JPH08175990A - PI3 kinase inhibitor and method for producing the same - Google Patents

Abstract

(57) [Summary] [Purpose] PI showing PI3 kinase inhibitory action at low concentrations.
A 3-kinase inhibitor and a method for producing the same are provided. [Structure] A didepside represented by the following general formula (I) is used as an active ingredient of a PI3 kinase inhibitor. Embedded image However, in the general formula (I), R represents a hydrogen atom, a β-D-glucopyranosyl group or a β-D-galactopyranosyl group.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a PI3 kinase inhibitor containing didepside as an active ingredient.

[0002]

2. Description of the Related Art Recently, PI3 kinase (Nature, 315 , 239-242) that phosphorylates the D-3 position of the inositol ring of phosphatidylinositol (PI).
(1985); Nature, 332 , 644-646 (19).
88)) has attracted attention because of its direct association with many growth factor receptors and oncogene products.

PI3 kinase has a different P
It has been revealed that it takes an I metabolic pathway and plays an important role in cell proliferation and canceration via tyrosine kinase. Therefore, inhibitors of PI3 kinase are expected to become a new type of antitumor cancer drug.

Many chemical substances have been put to practical use as pharmaceuticals in the field of chemotherapy for cancer, but in many cases, not only the drug efficacy is insufficient, but also the problem of tumor cell resistance to these drugs is clinically recognized. Complicating the usage of.
[Article 47th Annual Meeting of the Japanese Cancer Society, pp. 12-15 (19
1988)]]. Under such circumstances, the development of new antitumor substances is always required in the field of cancer treatment.

In addition, since the mechanism of action of conventional antitumor substances is based on the inhibitory action on the basic mechanism of cell division and proliferation, the action is not limited to cancer cells but to normal cells. However, the non-specific cytotoxic effect is caused, and as a result, side effects are caused during drug administration, which is a major clinical problem, which is not always satisfactory. Therefore, it is desired to develop an antitumor agent that acts specifically on cancer cells and has no side effect on normal cells.

Further, PI3 kinase is deeply involved in activation of neutrophils and platelets. Therefore, the PI3 kinase inhibitor is expected to become an anti-inflammatory agent or an anti-arteriosclerotic agent having a new mechanism by suppressing the activation of neutrophils and platelets.

[0007]

DISCLOSURE OF THE INVENTION The present invention is a PI3 kinase inhibitor which is always demanded and is expected to be used as a novel antitumor agent, antiinflammatory agent or antiarteriosclerotic agent and its production. It aims to solve these problems by providing a law.

[0008]

[Means for Solving the Problems] The present inventors have noticed that microorganisms produce bioactive substances such as antibiotics,
As a result of collecting a large number of samples from nature and examining various kinds of cultures separated from them, PI3 was found in the cultures of conidia stalk bundle-forming bacteria belonging to the incomplete filamentous fungi.
It was found that a substance having a kinase inhibitory action was contained, the structure of the substance was clarified, and the present invention was completed.

That is, the gist of the present invention is PI3 containing a didepside represented by the following general formula (I) as an active ingredient.
A kinase inhibitor and a microorganism that produces a didepside represented by the following general formula (I) are cultured in an appropriate medium to produce and accumulate didepside in the culture, and the didepside is collected from the culture. In the method, a conidial peduncle-forming bacterium D2949 strain (FERM P-147) belonging to the incomplete filamentous fungi as a microorganism producing didepside.
11) is used.

[0010]

Embedded image

However, in the above general formula (I), R represents a hydrogen atom, a β-D-glucopyranosyl group or a β-D-galactopyranosyl group.

The present invention will be described in detail below. <1> PI3 Kinase Inhibitor of the Present Invention The PI3 kinase inhibitor of the present invention contains the didepside represented by the general formula (I) (hereinafter, simply referred to as “didepside”) as an active ingredient. This didepside is
As a compound having cyclic adenosine-3 ', 5'-monophosphate phosphodiesterase inhibitory activity
No. 77 publication.

However, it is completely unknown that these compounds have a PI3 kinase inhibitory action. The present invention was made on the basis of the findings for the first time that this didepside has a PI3 kinase inhibitory action. The physicochemical properties and PI3 kinase inhibitory action of this didepside are shown in Examples below. The method for obtaining didepside used in the present invention will be described later.

