Caloporoside derivatives, methods of their preparation and use

Details Caloporoside derivatives, methods of their preparation and use Caloporoside derivatives, methods of their preparation and use

2002-03-08

2003-07-22

Barts, Samuel (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

C514S023000, C536S108000, C536S103000, C536S004100

Reexamination Certificate

active

06596694

ABSTRACT:

The present invention relates to novel caloporoside derivatives. The caloporoside derivatives may be formed by fermentation of microorganisms, such as
Gloeoporus dichrous
Bres. ST001714 (DSM 13784). The invention also relates to a process for preparing caloporoside derivatives, drugs comprising such compounds, and methods of their use. The invention further relates to the microorganism
Gloeoporus dichrous
Bres. ST001714 (DSM 13784).
Caloporoside was described for the first time in 1994 as a phospholipase C inhibitor (W. Weber et al. (1994)
J. Antibiotics,
47:1188-1194). In the same year, two similar secondary metabolites were isolated (R. Shan et al. (1994)
Nat. Prod. Lett.,
4:171-178). The compounds of formula I, described below, possess a different structure from those described in the prior art.
Cancer is usually a fatal disease in humans and animals caused by uncontrolled growth of endogenous cells. Cancer refers to the formation of malignant growths or neoplasms (i.e., tumors or carcinomas), or the malignant degeneration or disturbed maturation of white blood cells (leukemia or cancers of other blood cells). Cancer cells are formed through transformation of endogenous cells. The malignancy of cancer cells is evident from the autonomy of growth, i.e., their ability to grow and infiltrate in an uninhibited manner that is not restrained by the normal growth pattern of the organ; and from tissue destruction. A reliable indication of malignancy is the transfer (metastasis) of the disease away from the original site of the tumor to other parts of the body through the blood or lymph systems. Cancer is one of the most frequent causes of death in humans, and consequently there is a great demand for methods and agents that heal, treat, or prevent the disease.
Aside from radical surgical removal of a tumor, therapy for malignant tumors includes radiological therapy with X-rays, &agr;-, &bgr;- and &ggr;-rays, immunotherapy, and chemotherapy. Immunotherapy can presently be used only in a restricted manner. Chemotherapy of tumors refers to the administration of cytotoxic compounds to treat tumors and tumor cells remaining after local surgical treatment or irradiation. These substances interfere with certain processes of cell division. Consequently, tissues having a high proportion of dividing cells, such as the rapidly growing tumor tissue, are more sensitive to the cytotoxic effects. Typical chemotherapeutic agents include alkylating compounds, such as cyclophosphamide (The Merck Index, 12th Ed. page 463); antimetabolites, such as methotrexate (The Merck Index, 12th Ed. page 1025); alkaloids, such as vincristine (The Merck Index, 12th Ed. page 1704); and antibiotics, such as daunomycin (The Merck Index, 12th Ed. page 479) and adriamycin (The Merck Index, 12th Ed. page 581-582). However, all of these agents have major disadvantages owing to severe side effects, limiting their effective therapeutic use. Thus, the death of the patient may be delayed, but not prevented. In addition, the cancer cells develop resistance to such agents. When this occurs, the drugs no longer exhibit the intended therapeutic effect, but still cause toxic side effects. In addition, since combined or sequential use of cytotoxics exceeds the efficacy of a single cytotoxic (monotherapy), it also possible that the toxic side effects will be more than additive in their effects. For all these reasons, novel chemotherapeutic agents are urgently needed and are therefore being sought worldwide.
