JP2004161745A - New fermentation product and method for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new fermentation product useful as a geranylgeranyl pyrophosphate (GGPP) synthase inhibitor and an antitumor agent. <P>SOLUTION: This new fermentation product, 4-(2, 3-dihydroxy-5-methylphenoxy)-2-dihydroxy-6-methylbenzoic acid is collected from a cultured material obtained by culturing microorganisms belonging to the genus Beauveria. Since the compound has a GGPP synthase inhibitory effect, it is useful as the GGPP synthase inhibitor or for the prevention and treatment of morbid states or diseases associated with GGPP or its geranygeranylation. Especially, since the compound is confirmed to have a cell proliferation inhibitory activity and infiltration inhibitory activity in various cancer cells, it is useful as the anticancer agent. <P>COPYRIGHT: (C)2004,JPO

Description

  The present invention relates to a medicament, particularly a geranylgeranyl pyrophosphate synthase inhibitor, a novel fermentation product useful as an antitumor agent, and a salt or ester thereof.

Geranylgeranyl pyrophosphate (hereinafter, abbreviated as GGPP) is synthesized by GGPP synthase and used for geranylgeranylation of low-molecular-weight G proteins belonging to the Rho family and the Rac family (Proc. Natl. Acad. Sci. USA. 87, 8960-8964, 1990). Geranylgeranylation is essential for the above-mentioned low molecular weight G protein to bind to cell membranes and its own regulator, and is a necessary step for activation (J. Biol. Chem. 271: 5289-5292, 1996; Annu. Rev. Cell Biol. 10, 181-205, 1994; Biochem. Soc. Trans. 20, 497-499, 1992; Annu. Rev. Biochem. 65, 242. -269, 1996). The Rho family regulates cytoskeletal rearrangement, metastasis and invasion, and that the Rho family protein RhoA regulates cyclin (Cyclin) D1 expression (Nat. Cell Biol. 3, 950-957). And J. Biol. Chem. 273: 3649-3653, 1998) and that the expression of p21 and p27 is inhibited (Nature: 394, 295-298 1998; J. Biol. Biol. Chem. 272, 32966-32971, 1997; and J. Biol. Chem. 272, 13-16, 1997), Rac stimulates transcription of the Cyclin D1 promoter. (Mol. Cell. Biol. Vol. 17, pp. 1324-1335, 1997), and Rho and Rac family proteins are important not only for cytoskeletal structure and cancer metastasis but also for cancer cell growth. There have been many reports of the role being played. Therefore, drugs that inhibit the synthesis or activity of GGPP are expected to be new types of antitumor agents. In recent years, GGPP inhibited the DNA binding activity of the nuclear receptor LXRα-RXR (Proc. Natl. Acad. Sci. USA. 94: 10588-10593, 1997). It is pointed out that GGPP itself plays an important role in vivo, including its importance (J. Bone Miner Res. Vol. 15, pp. 650-652, 2000), and further elucidation of the function of GGPP is expected. Have been.
Although it is expected to be useful as a prophylactic or therapeutic agent for the elucidation of the function of GGPP and for GGPP and its geranylgeranylation, no compound that inhibits GGPP synthase has yet been reported.

  There is a strong need for the creation of compounds that inhibit GGPP synthase and are useful for elucidating the function of GGPP, and for the creation of GGPP inhibitors that are useful as agents for preventing or treating pathological conditions or diseases involving geranylgeranylation.

The present inventors have conducted intensive studies on substances produced by many naturally occurring microorganisms. As a result, the incomplete filamentous fungus Beauveria felina QN22047 belonging to the genus Beauveria was found to inhibit GGPP synthase inhibition. It has been found that a novel compound having an activity, a cancer cell proliferation inhibitory activity and a cancer cell invasion inhibitory activity is produced. Then, the microorganism was cultured, and the novel compound was successfully isolated from the culture, thereby completing the present invention.
That is, the present invention relates to 4- (2,3-dihydroxy-5-methylphenoxy) -2-hydroxy-6-methylbenzoic acid represented by the following formula, or a salt or ester thereof.

Further, the present invention relates to a compound belonging to the genus Beauveria, and comprising 4- (2,3-dihydroxy-5-methylphenoxy) -2-hydroxy-6-methylbenzoic acid (hereinafter abbreviated as QN22047-5A substance) or a salt thereof. The present invention relates to a method for producing a QN22047-5A substance or a salt thereof, comprising culturing a microorganism having the ability to produce a QN22047-5A substance or a salt thereof from the culture. Examples of the microorganism belonging to the genus Beauveria having the ability to produce the QN22047-5A substance or a salt thereof include Beauveria felina (Beauveria felina) QN22047 strain isolated from the soil by the present inventors. It is one of the most effectively used strains. The present invention also relates to the Beauveria felina strain QN22047 itself.
Furthermore, the present invention relates to a medicament characterized by containing a QN22047-5A substance or a salt thereof or an ester thereof as an active ingredient, particularly to a geranylgeranyl pyrophosphate synthase inhibitor and an antitumor agent.