When the PI3 kinase inhibitor of the present invention is used as a medicine, it can be formulated into a preparation suitable for the administration route together with a usual preparation carrier. For example, for oral administration, it is prepared in the form of tablets, capsules, granules, powders, solutions and the like. In preparing a solid preparation for oral administration, conventional excipients, binders, lubricants, other coloring agents, disintegrating agents and the like can be used.

Examples of the excipient include lactose, starch, talc, magnesium stearate, crystalline cellulose, methyl cellulose, carboxymethyl cellulose,
Examples thereof include glycerin, sodium alginate, and gum arabic. Examples of binders include polyvinyl alcohol, polyvinyl ether, ethyl cellulose, gum arabic, shellac, and sucrose. Examples of lubricants include magnesium stearate and talc. In addition, commonly known colorants and disintegrants can be used.

The tablets may be coated by a known method. Liquid formulations are aqueous or oily suspensions,
It may be a solution, syrup, elixir or the like, and may be prepared by a commonly used method. When preparing an injectable solution, pH adjuster, buffer, stabilizer, isotonic agent, local anesthetic, etc. are added to didepside and subcutaneously added by a conventional method.
Intramuscular and intravenous injections can be manufactured. Further, as a base for producing a suppository, for example, an oily base such as cacao butter, polyethylene glycol, lanolin, fatty acid triglyceride, Witepsol (registered trademark of Dynamite Nobel) can be used.

Further, PI3 other than the didepside of the present invention
A kinase inhibitor may be used in combination, but use with another PI3 kinase inhibitor is not essential to the present invention. The preparation thus prepared is expected to have a therapeutic effect on various cancers or tumors, various inflammations, arteriosclerosis, and the like. The dose varies depending on the patient's symptoms, weight, age, etc. and cannot be taken uniformly, but the amount of didepside is usually preferably in the range of about 10 to 2000 mg per adult per day, which is usually taken daily. It is desirable to administer in 1 to 4 divided doses.

<2> Method for Obtaining Didepside Used in the Present Invention The above-mentioned didepside used in the present invention is obtained by, for example, culturing a microorganism producing the same, in a suitable medium, that is, a culture product thereof, that is, cells and / or a culture supernatant. From, by isolating didepside or by chemically modifying the resulting didepside. Such microorganisms include
Examples thereof include molds classified into the incomplete filamentous fungi, and more specifically, the conidia stalk bundle-forming bacterium (Synnematous fungii: Synnematous fung) belonging to the incomplete filamentous fungi described below.
i) D2949 strain can be mentioned.

The culture of the above microorganisms, the isolation and purification of didepside will be described in detail below.

(1) Culture In the present invention, for example, it is classified into incomplete filamentous fungi,
Microorganisms that produce didepside are cultivated in a medium containing nutrients that can be utilized by normal microbes. As the carbon source, glucose, starch syrup, dextrin, sucrose, starch, molasses, animal / vegetable oil and the like can be used. As the nitrogen source, soybean powder, wheat germ, corn steep liquor, cottonseed meal, meat extract, peptone, yeast extract,
Ammonium sulfate, sodium nitrate, urea, etc. can be used.
In addition, if necessary, it is effective to add to the medium inorganic salts capable of producing sodium, potassium, calcium, magnesium, cobalt, chlorine, phosphoric acid, nitric acid and other ions. In addition, organic and inorganic substances that help the growth of bacteria and promote the production of didepside can be appropriately added to the medium.

As the culturing method, the culturing method under aerobic conditions, particularly the solid culturing method using an agar medium or the like and the submerged culturing method using a liquid medium are most suitable. A suitable temperature for culturing is 15 to 30 ° C, but in many cases, the culturing is performed at around 20 to 27 ° C. The production of didepside varies depending on the medium and culture conditions, but in the agar medium surface culture method, which is a solid culture method in a flask, the accumulation reaches the maximum usually for 7 to 21 days. When the accumulated amount of didepside in the culture reaches the maximum, the culture is stopped, and the didepside is isolated and purified from the culture.

(2) Chemical modification The didepside used in the present invention can also be obtained, for example, by chemically modifying the didepside obtained from the culture.

For example, the didepside of the present invention having a glycoside bond can be obtained by solvolysis under acidic conditions. Didepside having a glycoside bond, for example, in a polar solvent such as water, ethanol, methanol, by reacting sulfuric acid, hydrochloric acid or the like at an appropriate concentration,
The glycoside bond-eliminating didepside is led and the glycoside bond-eliminating didepside is isolated and purified from the reaction mixture.