Cyclin-dependent kinases (CDKs) play a central role in regulating the cell cycle. They catalyze phosphorylation reactions, setting in motion a signaling cascade which initiates a transition from the G1 phase (growth phase 1) into the S phase (synthesis phase) of the cell cycle. Cyclin-dependent kinases therefore represent a promising therapeutic target for the treatment of cancer and other diseases affected by a pathological disturbance of cell proliferation. Low-molecular-weight inhibitors, which regulate the cell cycle and prevent uncontrolled cell division, would be useful as drugs to treat cancer patients.
Surprisingly, it has been found that the microorganism strain
Gloeoporus dichrous
(Fr.: Fr.) Bres. ST 001714 (DSM 13784) is capable of forming highly active novel cytotoxics which inhibit cyclin-dependent kinases at very low concentrations.
The invention accordingly relates to caloporoside derivatives, such as those formed by the
Gloeoporus dichrous
strain (Fr.: Fr.) Bres. ST 001714, DSM 13784, and the physiologically tolerated salts, esters and other chemical equivalents thereof.
The invention thus relates to compounds of the general formula I
in which
R
1
, R
2
and R
3
, independently of one another, are H or an acyl radical having 2-10 carbon atoms, 2 to 6 atoms, or 2 atoms; and
R
4
is H or —C(O)(CH
2
)
n
COOH, in which n is from 1 to 7, 1 to 3, or 1 or 2;
with the exception that R
1
, R
2
, R
3
and R
4
are not all H;
and physiologically tolerated salts thereof.
The acyl radicals in the compounds of formula I may be straight-chain or branched, saturated or mono- or diunsaturated.
An example of an acyl radical having 2 carbon atoms is an acetyl radical.
Examples of saturated, unbranched acyl radicals include an acetyl radical (C=2), propionyl radical (C=3), butyryl radical (C=4), valeryl radical (C=5), capronyl radical (C=6), oenanthyl radical (C=7), caproyl radical (C=8), perlagonyl radical (C=9) and capryl radical (C=10).
Examples of monounsaturated, unbranched acyl radicals include an acryloyl radical (C=3), crotonoyl radical (C=4), and a vinylacetyl radical (C=4).
An example of a diunsaturated, unbranched acyl radical is a sorbyl radical (C=6).
Caloporosides are weak antibiotics which consist of a salicylic acid and a disaccharide. The two structural units are linked via an alkyl chain. The sugar moiety of the compound of formula I may be a disaccharide consisting of a D-pyranose of an aldohexose (e.g., D-glucopyranose or D-galactopyranose) and the aldonic acid of an aldohexose (e.g., D-gluconic acid). For example, the sugar moiety may be D-mannopyranosyl-D-mannonic acid, which is unsubstituted or substituted by R
2
, R
3
and/or R
4
as defined above.
The invention furthermore relates to
a) a compound of formula I in which R
1
is acetyl; and R
2
, R
3
, and R
4
are H (=caloporoside B: empirical formula: C
38
H
62
O
16
, MW 774.9) and physiologically tolerated salts thereof;
b) a compound of formula I in which R
1
and R
3
are acetyl; R
2
is H; and R
4
is malonyl (=caloporoside C: empirical formula: C
43
H
66
O
20
, MW 902.99) and physiologically tolerated salts thereof;
c) a compound of formula I in which R
1
and R
2
are H; R
3
is acetyl; and R
4
is malonyl (=caloporoside D: empirical formula: C
41
H
64
O
19
, MW 860.96) and physiologically tolerated salts thereof;
d) a compound of formula I in which R
1
and R
3
are H; R
2
is acetyl; and R
4
is malonyl (=caloporoside E: empirical formula: C
41
H
64
O
19
, MW 860.96) and physiologically tolerated salts thereof;
e) a compound of formula I in which R
1
, R
2
, and R4 are H; and R
3
is acetyl (=caloporoside F: empirical formula: C
38
H
62
O
16
, MW 774.9) and physiologically tolerated salts thereof.
Centers of chirality in the compounds of formula I, unless stated otherwise, may be in the R or the S configuration. The invention relates to both optically pure compounds and stereoisomeric mixtures, such as enantiomeric mixtures and diastereomeric mixtures.
The compounds of formula I can be obtained in accordance with the invention by fermentation of microorganisms, such as
Gloeoporus dichrous
(Fr.:Fr.) Bres. ST001714, DSM 13784, or of one of its variants or mutants, under suitable conditions in a culture medium until one or more of the caloporoside derivatives of formula I accumulates in the culture medium. The caloporoside derivatives are obtained by subsequent isolation of the compounds and, if desired, conversion

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