  The QN22047-5A substance of the present invention or a salt or ester thereof has a GGPP synthase inhibitory action, as shown in Examples described later, and therefore, a pathological condition involving GGPP synthase inhibitor or GGPP or geranylgeranylation thereof. It is useful as an agent for preventing or treating diseases. In particular, the compound of the present invention has a good cell growth inhibitory activity against various cancer cells, and further has an invasion inhibitory activity on cancer cells, and thus is an antitumor agent having an inhibitory action on cancer metastasis. Useful. The compounds of the present invention are also useful for elucidating the functions of GGPP.

The present invention also encompasses various hydrates and solvates of the QN22047-5A substance or a salt or ester thereof, a crystal thereof, and a crystal polymorph thereof.
The QN22047-5A substance has one carboxy group, and pharmaceutically acceptable esters thereof are also included in the present invention. Examples of the ester of the present invention include esters composed of well-known aliphatic or aromatic ester residues, preferably C1 to C4 alkyl esters, and particularly preferably methyl or ethyl esters. Further, the ester of the present invention also includes an ester comprising an ester residue such as an acetoxymethyl and pivaloyloxymethyl group which is easily hydrolyzed in a living body and converted into a carboxy group. Examples of the ester residue forming such a prodrug include the groups described in Prog. Med. 5: 2157-2161 (1985) and Hirokawa Shoten, 1990, “Development of Pharmaceuticals,” Vol. 7, Molecular Design 163-198. And the groups described in the above.

  Further, the compound of the present invention may form a salt. There is no particular limitation as long as it is a pharmaceutically acceptable salt, and it is a salt with an inorganic or organic base, specifically, an inorganic base such as sodium, potassium, magnesium, calcium, aluminum, methylamine, ethylamine, Examples thereof include salts with organic bases such as ethanolamine, and basic amino acids such as lysine and ornithine.

(Manufacturing method)
The QN22047-5A substance or a salt thereof of the present invention can be produced using a microorganism belonging to the genus Beauveria and capable of producing the QN22047-5A substance. Examples of such a microorganism capable of producing the QN22047-5A substance or a salt thereof include, for example, an imperfect filamentous fungus Beauveria felina belonging to the genus Beauveria isolated from soil collected in Kajikazawa Town, Minamikoma County, Yamanashi Prefecture. (Beauveria felina) QN22047 strain can be mentioned. The bacteriological properties of this strain are as follows.

1. Properties in Various Mediums (1) Potato / Glucose Agar Medium Colonies become 21 mm in diameter after culturing at 24 ° C. for 14 days. The colony surface is velvety and has many wrinkles, and the basal hyphal layer is slightly raised. The periphery is light yellow and the center is light purple. Conidium formation is good. The back of the colony is yellow brown.
(2) Malt extract agar medium After culturing at 24 ° C. for 14 days, the colony becomes 32.5 mm in diameter. Very little aerial hyphae are formed, resulting in flat, thin colonies. No conidia are formed. The colony front and back are light yellow-brown.
(3) Tzapek agar medium The colony has a very small growth of 7 mm in diameter when cultured at 24 ° C. for 14 days. No aerial mycelia are formed, resulting in flat, thin colonies. No conidia are formed. Both colony front and back are white.
(4) Sabouraud agar medium The colony becomes 23 mm in diameter after culturing at 24 ° C. for 14 days. The colony surface is velvety to fluffy and has many wrinkles, and the basal hyphal layer is slightly raised. The periphery is light brown and the center is grayish white. No conidia are formed. The back of the colony is yellow brown.

2. Physiological properties Growth temperature: grows in the range of 15-35 ° C, optimal growth temperature is 24-28 ° C.
Growth pH: Grow in the range of 5 to 11, and the optimum growth pH is 6 to 10.

3. Morphological characteristics Strains grown on potato-glucose agar medium were observed under a microscope. The mycelium is colorless and has partitions, and the surface is smooth. The conidiophores arise from aerial hyphae and stand upright or irregularly, solitary or several. Conidium-forming cells may be swollen, flask-shaped, bent, and the base may be elongated. The size is 3 to 8 × 2 to 3 μm, and often produces 2 to 4 small protrusions. Conidia are colorless, smooth, subspherical, oval or oval, and are 3-4 x 2.5-3 m. As the culture proceeds, the conidia become clusters for each branch. No chlamydospore formation is observed.

  Based on the above bacteriological properties, the taxonomic position of the QN22047 strain was searched for from among known fungi, and almost coincided with the description of Beauveria felina. Therefore, this strain was named Beauveria felina strain QN22047. This strain has been deposited with the National Institute of Advanced Industrial Science and Technology, Patent Organism Depositary under the accession number FERM P-19056. In addition, since microorganisms cause mutations artificially or naturally, the Beauveria felina QN22047 strain of the present invention can be produced by using ultraviolet rays, X-rays, chemical agents, etc., in addition to microorganisms isolated from nature. Mutants mutated and natural mutants thereof are also included.