(3) Isolation and purification of didepside Since the didepside used in the present invention is a fat-soluble substance,
This property can be utilized for isolation and purification from the culture or the modification reaction mixture. That is, for example, a solvent extraction method using ethyl acetate, chloroform, etc .; silica gel, alumina, ODS, Diaion H
Column chromatography using a synthetic adsorbent such as P-20 (manufactured by Mitsubishi Chemical Corporation) or a gel filtration agent such as Sephadex LH-20 (manufactured by Pharmacia), or high performance liquid chromatography; Preparative thin-layer chromatography and the like used as a carrier are effective.

<3> Method for producing didepside of the present invention The method for producing didepside of the present invention is carried out by conidial stalk-forming bacterium D2949 strain (hereinafter referred to as “D294
9 "may be abbreviated). The D2949 strain is a kind of fungus newly isolated from the dicotyledonous plant by the present inventors, and its mycological properties are as follows.

Morphological properties of strain D2949 Potato dextrose agar (PDA), malt agar (M
A), oatmeal agar (OA), and Miura medium (LC)
In A), the growth is moderate at 27 ° C., and the diameter of the colony is 5 to 6 cm after one week of culture, and the morphology is flat and velvety. The colony is gray green to dark gray green, and the back surface is gray green to dark brown. The basal hyphae are branched, have a large number of septa, reach a width of 3.1 μm, and have a brown color. The development of aerial hyphae is abundant and the hyphae are branched and have septa.

After 2 weeks of culturing, conidia peduncles (conidia peduncle bundles) densely formed on the surface of the medium are formed, and the conidia pedicle bundle reaches a height of 10 mm and a width of 25 to 73 μm. In the case of the conidial stalk-forming bacterium (Synnematous fungi), conidia formation is usually observed at the tip or side of the conidial stalk bundle, but D2
In the 949 strain, no characteristic morphology such as conidia could be observed in any medium. Growth temperature (cultivated on PDA for 1 week): 15-30 ° C
(Optimal temperature 27 ° C) Growth pH (on LCA, 1 week of culture): 3-9 (optimum growth pH 6-7)

Based on the above properties, the D2949 strain was designated as the conidial stalk bundle forming strain D2949 strain belonging to the incomplete filamentous fungi. The D2949 strain has been deposited at the Institute of Biotechnology, National Institute of Industrial Science and Technology with the deposit number of FERM P-14711.

In the present invention, the above-mentioned bacterium is cultivated in a medium containing nutrients that can be utilized by ordinary microorganisms. As a nutrient source, glucose, starch syrup, dextrin, sucrose, starch, molasses, animal and vegetable oils, etc. can be used.
As a nitrogen source, soybean flour, wheat germ, corn steep liquor, cottonseed meal, meat extract, peptone, yeast extract,
Ammonium sulfate, sodium nitrate, urea, etc. can be used. In addition, if necessary, it is effective to add to the medium inorganic salts capable of producing sodium, potassium, calcium, magnesium, cobalt, chlorine, phosphoric acid, sulfuric acid and other ions. In addition, organic and inorganic substances that help the growth of bacteria and promote the production of the present didepside can be appropriately added to the medium.

As the culture method, a culture method under aerobic conditions,
Particularly, the solid culture method and the deep culture method are suitable. The suitable temperature for culturing is 15 to 30 ° C., more preferably 20 to 30 ° C.
Incubate at around 27 ° C. Although the production of didepside varies depending on the medium and culture conditions, it usually reaches the maximum in 2 to 14 days in any of solid culture, shaking culture, and tank culture. When the accumulated amount of didepside in the culture reaches the maximum, the culture is stopped, and the target substance is isolated and purified from the culture medium.

Since the didepside used in the present invention has a PI3 kinase inhibitory activity at a low concentration as shown in Examples below, a PI3 kinase inhibitor containing the same is an effective antitumor agent, antiinflammatory agent, antiarterial agent. It is expected that it can be used as a curing agent.

[0032]

EXAMPLES Examples of the present invention will be shown below, but various production methods can be devised based on the properties of didepside.

Therefore, the present invention is not limited to the present embodiment, and of course the means for modifying the didepd shown in the embodiment,
Produced by known means based on the properties of didepside,
P that contains concentrated, extracted and purified didepside as the active ingredient
All I3 kinase inhibitors are included in the present invention.

