C-glycoside analogs and methods for their preparation and use

Details C-glycoside analogs and methods for their preparation and use C-glycoside analogs and methods for their preparation and use

1999-08-09

2001-06-12

Lee, Howard C. (Department: 1623)

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

Organic compounds

Carbohydrates or derivatives

C536S001110, C536S017900, C536S018500, C536S119000, C536S123000, C536S123130

Reexamination Certificate

active

06245902

ABSTRACT:

BACKGROUND OF THE INVENTION
Gangliosides are cell-surface sialic acid containing glycolipids. They are found in high concentration on the surface of central nervous system cells. Gangliosides are believed to play a role in important biological events such as cell growth regulation, cell-cell adhesion and malignancy (Taki, T., et al.,
J. Biol. Chem,
1986, 261, 3075-3078; Hirabayashi, Y., et al.,
J. Biol. Chem,
1990, 265, 8144-8151; atta, S. G., et al.,
J Develop. Brain Res.,
1986, 27, 243-252; and Leeden, R. W.
J. Neurosci. Res.
1984, 12, 147). Gangliosides typically consist of fatty acids (e.g. steric acid) sphingosine, hexoses (e.g. galactose and glucose), galactosamine, and sialic acids (
The Merck Index,
10 ed., 1983B, Martha Windholz ed., Merck Co. Inc., Rahway, N.J., U.S.A., p 623 (4227)).
GM4 (1,
FIG. 1
) is structurally the simplest ganglioside, and has been isolated as a minor component from brain, rat kidney, mouse erythrocytes and chicken egg yolk (Hakamori, S. in
Handbook of Lipid research,
Vol. 3,
Sphingolipid Biochemistry;
Kanfer, J. N., Hakamori S., Eds; Plenum Press: New York, pp 99-101 (1983); Hakamori,
S. Annu. Rev. Biochem.,
1981, 5, 733-764; and Nores, G. A., et al.,
J. Immunol.,
1987, 139, 3171-3176). GM4 is an important cell adhesion molecule in cell growth and tissue regeneration, and promotes neuron adhesion through its interaction with myelin-associated glycoprotein (Yang, L. J., et al.,
Proc. Nat. Acad. Sci. USA
1996, 93, 814-818).
GM3 (2,
FIG. 1
) was first isolated from equine erythrocytes and is known to modulate the epidermal growth factor (EGF) and the platelet-derived growth factor (PDGF) receptors. Tumors, such as those involved in brain cancer, overexpress EGF receptor. GM4 and GM3 are also found in high concentration in tumor cells (Yamakawa, T.; Suzuki, S. J.
Biochem
1952, 39, 383-402; Rebbaa, A., et al.,
Glycobiology
1996, 6, 399-406; Bremer, E., et al.,
J. Biol. Chem,
1986, 261, 2434-2440; Hanai, N., et al.,
Biochem. Biophys. Res. Commun.
1987, 147, 127-134; and Carubia, J. M., et al.,
Biochem. Biophys. Res. Commun.
1984, 120, 500-504).
The sialic acid N-Acetylneuraminic acid is often found at the non-reducing end of the oligosaccharide component of gangliosides. N-Acetylneuraminic acid is involved in a number of important biological events including: intracellular interactions such as adhesion, aggregation and agglutination; mask of antigenic oligosaccharides and suppression of undesired immune reactions; influence on the cell membrane permeability for ions, amino acids and proteins; and protection of glycoproteins against proteolysis (
Sialic Acids;
Schauer, R. (Ed.); Springer-Verlag: New York, 1985;
Biological Roles of Sialic Acid;
Rosenberg, V.; Shengrund, C. (Eds.); Plenum; New York, 1976; Sharon, N.
Complex carbohydrates;
Addison-Wesley: London, 1975; and Varki, A.
Glycobiology,
1992, 2, 25-40). Terminal N-acetylneuraminic acid is an attachment site of pathogens to the cells and often, the removal of this carbohydrate initiates catabolic and inflammatory processes (Sharon, N.; Lis, H.
Science,
1989, 266, 227-234; Lis, H.
Lectins;
Chapman and Hall: London, 1989).
In vivo, sialic acid containing glycoconjugates are catabolized by the removal of the terminal sialic acid residue through the action of hydrolase type enzymes called neuraminidases that cleave the glycosidic bond of N-acetylneuraminc acid (Air, G. M.; Laver, W.
Proteins: Structure, Function and Genetics,
1989, 6, 341-356). Thus, analogs of sialic acid containing glycoconjugates having a diminished susceptibility to such catabolism would be expected to have increased biological half-lives, and as a result, would be expected to possess significant therapeutic potential. Therefore, the design of nonhydrolyzable analogs of N-acetylneuraninic acid glycosides may provide a useful means to control, at the molecular level, events of crucial importance to glycobiology and immunology.
