Chemistry: molecular biology and microbiology – Micro-organism – tissue cell culture or enzyme using process... – Preparing heterocyclic carbon compound having only o – n – s,...
Reexamination Certificate
2001-03-19
2002-10-15
Marx, Irene (Department: 1651)
Chemistry: molecular biology and microbiology
Micro-organism, tissue cell culture or enzyme using process...
Preparing heterocyclic carbon compound having only o, n, s,...
C435S242000, C435S242000, C435S242000, C435S244000, C549S510000
Reexamination Certificate
active
06465221
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method of producing a taxane-type diterpene including taxol which is useful as a therapeutic agent for ovarian cancer, mammary cancer, lung cancer and the like.
2. Description of the Prior Art
Taxol, which is useful as a therapeutic agent for ovarian cancer, mammary cancer, lung cancer and the like, is a taxane-type diterpene identified after being isolated from
Taxus brevifolia
NUTT, which is a plant belonging to genus Taxus, family Taxaceae and has a complex ester group which is related to the above-mentioned pharmacological activity. Taxol can be found in all the parts of the plant body of Taxus brevifolia NUTT, but the bark has been reported to exceed all others in its content of the taxol. At present, taxol is collected from a natural or a cultivated plant body, however, the plant belonging to genus Taxus grows slowly, and it takes more than 10 years to grow to a height of 20 cm above the ground, besides the tree dies after its bark is taken off, thus it has not been easy to obtain a large amount of taxol. It would be advantageous if a taxane-type diterpene such as taxol and/or baccatin III which is a precursor of taxol, can be synthesized by the use of tissue culture, since a large amount of taxol can be easily obtained without cutting down the trees.
As a conventional method of producing taxol by utilizing cultured plant cells, a US patent was issued on a production method utilizing cultured cells of
Taxus brevifolia
NUTT (U.S. Pat. No. 5,019,504), however, the amount of taxol production described therein is 1-3 mg/l, and that is insufficient for the industrial production. Besides, the production of taxol by the cell culture utilizing the conventional tissue culture technique is unstable and even when a primary cell of high productivity can be obtained by selection, it is difficult to keep its content by subculturing [E. R. M. Wickremesine et al., World Congress on Cell and Tissue Culture (1992)].
On the other hand, as a prior art in the taxol production, a semisynthetic method from baccatin III, which is a precursor in biosynthesis of taxol, is disclosed in the specification of U.S. Pat. No. 5,015,744 issued to Holton et al. By the use of the plant tissue culture, a raw material for the semisynthetic process such as baccatin III can be produced, thus the plant tissue culture can be also utilized for taxol production by the above-mentioned semisynthetic process.
OBJECTS AND SUMMARY OF THE INVENTION
The object of the present invention is to provide a simple method of producing a taxane-type diterpene by plant tissue culture.
As a result of the intensive study, the present inventors found that the productivity of the taxane-type diterpene in the cultures can be improved by carrying out the culture of a cultured cell or a cultured tissue of a plant which produces the taxane-type diterpene, in the presence of coronatines, a bacterium which produces the coronatines, a culture solution or a culture extract of such bacteria, cyclic polysaccharides, fatty acids or an imino or amino derivative of jasmonic acids, and completed the present invention.