Example 1 <1> Cultivation of strain D2949 40 g of water candy, 3 g of soybean oil, Solpy (manufactured by Nisshin Oil Co., Ltd.,
20 g of powdered soybean protein, 10 g of Pharmamedia (trademark of Toledas, trademark of cottonseed meal), 5 g of sun grain (trademark of soluble vegetable protein, made by Sangros), CaCO
_{3 3g, FeSO 4 · 7H 2} O 10mg, CoCl 2 ·
200 ml each of 40 ml of a medium (pH 6.0) containing 10 mg of 6H ₂ O, 10 mg of NiCl ₂ and 1 L of tap water.
The mixture was dispensed into 20 Erlenmeyer flasks and autoclaved at 121 ° C. for 20 minutes. One platinum loop of D2949 strain was inoculated into this medium for seed culture, and shake culture was carried out at 210 rpm for 4 days at 27 ° C.

Separately, maltose 80 g, KH ₂ PO ₄ 4.
_{2g, K 2 HPO 4 0.8g,} MgSO 4 · 7H 2 O 1
g, NH ₄ NO ₃ 1 g, FeSO ₄ · 7H ₂ O 2 mg, Z
_{nSO 4 · 7H 2 O 3.2mg,} CuSO 4 · 5H 2 O
0.3 mg, MnSO ₄ .7H ₂ O 0.2 mg, (N
_{H 4) 6 Mo 7 O 24} · 4H 2 O 0.2mg and the Göttingen University medium containing demineralized water 1L (pH 6.0) 40 m
Dispense 1 into each of 20 200 ml Erlenmeyer flasks for 12
The autoclave was sterilized for 20 minutes at 1 ° C.

This main fermentation medium was inoculated with 4 ml each of the seed culture solution, and shake-cultured at 27 rpm at 27 ° C. for 7 days.

<2> Purification of Didepside Produced by Culture To the culture solution obtained above, 40 ml of acetone was added per flask, and the mixture was extracted with stirring to obtain 1.4 L of an acetone aqueous solution.

After distilling off the solvent under reduced pressure, 500 ml of water
And 500 ml of ethyl acetate were added, and the aqueous layer was adjusted to pH 2 with hydrochloric acid and extracted. The ethyl acetate layer was separated and the solvent was distilled off under reduced pressure to obtain 7.2 g of residue. Suspend this in distilled water,
Octadecyl silica gel (MCI GEL ODS 1M
Y) Charged onto a column packed with 50 g. The column was washed with 250 ml of acetonitrile-water mixture (3: 2), and then the fraction eluted with 250 ml of acetonitrile-water mixture (4: 1) was concentrated under reduced pressure to obtain 840 mg of crude didepside.

109 mg of the crude didepside obtained above
Preparative silica gel TLC plate (MERCK, P
SC-Fertigplatten Kieselgel 60F ₂₅₄₅ , 20x2
0 cm, Schichtdicke (layer thickness) 2 mm) 6 sheets,
Chloroform-isopropanol-water-
Separation was performed by developing three times with a mixed solution of acetic acid (100: 40: 5: 1).

Since didepside was separated into Rf 0.45 (didepside 1) and Rf 0.30 (didepside 2), each fraction was scratched from a TLC plate and eluted with a developing solvent.

After each solvent was distilled off, acetonitrile-
Suspended in a water mixture (1: 4) and charged on an octadecyl silica gel column (Waters, Sep-Pak Cartidge),
After washing with 5 ml of the same mixed solution, an acetonitrile-water mixed solution (4:
1) Elution was performed with 5 ml, and the solvent was distilled off from the eluate to give didepside 1 56.8 mg and didepside 2 45.3 mg.

<3> Preparation of didepside by chemical modification 41.0 mg of didepside 1 obtained in the above <2>
After reacting for 22 hours at room temperature in methanol containing 5% HCl, the solvent was distilled off under reduced pressure. The residue is dissolved in a small amount of chloroform and chloroform: methanol:
A silica gel column (silica gel 5 g) packed with an acetic acid mixed solution (200: 4: 1) was charged and developed with the same mixed solution to obtain 6.3 mg of crude didepside 3. This was triturated in n-hexane to give 3.6 mg didepside 3.

