Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1996-04-16
1998-08-11
Kight, John
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
514 23, 514 24, 514 25, 514 53, 514 54, 514 61, 536 187, 536 53, 536 54, 536 553, 536120, 536122, 536123, 5361231, 53612313, A61K 3170, C08B 302, C08B 304, C08B 504
Patent
active
057928428
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a ganglioside GM3 derivative in which a hydroxyl group at the C-9 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 group, 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 so on, 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, on a cell surface of the influenza virus, hemaglutinine and sialitase which identify the saccharide chain containing sialic acid are present, and they 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, they are important components to prevent infections of the virus (Y. Suzuki, Biochemistry, 62 (4), 231-260 (1990)).
From the above view point, Suzuki et al studied the influence of various ganglioside derivatives on the activity of influenzaneuraminidase, and obtained interesting results (Suzuki et al, Glycoconjugate J., 7 (1990)).
Such compound that is bound with the virusneuraminidase 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 acids, 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 so on, 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 is one of the important constitutive components of the ganglioside which contributes to the various life phenomena. Then, it
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Liu et al., J. Amer. Chem. Soc., vol. 114(10): 3901-3910, (1992). (Abstract Only).
Selected Lecture Notes from 3rd European Training Course on Carbohydrates 1994 (Jun. 26-Jul. 1, 1994), Monastery Rolduc, Kerkrade--The Netherlands (Abstract Only).
Suzuki, "Seita No Kagaku" (Science of Living Bodies), 38 (4), pp. 332-339 (1987).
Suzuki, Biochemistry, 62 (4), pp. 231-260 (1990).
Suzuki et al, Glycoconjugate J, vol. 7, pp. 346-356 (1990).
Sharma et al, Carbohydrate Research, vol. 175, No. 1, pp. 25-34 (1988).
Petrie III et al, Carbohydrate Research, vol. 186, No. 2, pp. 326-334 (1989).
Iida Takao
Ohira Yutaka
Daikin Industries Ltd.
Kight John
Lee Howard C.
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