Microorganism producing terphenyl compounds

Details Microorganism producing terphenyl compounds Microorganism producing terphenyl compounds

2000-04-17

2001-09-18

Keys, Rosalynd (Department: 1621)

Chemistry: molecular biology and microbiology

Micro-organism, per se ; compositions thereof; proces of...

Fungi

C435S256100, C435S913000

Reexamination Certificate

active

06291231

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a compound which is useful as a pharmaceutical ingredient, a process for producing the same and use of the same. Specifically, a novel terphenyl compound which has an immunosuppressive, antiinflammatory and antitumor activity, a process for producing the same and an immunosuppressive, antiinflammatory and antitumor agent which comprises the same are provided.
BACKGROUND ART
A transplantation of a tissue or an organ which is frequently performed in recent years is attracting attention as a method for recovering a dysfunctional organ or tissue. However, a rejection symptom for excluding a transplanted part after an operation is a serious problem and it is not going too far to say that a success of the transplantation depends on prevention of the rejection symptom.
In these situations, an immunosuppressive agent is being used for prevention and a treatment of a rejection symptom against a transplantation of an organ or a tissue or a graft-versus-host reaction which is caused by a bone marrow transplantation and is an important pharmaceutical agent. The immunosuppressive agent is often used for treating not only a rejection symptom caused by a transplantation but also autoimmune diseases such as chronic rheumatoid arthritis, allergic diseases and the like. Recently, various immunosuppressive agents such as azathioprine, corticoid, cyclosporin A, tacrolimus and the like are developed and clinically used but they are not so satisfactory in view of their effect and side effect.
Many antitumor agents are also clinically used, but most of them have both a potent antitumor activity and toxicity as a side effect, which limits the dosage.
In these situations, a development of an immunosuppressive or antitumor agent which has a potent activity and can safely be used has been desired.
The compounds which belong to the same type as the compounds of the present invention are described in Chemical Pharmaceutics Bulletin, 24 (4), 613-620 (1976), The Journal of Antibiotics, 32 (6), 559-564 (1979), Agricultural Biological Chemistry, 49 (3), 867-868 (1985) and the like. In these literature, these compounds are indicated to have a toxicity against sea urchin embryo cells and Hela cells but their immunosuppressive and antiinflammatory activity are not mentioned at all.
DISCLOSURE OF INVENTION
An object of the present invention is to provide a novel compound which has an immunosuppressive, antiinflammatory or antitumor activity, a process for producing the same and an immunosuppressive, antiinflammatory or antitumor agent comprising the same.
The present inventors found a compound which has a potent immunosuppressive, antiinflammatory and antiproliferative activity on tumor cells in a culture broth of
Aspergillus candidus
RF-5762, a kind of filamentous fungus, isolated and purified the active compound and accomplished the present invention.
The present invention provides a compound of the formula (I):
wherein R
1
is hydrogen or hydroxy and R
2
is hydroxy or methoxy, pharmaceutically acceptable salts or hydrates thereof. The present invention provides a process for producing the compound (I) which comprises cultivating a microorganism which belongs to the genus Aspergillus and can produce the compound (I) and collecting the compound (I) from the obtained culture. Furthermore, the present invention provides the process for producing the compound (I) which comprises a compound of the formula (II), a precursor of the compound (I):
wherein R
1
and R
2
are the same as defined above is subjected to a reaction of 3-methyl-2-butenylation.
In an other embodiment, the present invention provides a pharmaceutical composition, specifically, an immunosuppressive, antiinflammatory or antitumor agent comprising the compound (I). Furthermore, the present invention provides a method for suppressing an immune reaction, treating or preventing inflammation or treating tumor which comprises administering the compound (I). Another object of this invention is to provide the use of the compound (I) for the manufacture of a medicament for suppressing an immune reaction, treating or preventing inflammation or treating tumor. Furthermore, the present invention relates to a microorganism which belongs to
Aspergillus candidus
and produces the compound (I).
BEST MODE FOR CARRYING OUT THE INVENTION
A process for producing the compound (I) of the present invention by cultivating a microorganism and by a chemical synthesis is as follows.
A Process by Cultivating a Microorganism
In the present process by cultivating a microorganism, the compound (I) is isolated by the method that a microorganism which can produce the compound (I) of the present invention is cultivated in such a medium composition and under such a condition as being used in usual fermentation production and the fermentation products are separated and collected in a usual manner.
The microorganism which can produce the compound (I) of the present invention includes a fungus which belongs to the genus Aspergillus, for example,
Aspergillus candidus
RF-5762. The morphological character of
Aspergillus candidus
RF-5762 is as follows.
Colonies of this strain on a Czapek's agar medium are white or yellowish white and flat. Their margins are jagged.
A production of a conidial head is good and the reverse side of the colony is colorless or yellowish white. Sometimes this strain produces a brown pigment in an agar. The conidial head is flat spherical in shape of 150-250 &mgr;m in diameter and torn to branch later. At the same time a small conidial head of 25-50 &mgr;m in diameter is shaped.
Conidiophores are 20-300 &mgr;m in length and 4.0-6.0 &mgr;m in diameter, their wall are thin and they have dissepiments.
A vesicle is spherical or flat spherical in shape and 13.0-15.0×13.0-15.0 &mgr;m. In the surface a metula is formed but in that of a small conidial head it is not formed and the conidial head becomes penicillus.
A metula is 3.5-4.5×6.5-7.5 &mgr;m and sometimes becomes hypertrophic to be spherical or pear-shaped and 10.0-14.0×10.0-14.0 &mgr;m in size.
A phialide is 1.5-2.5×4.0-8.0 &mgr;m in size. A conidium is spherical of 2.5-4 &mgr;m in diameter and the surface is smooth.
Growth temperature is 14° C.-36° C. and optimal growth temperature is 22° C.-32° C.
The above characters were compared with those of known species of the genus Aspergillus described in literature (The genus Aspergillus, 347-350 (1965), Williams&Wilkins; Journal of the Antibacterium and Antifungal Agents, 19(9), 489-495 (1991); Picture book of Fungi (the latter volume), 1006-1045 (1977), Koudan-sya,; Compendium of Soil Fungi Reprint, 1993, 83-85). As a result, the present fungi was identified as
Aspergillus candidus
Link ex Link 1824.
The strain has been deposited under accession No. FERM P-15439 with National Institute of Bioscience and Human Technology (Higashi 1-1-3, Tsukuba, Ibaraki, 305, JAPAN) on Feb. 15, 1996 and then was transferred to the International Deposition under the Budapest Treaty on Mar. 21, 1997 under accession No. FERM BP-5882.
As a medium for producing the present compound (I), either synthetic or natural medium which contains a suitable amount of carbon sources, nitrogen sources and minerals is preferably used. Vitamins or other nutrients may optionally be added if necessary.
Carbon sources to be used are at least one selected from general carbon sources such as sugars such as glucose, maltose, fructose, sucrose, starch and the like, alcohols such as glycerol, mannitol and the like, amino acids such as glycine, alanine, asparagine and the like, organic acids such as gluconic acid, pyruvic acid, acetic acid and the like, fatty acids and glycerides of them such as oleic acid, stearic acid and the like in consideration of the utilization of the microorganism.
Nitrogen sources to be used are at least one selected from organic nitrogenous-compounds such as soybean powder, corn steep liquor, beef extract, peptone, yeast extract, various amino acids and the like and inorganic nitrogenous compounds s

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