<4> Structure determination of didepside (1) Structure of didepside 1 As a result of structural analysis of didepside 1 thus purified by the following physicochemical properties, R in the general formula (I) was β-D. -Identified to be TPI-1, a glucopyranosyl group.

1) Positive ion SI mass spectrum: 6
71 ([M + Na] ⁺ ) -anion SI mass spectrum: 647 ([M−H] ⁻
) 2) UV spectrum (in methanol) λ max (nm):
253 3) ¹ H-NMR (in deuterated methanol, 500 MHz) δ
(Ppm): 0.88 (3H, t, J = 6.8Hz), 0.90 (3H, t, J = 6.7Hz), 1.29 (16H, m), 1.61 (4H, m), 2.66 (2H, m), 2.97 (2H, t, J = 7.6Hz), 3.4 to 3.5 (4H, m), 3.72 (1H, dd, J = 5.0Hz, 12.2Hz), 3.90 (1H, d, J = 12.2Hz), 4.93 (1H , d, J = 6.9Hz), 6.43 (1H, d, J = 2.5Hz), 6.59 (1H, d, J = 2.5Hz), 6.62 (1H, d, J = 2.3Hz), 6.69 (1H, d , J = 2.3Hz)

4) ¹³ C-NMR (12 in deuterated methanol)
5MHz) (ppm): 14.4 (q), 14.4 (q), 23.7 (t), 23.7 (t), 30.3 (t), 30.3 (t), 30.6 (t), 30.8 (t), 32.7 (t) , 33.0 (t), 33.0 (t), 33.0 (t), 34.9 (t), 36.8 (t), 62.6 (t), 71.3 (d), 75.0 (d), 78.1 (d), 78.3 (d) , 102.4 (d), 103.1 (d), 108.9 (d), 111.8 (d), 113.9 (s), 115.9 (s), 116.0 (d), 145.0 (s), 149.0 (s), 155.4 (s) , 158.1 (s), 161.6 (s), 164.0 (s), 168.1 (s), 174.2 (s)

The above physicochemical data were in agreement with the literature values of TPI-1 (Japanese Patent Publication No. 5-1777).

(2) Structure of didepside 2 The didepside 2 purified as described above was subjected to structural analysis based on the following physicochemical properties, and as a result, the above formula (I) was obtained.
In the above, TPI- in which R is a β-D-galactopyranosyl group
Was identified as 2.

1) Positive ion SI mass spectrum: 6
71 ([M + Na] ⁺ ) -anion SI mass spectrum: 647 ([M−H] ⁻
) 2) UV spectrum (in methanol) λ max (nm):
253 3) ¹ H-NMR (in heavy methanol, 500 MHz)
δ (ppm): 0.87 (3H, t, J = 6.9Hz), 0.89 (3H, t, J = 6.8Hz), 1.28 (16H, m), 1.61 (4H, m), 2.67 (2H, m), 2.96 (2H, t, J = 7.8Hz), 3.58 (1H, dd, J = 3.0Hz, 9.8Hz), 3.68 (1H, dd, J = 6.0Hz, 6.0Hz), 3.75 (1H, dd, J = 5.2Hz, 11.2Hz), 3.81 (2H, m), 3.89 (1H, d, J = 3.5Hz), 4.87 (1H, d, J = 7.8Hz), 6.41 (1H, d, J = 1.9Hz), 6.59 (1H, d, J = 1.9Hz), 6.63 (1H, d, J = 2.3Hz), 6.70 (1H, d, J = 2.3Hz)

4) ¹³ C-NMR (12 in deuterated methanol)
5MHz) (ppm): 14.4 (q), 14.4 (q), 23.7 (t), 23.7 (t), 30.3 (t), 30.3 (t), 30.6 (t), 30.9 (t), 32.7 (t) , 33.0 (t), 33.0 (t), 33.1 (t), 34.9 (t), 36.8 (t), 62.4 (t), 70.2 (d), 72.4 (d), 75.0 (d), 77.2 (d) , 102.4 (d), 103.8 (d), 109.0 (d), 111.7 (d), 114.1 (s), 115.8 (s), 116.0 (d), 144.9 (s), 149.0 (s), 155.3 (s) , 158.3 (s), 161.5 (s), 164.0 (s), 168.1 (s), 174.3 (s)

The above physicochemical data were in agreement with the literature values of TPI-2 (Japanese Patent Publication No. 5-1777).