Accordingly the present invention is a method of producing a taxane-type diterpene wherein a cell and/or a tissue of a plant which produces a taxane-type diterpene is cultured in the presence of at least one substance selected from the group consisting of coronatines, a bacterium which produces the coronatines, a culture solution or a culture extract of such bacterium, cyclic polysaccharides, fatty acids, and a compound represented by the general formula (X):
[wherein,
Y is hydrogen atom, hydroxyl group, cyano group, NR
28a
R
28b
(wherein R
28a
and R
28b
independently represent hydrogen atom, carbamoyl group, acyl group having 1 to 12 carbon atoms, alkyl group having 1 to 12 carbon atoms, aryl group, aryl group having a substituent, arylalkyl group, arylalkyl group having a substituent or alkylsulfonyl group having 1 to 12 carbon atoms), OR
29
(wherein R
29
is acyl group having 1 to 12 carbon atoms, alkyl group having 1 to 12 carbon atoms, aryl group, aryl group having a substituent, arylalkyl group or arylalkyl group having a substituent),—CO—R
30
(wherein R
30
represents hydrogen atom, amino group, alkylamino group having 1 to 12 carbon atoms), alkyl group having 1 to 12 carbon atoms, aryl group, aryl group having a substituent, arylalkyl group, arylalkyl group having a substituent, aminosulfonyl group or alkylsulfinyl group having 1 to 12 carbon atoms;
R
1a
, R
1b
, R
1c
, R
1d
, R
1e
and R
1f
independently represent hydrogen atom, hydroxyl group, alkyl group having 1 to 12 carbon atoms, alkoxy group having 1 to 12 carbon atoms, aryl group, aryl group having a substituent, arylalkyl group or arylalkyl group having a substituent; R
20
, R
21
, R
22
, R
23
and R
24
independently represent hydrogen atom, hydroxyl group, alkyl group having 1 to 12 carbon atoms, aryl group, aryl group having a substituent, arylalkyl group or arylalkyl group having a substituent;
a side chain consisting of C
1
—C
2
—C
3
—C
4
—C
5
—C
6
may contain one or more double bonds;
R
25
represents hydroxyl group, OM (wherein M is alkaline metal atom, alkaline earth metal atom or NH
4
), NR
26a
R
26b
(wherein R
26a
and R
26b
independently represent hydrogen atom, acyl group having 1 to 12 carbon atoms, alkyl group having 1 to 12 carbon atoms, aryl group, aryl group having a substituent, arylalkyl group, arylalkyl group having a substituent or amino acid residue), OR
27
(wherein R
27
represents alkyl group having 1 to 12 carbon atoms, aryl group, aryl group having a substituent, arylalkyl group, arylalkyl group having a substituent or carbohydrate residue), alkyl group having 1 to 12 carbon atoms, aryl group, aryl group having a substituent, arylalkyl group or arylalkyl group having a substituent;
n is an integer of 1-7;
and in the above-mentioned five-membered ring, a double bond may be formed between the neighboring member carbon atoms],
or represented by the general formula (XI):
[wherein,
R
1a
, R
1b
, R
1c
, R
1d
, R
1e
, R
1f
and R
1g
independently represent hydrogen atom, hydroxyl group, alkyl group having 1 to 12 carbon atoms, alkoxy group having 1 to 12 carbon atoms, aryl group, aryl group having a substituent, arylalkyl group or arylalkyl group having a substituent; R
20
, R
21
, R
22
, R
23
and R
24
independently represent hydrogen atom, hydroxyl group, alkyl group having 1 to 12 carbon atoms, aryl group, aryl group having a substituent, arylalkyl group or arylalkyl group having a substituent;
a side chain consisting of C
1
—C
2
—C
3
—C
4
—C
5
—C
6
may contain one or more double bonds;
R
25
represents hydroxyl group, OM (wherein M represents alkaline metal atom, alkaline earth metal atom or NH
4
), NR
26a
R
26b
(wherein R
26a
and R
26b
independently represent hydrogen atom, acyl group having 1 to 12 carbon atoms, alkyl group having 1 to 12 carbon atoms, aryl group, aryl group having a substituent, arylalkyl group, arylalkyl group having a substituent or amino acid residue), OR
27
(wherein R
27
represents alkyl group having 1 to 12 carbon atoms, aryl group, aryl group having a substituent, arylalkyl group, arylalkyl group having a substituent or carbohydrate residue), alkyl group having 1 to 12 carbon atoms, aryl group, aryl group having a substituent, arylalkyl group or arylalkyl group having a substituent;
n is an integer of 1-7;
R
31a
and R
31b
independently represent hydrogen atom, hydroxyl group, acyl group having 1 to 12 carbon atoms, alkyl group having 1 to 12 carbon atoms, alkoxy group having 1 to 12 carbon atoms, aryl group, aryl group having a substituent, arylalkyl group, arylalkyl group having a substituent or amino acid residue;
and in the above-mentioned five-membered ring, a double bond may be formed between the neighboring member carbon atoms], then the taxane-type diterpene is recovered from the resulting cultures.
The taxane-type diterpene, which is an object of the method of the pres
Hara Yasuhiro
Tan Hiroaki
Tomino Ikuo
Yukimune Yukihito
Birch & Stewart Kolasch & Birch, LLP
Marx Irene
Mitsui Chemicals Inc.
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