Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1999-05-06
2000-07-04
Peselev, Elli
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 171, 536 172, 536 174, 536 175, 536 187, 536 54, C07H 1500, C07H 1700
Patent
active
060840811
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a Lewis X derivative in which hydroxyl at 6-position of N-acetylglucosamine is substituted with fluorine, and to a synthetic intermediate thereof. This derivative and synthetic intermediate are useful, for example, as a sugar chain-related physiologically active substance and an intermediate for synthesis thereof.
In this specification, Ac denotes acetyl, Me denotes methyl, Bz denotes benzoyl and Bn denotes benzyl.
BACKGROUND ART
Sialyl Lewis X sugar chain, which is an oligosaccharide containing fucose, has recently attracted attention as a molecule involved in homing phenomena in which upon inflammation, leukocytes interact with vascular endothelial cells and bleed out of the blood vessel.
Some of the homing phenomena start with interaction of the sialyl Lewis X oligosaccharide with a lectin-like cell adhesion molecule called selectin. Therefore, if the sialyl Lewis X oligosaccharide can be used as a selectin binding inhibitor, it is expected to suppress acute inflammations depending on neutrophils (one of leucocytes) and on selectin. In fact, a group of the University of Michigan demonstrated that administration of sialyl Lewis X sugar chain (3) ameliorates acute pulmonary inflammation that has been experimentally induced in rats using a cobra venom factor [M. S. Mulligan et al., Nature 364, 149 (1993)].
Later, as a result of synthesis of various sialyl Lewis X derivatives and study about their structure-activity relationship, it became clear that the following portions are important as counter ligands: (i) carboxylic acid of sialic acid, (ii) the residue of fucose and (iii) hydroxyl groups at 4- and 6-positions of galactose. Also concerning inhibitory activity against one of the selectins called P-selectin, recent work has revealed that a sugar chain (4) deoxidized at 1-position of the reducing terminal is about 20 times as potent in inhibitory activity as the above sugar chain (3). Furthermore, a potent selectin blocker "GSC-150" (5) has been developed by synthesis of a Lewis X derivative by substituting sialic acid of a sialyl Lewis X with an acidic functional group (e.g., sulfonic acid, phosphoric acid, carboxylic acid, etc.) and subsequent study of its selectin-adhesion inhibitory activity. A branched long chain alkyl exists at a reducing terminal of this compound, and this portion is thought to play a key role in expression of the inhibitory activity [H. Kondo et al., Journal of Medicinal Chemistry 39, 1339 (1996); H. Kondo et al., Journal of Medicinal Chemistry 39, 2055 (1996); A. Hasegawa et al., Journal of Carbohydrate Chemistry 14, 353 (1995). ##STR2##
As seen from the above, Lewis X derivatives are known as ligand portions of E-, P- or L-selectin having action as a cell adhesion molecule, and are important compounds having a function as a recognition element of cells specifically expressing these selectins. It is meaningful to synthesize sialyl Lewis X derivatives modified with fluorine in an organic chemical manner and to provide them in practical amounts.
As such a compound, the present inventors conceived a Lewis X derivative having fluorine in place of hydroxyl at 6-position of N-acetylglucosamine. However, there was no known method for position-selective fluorination to synthesize a Lewis X sugar chain in which hydroxyl at 6-position of N-acetylglucosamine is fluorinated.
An object of the present invention is to provide a new fluorine-containing Lewis X derivative and a synthetic intermediate thereof.
The fluorine-containing Lewis X derivative and the synthetic intermediate according to the invention are useful as a 6-fluorine derivative and an intermediate for synthesis of its analogues, the 6-fluorine derivative possessing improved metabolic stability as compared with conventional selectin blockers such as 1-deoxy sialyl Lewis X (4) and GSC-150 (5).
The fluorine-containing Lewis X derivative of the invention has selectin inhibitory activity because it contains (i) carboxylic acid of sialic acid, (ii) the residue of fucose and (
REFERENCES:
A. Hasegawa et al., Synthesis of sialyl Lewis X ganglioside and analogs. Methods Enzymol., vol. 242 (1994 p. 158-173.
Y. Wada et al., Studies on selectin blockers. 2. Novel selectin blocker as potential therapeutics for inflammatory disorders. J. Med. Chem., vol. 39 (1996. May) p. 2055-2059.
H. Ohmoto et al., Studies on selectin blocker. 1. Structure-activity relationships of sialyl Lewis X analogs. J. Med. Chem., vol. 39 (1996. Mar.) p. 1339-1343.
A. Hasegawa et al., Synthetic studies on sialoglycoconjugates 70: Synthesis of Sialyl and sulfo Lewis X analogs containing a ceramide or 2-(tetradecyl) hexadecyl residue. J. Carbohydr. Chem. vol. 14, No. 3 (1995) p. 353-368.
Iida Takao
Ohira Yutaka
Daikin Industries Ltd.
Peselev Elli
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