Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-07-13
2003-12-30
Low, Christopher S. F. (Department: 1653)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S009100, C514S018700, C514S019300, C530S317000, C530S323000, C530S330000, C530S331000, C530S344000
Reexamination Certificate
active
06670326
ABSTRACT:
This application is a 371 of PCT/JP00/00110, filed Jan. 12, 2000.
1. Technical Field
The present invention relates to a novel compound or a pharmaceutically acceptable salt thereof, which has a cytotoxic activity and TGF-&bgr; like activity for human cancer cells and is useful as medicaments, particularly as an antitumor agent, and to a pharmaceutical composition which contains said compound as the active ingredient.
2. Background Art
It is known that mitomycin C, bleomycin, adriamycin or the like compound derived from a microbial metabolite shows cytotoxic activity for human cancer cells, and these compounds are conventionally used as antitumor agents in the clinical field. Also, a depsipeptide compound is disclosed as an antitumor substance (European Patent Publication No. 352646).
Even at present, creation of antitumor agents having an unconventional chemical structure and novel skeleton is under examination.
On the other hand, TGF-&bgr; is first drawing attention as a factor which accelerates proliferation of cells and also accelerates transformation, it was now revealed that TGF-&bgr; acts as a factor which inhibits growth of various animal cells by the studies on its mechanism of actions (
Cell
, vol. 63, pp. 245-247, 1990). In addition, a large number of reports have been published regarding its relation to tumor cells (
Br. Med. J
., vol. 296, pp. 1621-1624, 1988
; Br. J. Cancer
, vol. 61, pp. 612-617, 1990
; Br. J. Cancer
, vol. 69, pp. 1006-1009, 1994
; J. Cell Physiol
., vol. 172, pp. 1-11, 1997
; Growth Factors
, vol. 7, pp. 207-213, 1992
; J. Biol. Chem
., vol. 272, pp. 3967-3972, 1997
; Nature
, vol. 360, pp. 361-364, 1992). Also, it has been reported that TGF-&bgr; receptor acts as a tumor suppressor gene in various tumors (
International J. Hematology
, vol. 65, pp. 97-104, 1997). In consequence, a compound exhibiting TGF-&bgr; like activity has a possibility of becoming therapeutic agents for diseases related to said activity, such as an antitumor agent.
DISCLOSURE OF THE INVENTION
The invention aims at providing a novel compound which has a cytotoxic activity and TGF-&bgr; like activity for human cancer cells and is useful as an antitumor agent and a medicament which contains the same.
As a result of intensive studies on natural compounds produced by many microorganisms, the present inventors have found a microorganism, a microorganism of new species belonging to the genus Pseudomonas, which has the ability to produce a compound having excellent cytotoxic activity and TGF-&bgr; like activity for human cancer cells. Thereafter, the present inventors have cultured said microorganism and succeeded in isolating a novel depsipeptide compound from said culture mixture, which has a completely different structure from that of the aforementioned known depsipeptide compound (European Patent Publication No. 352646) in terms of the following chemical structure which has hydroxyl group at the 3-position, an R group (a group selected from any one of isopropyl group, sec-butyl group or isobutyl group) at the 4-position and methyl group at the 8-position, thereby accomplishing the invention.
Accordingly, the invention relates to (1) a depsipeptide compound represented by the following general formula
(wherein R represents isopropyl group, sec-butyl group or isobutyl group) or a pharmaceutically acceptable salt thereof. The invention also relates to a pharmaceutical composition which comprises the aforementioned depsipeptide compound or a pharmaceutically acceptable salt thereof as the active ingredient, preferably said pharmaceutical composition which is an antitumor agent.
The following describes the invention in detail. The depsipeptide compound of the invention or a pharmaceutically acceptable salt thereof can be obtained by culturing a said compound-producing bacterium belonging to the genus Pseudomonas in a nutrient medium and collecting accumulated said compound from the culture mixture in the usual way. Any microorganism can be used as the microorganism to be used in the production method of said compound, with the proviso that it is a microorganism which belongs to the genus Pseudomonas and has the ability to produce said compound. As such a microorganism, a bacterial strain Pseudomonas sp. Q71576 belonging to the genus Pseudomonas isolated from a soil sample collected at Mochizuki-cho, Kitasaku-gun, Nagano Prefecture, for example, can be cited. Bacterial properties of this strain are as follows.
