, and the like, and they are localized in various tissues as minor components in biomembranes.
In these years, the gangliosides attract attentions, as they are revealed to play a fundamental role as receptor molecules for various cytotoxins, hormones, interferons, neurotransmitters, and influenza viruses (Y. Suzuki, "SEITAI NO KAGAKU" (Science of Living Bodies), 38 (4), 332-339 (1987)).
For example, hemagglutinin and sialidase which identify the saccharide chain containing sialic acid are present on the cell surface of the influenza virus and play an important role in absorption and penetration of the influenza virus in mammal cells. When mechanisms of the absorption and penetration of the influenza virus are viewed from the host side, hemagglutinin and sialidase are important components to prevent infections of the virus (Y. Suzuki, Biochemistry, 62 (4), 231-260 (1990)).
From the above point of view, Suzuki et al studied the influence of various ganglioside derivatives on the activity of influenzasialidase, and obtained interesting results (Suzuki et al, Glycoconjugate J., 7 (1990)).
Such a compound that is bound with the virussialidase strongly but does not act as a substrate is extremely useful in the analysis of a three-dimensional active center structure of this enzyme, and also expected to open a new way for preventing virus infection.
The sialic acid moiety which is partially acetylated in the ganglioside is protected against the function of sialidase, and assumed to be a factor which will cause a carcinomatous change on antigenicity of human melanoma and a change on the antigenicity of cytopolysaccharide. Further, the partially acetylated sialic acid residue may have an important function in the bonding of the ganglioside with the virus.
Sialic acid is a collective name of a group of neuramic acid derivatives, and has acetyl or glycolyl groups as substituents of amino groups, and an acetyl, lactyl, phosphate ester, sulfate ester or methyl group as a substituent of a hydroxyl group. Today, 30 sialic acids are found, and their chemical structures have been determined.
In addition, it is found that the ganglioside takes part in the mechanisms of proliferation and metastasis of cancer cells. That is, the natural ganglioside GM3 has a property to suppress the proliferation of cells, and it is desired to selectively exercise this function on the cancer cells. Since the adhesion of the cancer cells to endothelial cells in blood vessels and exudation of the cancer cells outside the blood vessels are caused by the function of the ganglioside in the cancer metastasis, it is desired to provide a medical agent which prevents the metastasis.
The major functions of the sialic acid are 1) charging negative charge to complex carbohydrates, and cell membranes; 2) influence on a conformation of the glycolipids and glycoproteins; 3) information transfer; 4) masking of antigen sites; and the like, and increasing interest will be given to the functions of sialic acid.
As explained above, the gangliosides take part in various life phenomena as the functional molecule. Among the constitutive components of the ganglioside, sialic acid is assumed to have a large influence on the expression of activities thereof.
As seen from the above descriptions, sialic acid i

REFERENCES:
patent: 4675287 (1987-06-01), Reisfeld et al.
patent: 5350841 (1994-09-01), Romeo et al.
patent: 5583208 (1996-12-01), Iida et al.
patent: 5627290 (1997-05-01), Iida et al.

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