Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1995-05-08
1996-12-10
Kunz, Gary L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 172, 536 184, 536 185, 552 10, 568495, 514 25, C07H 1502, C07H 100, A61K 3170
Patent
active
055832083
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a ganglioside GM3 derivative containing fluorine atoms in a ceramide portion thereof, to intermediates thereof and to processes for preparing the same.
DESCRIPTION OF THE PRIOR ART
Glycolipids of mammals belong to a sphingoglycolipid which consists of a lipid portion so called ceramide in which a sphingosine of a long chain aminoalcohol is bonded to a long chain carboxylic acid via an amide linkage, a oligosaccharide chain in various types and sialic acid. Ganglioside is a collective name of sphingoglycolipids which particularly contain sialic acid.
Many of the gangliosides are generally localized on cell surfaces of animals, and a sialic saccharide chain portion thereof is directed to outside of the cell. Recent studies reveal that the gangliosides play an important role in fundamental life phenomena such as discrimination in cells, reception and response of information in cells, receptor function for hormone, virus, bacteria, cell toxin, etc., interceller distinction, differentiation and propagation of cells, malignant alteration, immunity, etc.
Among the gangliosides, attention is paid to ganglioside GM3 as a molecule which can develop various physiological activities relating to information communication in cells, differentiation and propagation of cells (S. Hakomori, J. Biol. Chem., 265 (1990), 18713-18716; M. Iwamori, Yukagaku, 40, 361-369 (1991)). In order to clarify the relationship between molecular structures of GM3 derivatives and physiological activities thereof, it is important to prepare various types of the GM3 derivatives which are constituents of biomembrane. Hasegawa synthesized a GM3 derivative in which a sialic acid portion thereof was modified in order to make the role of the sialic acid portion in ganglioside GM3 clear (A. Hasegawa, Carbohydr. Res., 230, 273 (1992)). However, modification of a ceramide portion in the ganglioside GM3 has scarcely been effected (A. Hasegawa et al., Carbohydr. Res., 9, 201 (1990)). If a GM3 derivative in which the ceramide portion thereof is modified is synthesized, physiological significance of the ceramide portion is expected to be made clear.
Hasegawa et al. also found out a process for introducing sialic acid to a specific position in a saccharide chain, which process is important for systematic and easy synthesis of gangliosides, and filed for patent application (Japanese Patent Kokai No. 101691/1991). However, according to the process, dimethyl(methylthio)sulfonium triflate (referred to as DMTST hereinafter) which is a reaction accelerator must be prepared immediately before the reaction. In addition, it is extremely difficult to reproduce a yield of 47%, which is described in the patent literature, in the synthesis of a sialyllactose portion which is a saccharide chain of ganglioside GM3 (see Comparative Example 1 of the present invention).
Kusumoto et al. report synthesis of a sialyllactose portion using similar compounds by a combination of N-bromosuccinimide and tetrabutylammonium triflate as reaction accelerators (K. Fukase et al., Tetrahedron Lett., 34, 2187, (1993)). The present inventor attempted to follow the process. However, the intended sialyllation did not proceed at all, and the lactose portion used as a starting substance was quantitatively recovered (see Comparative Example 2 of the present invention). Therefore, it is desired to provide a simpler process for synthesizing GM3 intermediates in higher yield.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a GM3 derivative having fluorine atoms in a ceramide portion thereof which is a lipid portion of ganglioside GM3, and intermediates thereof.
The present invention provides a fluorinated ganglioside GM3 derivative of the general formula (I): ##STR2## in which m is an integer of at least 2, n is an integer of 0 to 7 provided that m is larger than n, and R represents an alkyl group or a fluoroalkyl group.
The present invention also provides a fluorinated 2-azide sphingosine of the general formula
REFERENCES:
patent: 4851511 (1989-07-01), Hakomori et al.
patent: 4880572 (1989-11-01), Fujita et al.
S. Hakomori, J. Biol. Chem., vol. 265, No. 31, pp. 18713-18716 (1990).
M. Iwamori, Yukagaku, vol. 40, pp. 361-369 (1991).
A. Hasegawa et al., Carbohydr. Res., vol. 230, pp. 273-288 (1992).
A. Hasegawa et al., J. Carbohydr. Chem., vol. 9(2&3), pp. 201-214 (1990).
K. Fukase et al., Tetrahedron Letters, vol. 34, No. 13, pp. 2187-2190 (1993).
Iida Takao
Ohira Yutaka
Daikin Industries Ltd.
Fonda Kathleen Kahler
Kunz Gary L.
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