1) Morphological Properties
This strain is a Gram-negative rod and has motility by polar flagella. Size of the cell is 0.7 to 0.9 &mgr;m×1.0 to 1.4 &mgr;m. Spore formation is not found.
2) Cultural Properties
It forms light brown colonies on a bouillon agar medium. The colony is circular and its surface is smooth. By a bouillon liquid culture, it formed pellicle on the medium surface and the entire medium was turbid. By a bouillon gelatin stab culture, it liquefied gelatin. By a litmus milk culture, coagulation and peptonization were not found after 1 week of the culturing.
3) Physiological Properties
TABLE 1
Physiological properties of strain Q71576 (1)
Reduction of nitrate
negative
Denitrification reaction
negative
MR test
negative
VP test
negative
Formation of indole
negative
Formation of hydrogen sulfide
negative
Hydrolysis of starch
negative
Utilization of citric acid
positive
Utilization of nitrate
positive
Utilization of ammonium salt
positive
Formation of water-soluble fluorochrome
positive
Urease
negative
Oxidase
positive
Catalase
positive
Growth temperature range
3 to 32° C.
Optimum growth temperature
10 to 24° C.
Growth pH range
pH 5 to 9
Optimum growth pH
pH 6 to 8
Growth under anaerobic condition
negative
OF test
oxidation type
Arginine degradation reaction
positive
Growth in 3% NaCl-added bouillon medium
positive
TABLE 2
Physiological properties of strain Q71576 (2)
Acid production from saccharides
L-Arabinose
positive
D-Xylose
positive
D-Glucose
positive
D-Mannose
positive
D-Fructose
negative
Sucrose
negative
Inositol
negative
D-Mannitol
negative
D-Galactose
negative
Maltose
negative
Trehalose
negative
Lactose
negative
D-Sorbitol
negative
Glycerol
negative
Starch
negative
TABLE 3
Physiological properties of strain Q71576 (3)
Assimilation of saccharides
L-Arabinose
negative
D-Xylose
negative
D-Glucose
positive
D-Mannose
positive
D-Fructose
positive
Sucrose
negative
Inositol
positive
Rhamnose
negative
Raffinose
negative
D-Mannitol
positive
D-Galactose
positive
Maltose
negative
Trehalose
positive
Lactose
negative
D-Sorbitol
positive
Salicin
negative
Melibiose
negative
Glycerol
positive
Starch
negative
Xanthine
positive
Chitin
negative
In summarizing the above microbiological properties, this strain is a Gram-negative aerobic rod and has motility. Its growth temperature range is from 3 to 32° C., its oxidase test, catalase test, gelatin liquefaction reaction, citric acid utilization, inorganic nitrogen source utilization and arginine degradation reaction are positive, it forms acid from L-arabinose, D-xylose, D-glucose and D-mannose and the result of the OF test is oxidation type. On the other hand, results of the formation of hydrogen sulfide, formation of indole, VP test, reduction of nitrate and denitrification reaction are negative.
When the aforementioned properties were referred to Bergey's Manual of Systematic Bacteriology (1989) and other literature, this strain was identified as a bacterium belonging to the genus Pseudomonas and named Pseudomonas sp. Q71576.
In this connection, this strain, named Pseudomonas sp. Q71576, has been internationally deposited as FERM BP-6944 (deposited on Jan. 8, 1999) in National Institute of Bioscience and Human Technology, Agency of Industrial Science and Technology (Higashi 1-1-3, Tsukuba-shi, Ibaraki Prefecture, Japan, the postal code 305-8566). Also, since microorganisms are apt to cause artificial or spontaneous mutation, the Pseudomonas sp. Q71576 includes not only microorganisms isolated from the nature but also those which are artificially mutagenized with ultraviolet rays, X rays, chemical drugs a
Arao Nakako
Kamigiri Kazuma
Mori Masamichi
Nagai Koji
Seto Haruo
Kam Chih-Min
Low Christopher S. F.
Yamanouchi Pharmaceutical Co. Ltd.
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