Chrysomycin derivative compounds and use as antitumor agents

Details Chrysomycin derivative compounds and use as antitumor agents Chrysomycin derivative compounds and use as antitumor agents

1999-07-08

2000-02-29

Lee, Howard C.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

514 27, 514460, 536 111, 536 181, 536 182, 435119, A61K 3170, C07H 704

Patent

active

060309512

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to C-glycosides produced by microorganisms, and an unglycosidated product thereof. These C-glycosides have a growth-inhibiting activity, for example, against tumor cells.


BACKGROUND ART

A large number of compounds have been proposed as antibiotics produced by microorganisms and having an antitumor activity. However, they generally have strong toxicity to normal cells or do not necessarily exhibit excellent effectiveness against solid cancers.
Chrysomycins and their related compounds are known as antibiotics having an antitumor activity and low toxicity (for example, U. Weiss et al., The Journal of Antibiotics, Vol. 35, 1982, 1194-1199). In the course of investigations on antibacteriophage active substances, chrysomycins were found as antibiotics produced by Streptomyces sp. A-419 and having an in vivo antitumor activity against P388 lymphocytic leukemia in mice.
However, there still remains a need for the provision of a compound having low toxicity and exhibiting remarkable effectiveness against solid cancers. Accordingly, an object of the present invention is to provide compounds which, as compared with well-known compounds, have low toxicity and more excellent efficacy against solid cancers in particular.


DISCLOSURE OF THE INVENTION

In order to accomplish the above object, the present inventors have carried on the screening of various microbial products while using high growth-inhibiting activity against solid cancer cells in particular, as an index. As a result, it has been found that a certain bacterial strain belonging to the genus Streptomyces produces compounds which show as low toxicity as the aforesaid chrysomycins and have more excellent growth-inhibiting activity against solid cancer cells than the chrysomycins. By isolating and examining these active substances, it has been confirmed that they are C-glycosides which have a chromophore residue in common with the chrysomycins and related antibiotics (i.e., gilvocarcins) but differ therefrom in sugar residue and which have not been described in the literature of the prior art.
Accordingly, the present invention provides the compound Mer-1020dA, Mer-1020dB, Mer-1020dC or Mer-1020dD represented by the following formula (I): ##STR1## wherein the radicals R and X.about.Y are each of the following combinations of groups:


______________________________________ Compound R X.about.Y ______________________________________ Mer-1020 dA CH.sub.3 ##STR2## Mer-1020 dB CH.sub.3 ##STR3## Mer-1020 dC ##STR4## ##STR5## Mer-1020 dD ##STR6## ##STR7## ______________________________________
Moreover, the present invention also provides a pharmaceutical preparation comprising, as an active ingredient, at least one compound selected from the group consisting of the aforesaid compounds Mer-1020dA, Mer-1020dB, Mer-1020dC and Mer-1020dD, and a physiologically acceptable additive.
Moreover, the present invention also provides the use of at least one of the aforesaid compounds in the making of a pharmaceutical preparation, and a method for the treatment of a tumor which comprises administering at least one of the aforesaid compounds, optionally together with a physiologically acceptable additive, to a mammal, particularly a human being, having a tumor.
Moreover, the present invention also provides the compound Mer-1020dE which is represented by the following formula (II) and can be used as a precursor for the biosynthesis or chemical synthesis of the aforesaid compounds in particular: ##STR8##
Furthermore, the present invention also provides a fermentation process for preparing any of the compounds represented by the above formulae (I) and (II).


DETAILED DESCRIPTION OF THE INVENTION

For convenience' sake, the present inventors named the compounds of the present invention as described above. More specifically, these compounds can be specified by the following respective structural formulae in which various groups are united together.
Compound Mer-1020dA: ##STR9##
Compound Mer-1020dB: ##ST

REFERENCES:
patent: 4461831 (1984-07-01), Matson et al.
patent: 4598145 (1986-07-01), Matson et al.
M. Jung et al., Tetrahedron Letters, 29(21), 2517-2520,(1988).
D. Hart et al., Tetrahedron Letters, 30(38), 5093-5096,(1989).
R. Misra et al., J. Antibiotics, 38(9), 1280-1283,(1985).
G. Carter et al., J. Antibiotics, 38(2), 242-248, (1985).
U. Weiss et al., J. Antibiotics, 35(9), 1194-1201, (1982).
T. Wei et al., J. Antibiotics, 35(4), 545-548, (1982).

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