(3) Structure of didepside 3 The didepside 3 purified as described above was subjected to structural analysis based on the following physicochemical properties. As a result, the above formula (I) was obtained.
The R was identified to be TPI-5 in which R is a hydrogen atom.

1) FD mass spectrum: 486 (M ⁺ ) 2) UV spectrum (in methanol) λ max (mm):
270,305 3) ¹ H-NMR (in deuterated chloroform, 300 MH
z): 0.85 (3H, t, J = 6.6Hz), 0.88 (3H, t, J = 6.6Hz), 1.29 (16H, m), 1.65 (4H, m), 2.97 (4H, m), 6.32 ( 1H, d, J = 2.6Hz), 6.33 (1H, d, J = 2.6Hz), 6.61 (1H, d, J = 2.4Hz), 6.73 (1H, d, J = 2.4Hz), 11.27 (1H, S)

The above physicochemical data were in agreement with the literature values of TPI-5 (Japanese Patent Publication No. 5-1777).

Example 2 PI3 Kinase Inhibitory Effect of Didepside The PI3 kinase inhibitory activity of the didepside obtained in Example 1 was measured. This measurement is carried out by the method of Carpenter et al. (J. Biol. Chem., 265 , 19704-1971).
1 (1990)), using partially purified PI3 kinase from bovine liver.

That is, phosphatidylinositol 1
67 μM, [γ- ³² P] ATP (1.0 μCi), 50
mM Tris-HCl (pH 7.5), 50 mM NaC
1, 0.5 mM EGTA, 5 mM MgCl ₂ , 40
50 ml of a reaction solution containing ng bovine liver partially purified PI3 kinase as well as the didepside sample was incubated at 37 ° for 20 minutes.

500 ml of chloroform / methanol /
After the reaction was stopped by adding concentrated hydrochloric acid (200: 200: 1, (V / V / V)), 125 μl of 1N hydrochloric acid was added and mixed, followed by centrifugation (16,000 rpm, 10 seconds) to obtain 2 The layers were separated. After removing the upper layer, the solvent of the lower layer was distilled off, and the obtained reaction product was dissolved in 10 μl of chloroform and spotted on a thin layer plate (silka gel 60F ₂₅₄ ).

Thereafter, the thin layer plate was subjected to chloroform / methanol / 28% ammonium water / water (17.5: 25: 3.
75: 6 (V / V / V / V)). The phosphatidylinositol-3-phosphate fraction in the developed thin layer plate was confirmed by autoradiography. Further, this fraction was cut out and placed in a vial, 4 ml of methanol was added, and then phosphatidylinositol-
The radioactivity of ³² P incorporated in 3-phosphate was quantified by a liquid scintillation counter by the Cherenkov effect.

As a result, TPI-1, TPI-2, TP
The 50% inhibitory concentrations of I-5 were 15.8, 5.
It was 6,8.3 μM. As is clear from this result, the didepside used in the present invention has a PI3 kinase inhibitory activity at a low concentration.

[0059]

INDUSTRIAL APPLICABILITY The didepside used in the present invention exhibits a PI3 kinase inhibitory action at a low concentration.
I3 kinase inhibitors are expected as antitumor agents, antiinflammatory agents, antiarteriosclerotic agents and the like.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area C07H 15/203 C12P 7/62 19/44 // (C12P 7/62 C12R 1: 645) (C12P 19/44 C12R 1: 645) (72) Inventor Noriko Chiba 1000 Kamoshida-cho, Aoba-ku, Yokohama-shi, Kanagawa Sanryo Chemical Co., Ltd. Yokohama Research Institute (72) Inventor Takashi Mikawa 1000, Kamoshida-cho, Aoba-ku, Yokohama-shi, Kanagawa Address Sanryo Chemical Co., Ltd. Yokohama Research Institute

Claims (2)

[Claims] 1. A PI3 kinase inhibitor comprising a didepside represented by the following general formula (I) as an active ingredient. Embedded image However, in the general formula (I), R represents a hydrogen atom, a β-D-glucopyranosyl group or a β-D-galactopyranosyl group. 2. A method for producing didepside, which comprises collecting a didepside from the culture by culturing the didepside-producing microorganism represented by the general formula (I) in an appropriate medium to allow the produced dipside to be accumulated in the culture. According to the method, a conidial stalk-forming bacterium D2949 strain (FERM P-1) belonging to the incomplete filamentous fungi as a microorganism producing didepside.
4711).