For example, analogs of GM4, having improved half-lives would be expected to demonstrate stable cell adhesion over a prolonged period of time (Yang, L. J., et al.,
Proc. Nat. Acad. Sci. USA
1996, 93, 814-818). Additionally, analogs of GM3 (4, Scheme 1) having prolonged half-lives would be expected to inhibit EGF receptor mediated signal transduction (Rebbaa, A., et al.,
Glycobiology
1996, 6, 399-406).
Vlahov, I. R., et al.,
J. Am. Chem. Soc.,
1997, 119, 1480-1481 described the synthesis of methyl 5-acetamido-4,7,8,9-tetra-O-acetyl-2,6-anhydro-3,5-dideoxy-2-C-{(R)-hydroxy-[3-(methyl 2,4,6-tri-O-benzyl-3-deoxy-&agr;-D-galactopyranosidyl)]-methyl}-D-erythro-L-manno-nonate. However, attempts to use this C-disaccharide as a building block for the synthesis of analogs of GM3 and GM4 by converting the anomeric methyl group into acetate or thiophenyl failed.
Thus, there is currently a need for synthetic methods and synthetic precursors that can be used to prepare ganglioside C-glycoside analogs, as well as other glycoconjugates (e.g. glycopeptides and glycoproteins) with improved therapeutic potential (e.g. improved stability or pharmacodynamics).
SUMMARY OF THE INVENTION
The invention provides synthetic precursors (e.g. compound 22,
FIG. 3
) that are useful for preparing C-glycoside analogs of gangliosides (e.g. GM1-GM4), peptides, and proteins. The invention also provides synthetic methods useful for preparing such synthetic precursors, as well as compounds useful as intermediates for the preparation such synthetic precursors.
The invention provides a compound of formula I:
wherein:
R
1
is the residue of a sialic acid;
R
2
is hydrogen, hydroxy, or (C
1
-C
6
)alkanoyloxy;
R
3
is arylthio, optionally substituted on the aryl ring with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, nitro, cyano, trifluoromethoxy, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkanoyl, halo(C
1
-C
6
)alkyl, hydroxy(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxycarbonyl, (C
1
-C
6
)alkylthio, and (C
1
-C
6
)alkanoyloxy; and
A is the residue of a monosaccharide.
The invention provides a compound of formula 22a:
wherein:
Ra is aryl, optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, nitro, cyano, trifluoromethoxy, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkanoyl, halo(C
1
-C
6
)alkyl, hydroxy(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxycarbonyl, (C
1
-C
6
)alkylthio, and (C
1
-C
6
)alkanoyloxy;
each Rb is independently a suitable hydroxy protecting group;
Rc is (C
1
-C
6
)alkyl;
Rd is a suitable hydroxy protecting group;
each Re is independently a suitable hydroxy protecting group; and
Rf is (C
1
-C
6
)alkanoyl.
The invention provides a ganglioside that comprises a C-glycoside component of formula II:
wherein:
R
1
is the residue of a sialic acid;
R
2
is hydrogen, hydroxy, or (C
1
-C
6
)alkanoyloxy; and
A is the residue of a monosaccharide.
The invention provides a method for preparing compound 22:
comprising reacting a compound of formula 21:
with thiophenol.
The invention provides a method for preparing a compound of formula22a:
wherein:
Ra is aryl, optionaly substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of halo, nitro, cyano, trifluoromethoxy, (C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxy, (C
1
-C
6
)alkanoyl, halo(C
1
-C
6
)alkyl, hydroxy(C
1
-C
6
)alkyl, (C
1
-C
6
)alkoxycarbonyl, (C
1
-C
6
)alkylthio, and C
1
-C
6
)alkanoyloxy;
each Rb is independently a suitable hydroxy protecting group;
Rc is (C
1
-C
6
)alkyl;
Rd is a suitable hydroxy protecting group;
each Re is independently a suitable hydroxy protecting group; and
Rf is (C
1
-C
6
)alkanoyl;
comprising reacting a corresponding compound of formula 21a:
wherein Rg is aryl, optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of (C
1
-C
6
)alkoxy;
with the requsite arylthiol, to provide the compound of formula 22a.
The invention provides a method for preparing Neu5Ac&agr;3GalCer (3) comprising: hydrolyzing the methyl ester o

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