Tumor inhibiting saccharide conjugates

Details Tumor inhibiting saccharide conjugates Tumor inhibiting saccharide conjugates

1990-06-19

1997-04-22

Kunz, Gary L.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

514 54, 514118, 536117, 536 179, 536 185, A61K 3170, C07H 1500

Patent

active

056229364

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

In the Federal Republic of Germany, mortality due to cancer ranks second, following cardiovascular diseases, in mortality statistics. Besides surgery and radiation, anti-neoplastic chemotherapy has nowadays become an established cancer therapy.
In spite of excellent surgical technique, improved radiation therapy, and many newly developed chemotherapeutic agents, in the last years it was not possible to improve the heilungsrate of malignant tumors, although very good results have been achieved with single kinds of tumors, as f.i. Hodgkin lymphoma (morbus Hodgkin).
There is, therefore, still a need to render possible fundamental improvements in chemotherapy, based on steadily increasing knowledge on the biochemistry of the tumor cell.
The main object in developing of new anti-neoplastic chemotherapeutic agents is to improve the selectivity, and thus to decrease undesired side effects.
Although meanwhile many biochemical differences between the tumor cell and the normal cell are known, these differences are not too significant.
Many of the agents used at present therefore already has a certain selectivity, and thereby an useful therapeutic index, but there is still a long way to go to obtain absolute selectivity.
One possibility to reach that goal is the use of "pro-drugs", i.e. drugs which are activated in a particular way at the site or inside the target cell, or which are detoxified with particular efficiency by non-target cells. Following another approach one tries to direct the drug to the site of or into the target cell or at least to enrich it there ("drug targeting").
Many concepts of drug targeting are based on a specific binding of a drua to the target cell or cn different uptake mechanisms of non-target and target cell. Also quantitative differences can be utilized in this respect.
By using the hybridoma technique (Kohler and Milstein, 1975, Nature 256:495) it is f.i. possible to produce specific monoclonal antibodies (MAB's) and with their help to recognize tumor-associated antigens (TAA's).
The glycoside esters to be prepared can be obtained by known methods, in particular by the further modified Koenigs-Knorr reaction or the imidate method.
A summary for such Methods, and of stereo-selective glycosylation, for which at present, depending on the stereochemistry of the linkage desired, there are three basic methods available, is given in particular in Paulsen, 1984, Chem. Soc. Rev. 13: 15.
It is known, though, that not every linkage desired can be prepared stereoselectively, despite the many glycosylation methods available. Every glycosyl transfer presents as a unique problem, and there are often no universal reaction conditions (Schmidt, 1986, Angew. Chem. 98: 213).


SUMMARY OF THE INVENTION

Therefore, the present inventions relates to glycoconjugates of certain, effective anti-tumor agents to be used as anti-neoplastic agents largely preserving the activity of those agents, but strongly diminishing their toxicity.


BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the synthesis of benzylated bromoglycoses.
FIGS. 2A-2F show the structures of deprotected diastereomeric glycosyl-IPM conjugates.
FIG. 3 shows the FAB .sup.1 H-NMR spectrum (negative) of Glc-.beta.-IPM.
FIG. 4 shows the reaction of PM 4a with compounds 19 (2,3,4,6-tetra-O-benzyl .alpha.-D-glucopyranoside) and 21 (the respective mannosyl donor).
FIG. 5 shows possible synthetic pathways for glycosyl-PM conjugates 5 and 31.
FIG. 6a shows the 500 MHz .sup.1 H-.sup.1 H-2D-NMR spectrum of the cellobiose conjugate 51.alpha.;
FIG. 6b shows the 500 MHz .sup.1 H-.sup.1 H-2D-NMR spectrum of the cellobiose conjugate 51.beta.;
FIG. 7 shows a synthetic pathway for preparing 2,3,6,2',3',4',6'-hepta-O-benzyl lactose (compound 43) and 2,3,6,2',3',4',6'-hepta-O-benzyl cellobiose (compound 44).
FIG. 8a shows the effect over time of Glc-.alpha.-IPM on the proliferation of retrothelial sarcoma cells in vitro.
FIG. 8b shows the effect over time of Glc-.beta.-IPM on the proliferation of retrothelial sarcoma cells in vitro.
FIGS.

REFERENCES:
patent: 4716242 (1987-12-01), Engel et al.
patent: 4739095 (1988-04-01), Eibi
patent: 4849513 (1989-07-01), Smith et al.
patent: 5015733 (1991-05-01), Smith et al.
patent: 5055459 (1991-10-01), Andersson et al.
patent: 5194428 (1993-03-01), Agrawal et al.
Chemical Abstracts, No. 77679k, "Glycosyl Phosphites and Glycosyl Phosphoes" (vol. 69, 1968), p. 7279.
Chemical Abstracts, No. 25895f, "2,3,4,6-Tetra-O-acetyl-.alpha.,.beta.-glucopyranosyl esters of N-aryl-N',N'-bis-2-chloroethyldiamidophosphoric acid" (vol. 81, 1974), p. 454.

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