Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai
Reexamination Certificate
2001-12-11
2003-09-02
Barts, Samuel (Department: 1623)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Carbohydrate doai
C514S062000, C536S018700, C536S053000, C536S055200, C536S120000
Reexamination Certificate
active
06613748
ABSTRACT:
FIELD OF INVENTION
This invention relates to C-glucosyl ether lipids, including their synthesis and use.
BACKGROUND OF THE INVENTION
The study of C-glycoside analogs of bioactive O- and N-glycosides is a mature field. In addition to the focus on their structural and conformational properties as probes for the importance of the anomeric and exo-anomeric effects, the significance of C-glycosides is that they are essentially inert to degradation because the anomeric carbon has been transformed from a hydrolytically labile O- or N-acetal link to an ether linkage. The underlying assumption for the use of C-glycoside analogs in glycobiology is that the conformational differences between the O- (or N)-linked natural material and the C-linked analog will be minimal. The corollary to the minimal difference hypothesis is that the recognition and binding of the C-analog will be similar to that of the natural material.
In contrast to the large number of C-glycosides that have been synthesized, there have been surprisingly few direct O vs. C biological activity comparisons. The most thorough comparison was done for the C-lactose O-lactose case reported in significant papers in 1995, 1996, and 1998 by the Kishi and Schmidt and Jiminez-Barbero groups, who focus on nuclear Overhauser enhancement data and modeling results. There is partial but not complete agreement as to the similarities and differences in the conformation of ground-state and of binding conformations. Espinosa, et al.,
J. Am. Chem. Soc.,
118:10862-10871 (1996); Espinosa, et al.,
J. Am. Chem. Soc.,
120:1309-1318 (1998); Wei, et al.,
J. Org. Chem.,
60:2160-2169 (1995); Ravishankar, et al.,
J. Am. Chem. Soc.,
120:11297-11303 (1998). Recently, we reported a comparison between an antiproliferative 2-deoxyglucosyl glycerolipid (compound 1) and its exact C-analog (compound 2) where the C-glycoside showed a several fold weaker activity. Yang, et al.,
Org. Let.,
1:2149-2151 (1999).
Although C-glycosylamino compounds have been prepared (Gaurat, et al.,
Tetrahedron Lett.,
41:1187-1189 (2000)), there has been no previous preparation of a lipid that is coupled to a C-glycoside in which glucosamine is the parent carbohydrate. It is also noted that direct methods for making C-glycosides having 2-amino groups are recognized as being especially difficult to achieve “because of the incompatibility of neighboring nitrogen-based functional groups . . . with common glycosylation strategies” (Bertozzi et al.,
J. Org. Chem.
1996, 61, 6442-6445).
SUMMARY OF THE INVENTION
Briefly, the invention relates to a C-glucosyl ether lipid of the following formula:
wherein R
1
is a C
12
-C
20
alkyl or C
12
-C
20
alkenyl; R
2
is a C
1
-C
3
alkyl or a C
3
cycloalkyl; and nitrogen containing group. R
1
is preferably C
16
H
33
or C
18
H
37
, R
2
is preferably a C
1
-C
3
is preferably NH
2
, NHCOR
3
or NHSO
2
R
4
, wherein R
3
is a C
1
-C
3
alkyl, and R
4
is a C
1
-C
3
alkyl phenyl, a substituted phenyl or a substituted naphthyl. More preferably, X is NH
2
, R
1
is C
16
H
33
and R
2
is CH
3
. The invention also relates to a pharmaceutical composition containing the C-glucosyl ether lipid defined in the formula, as well as a method of treating an animal afflicted with cancer by administering a anti-cancer effective amount of the pharmaceutical composition.
The invention likewise relates to a method of synthesizing C-glucosyl ether involving a) synthesizing an ether lipid having an sn-2 carbon and an O-alkyl or O-cycloalkyl side chain attached to the sn-2 carbon; b) sulfur-linking a glucose derivative to the ether lipid synthesized in step a) to form a thioglycoside intermediate, the glucose derivative having a nitrogen containing group at the C2 position; and c) converting the thioglycoside intermediate to a C-glucosyl ether lipid via a Ramberg-Bäcklund rearrangement.
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Salari et al. “Inhibition of protein kinase C by ether-linked lipids is not correlated with their antineoplastic activity on WEHI-3B and R6X-B15 cells”, Biochem Biophys. Acta. vol. 1134(1): 81-88 (1991.), Elsevier Science, Oxford, United Kingdom.
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Byun et al. “A Short Synthesis of Antitumor Ether Thioglycolipids: Thioglycosidation of a Glucose Donor with a Tributylstannyl Sulfide Acceptor” Tetrahedron Letters, vol. 36(29): 5143-5146, (1995), Elsevier Science, Oxford, United Kingdom.
Kumar et al. “Preparation of Ether-linked 2-Acetamido-2-deoxy-&bgr;-Glycolipids via Zinc Chloride Promoted Coupling of Ac4GlcNAc-Cl with Lipid Hydroxy Groups”, Tetrahedron Letters, vol. 35(4): 505-508, (1994), Elsevier Science, Oxford, United Kingdom.
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Arthur Gilbert
Bittman Robert
Frank Richard W.
Barts Samuel
Burns Doane , Swecker, Mathis LLP
Henry Michael C.
The Research Foundation of the City University of New York
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