The culturing is performed according to a general microorganism culturing method. The medium used for the culture may be any medium as long as the microorganism used can grow, and a synthetic medium, a semi-synthetic medium, or a natural medium can be used.
As nutrients to be added to the medium, known nutrients for microorganisms can be used. For example, commercially available carbohydrates such as molasses, glucose, maltose, fructose, mannitol, potato starch, corn starch, dextrin, soluble starch and the like, oils and fats, and fats are available as carbon sources, and nitrogen sources are commercially available. Peptones, meat extracts, corn steep liquor, cottonseed meal, peanut flour, soy flour, yeast extract, NZ-amine, wheat germ, caseins, fishmeal, and inorganic or organic nitrogen sources such as sodium nitrate and ammonium nitrate Used.

As the metal salt, sulfates, hydrochlorides, nitrates, phosphates, carbonates and the like of Na, K, Mg, Ca, Zn, Fe, Mn, Co, Cu and the like can be added as required. If necessary, amino acids such as valine, leucine, isoleucine, phenylalanine, tryptophan, methionine, lysine, arginine, glutamic acid, aspartic acid, vitamins, oleic acid, methyl oleate, lard oil, silicone oil, surfactants, etc. Can be used as appropriate. In addition to these, any additive can be used as long as it is utilized by the present compound-producing bacterium and is useful for producing the present compound.
The cultivation method may be the same as a general cultivation method such as production of antibiotics, and the culturing method may be solid culture or liquid culture. In the case of liquid culture, any of stationary culture, shaking culture, and stirring culture may be performed, but aeration and stirring culture is particularly desirable. As the culture conditions, the culture temperature can be appropriately applied at a temperature at which the producing bacteria can grow and produce the compound of the present invention, that is, within the range of 15 to 35 ° C, but is preferably about 24 to 28 ° C. The pH can be appropriately applied in the range of 5 to 11, but is preferably 6 to 10. The culturing time varies depending on various conditions, and the compound of the present invention accumulates in the medium usually in about 1 to 30 days, preferably in about 3 to 10 days.

  In order to isolate the target compound from the culture, conventional extraction and purification means used for isolating a metabolite of a microorganism can be appropriately used. The substance in the culture may be a culture solution as it is, or a culture filtrate obtained by centrifuging or adding a filter aid to the culture to obtain a culture filtrate, which is not miscible with water such as ethyl acetate, chloroform, benzene, and toluene. Add solvent and extract. In addition, the culture solution is brought into contact with an appropriate carrier, the produced substance in the filtrate is adsorbed, and then the substance is extracted by eluting with a suitable solvent. For example, the substance is brought into contact with a porous adsorption resin such as Amberlite (registered trademark) XAD-2, Diaion (registered trademark, the same applies hereinafter) HP-20, Diaion CHP-20P, or Diaion SP-850. Then, the substance is eluted using a mixture of water and an organic solvent such as methanol, ethanol, acetone or acetonitrile. At this time, by increasing the mixing ratio of the organic solvent stepwise or continuously from a low concentration to a high concentration, a fraction containing the substance may be efficiently obtained.

Next, the substance-containing fraction obtained using each of the above-described procedures was subjected to column chromatography using silica gel, ODS, Toyopearl (registered trademark, the same applies hereinafter) HW-40, etc., centrifugal liquid distribution chromatography, Further pure separation and purification can be carried out by a conventional method such as thin layer chromatography, high performance liquid chromatography (HPLC) using ODS or the like.
The QN22047-5A substance obtained as described above can be subjected to a conventional salt formation reaction, if desired, to obtain a pharmaceutically acceptable salt.

  If desired, an ester of the QN22047-5A substance can be obtained by subjecting the QN22047-5A substance to a conventional esterification reaction. The reaction is described in, for example, “Experimental Chemistry Course (4th edition)” edited by The Chemical Society of Japan, Vol. 22 (1992) (Maruzen), and “Protective Groups in Organic Synthesis” by Greene and Wuts (3rd edition). This can be done by the method described. Specifically, the QN22047-5A substance and alcohols are subjected to a dehydration condensation method using an acid catalyst, a method via an acid halide, a dehydration condensation method using a carbodiimide, or the like, or may be trimethylsilylated diazomethane or the like. Esterification using a diazoalkane derivative (Bradford P. Mundy et al., “Name Reactions and Reagents in Organic Synthesis”, p.322-323 (JOHN WILEY & SONS)).

  The pharmaceutical composition of the present invention containing one or more of the QN22047-5A substance of the present invention or a salt thereof or an ester thereof as an active ingredient can be used as a pharmaceutical carrier, excipient, etc. commonly used in the art. Can be prepared by a commonly used method. Oral administration by tablets, pills, capsules, granules, powders, liquids, etc., or injections such as intravenous and intramuscular injections, suppositories, eye drops, eye ointments, transdermal solutions, ointments, Any form of parenteral administration using a transdermal patch, an inhalant, a transmucosal solution, a transmucosal patch, or the like may be used.

  As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such a solid composition, the one or more active substances include at least one inert excipient such as lactose, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicate. It is mixed with magnesium acid aluminate. The composition may contain an inert additive such as a lubricant such as magnesium stearate, a disintegrant such as sodium carboxymethyl starch, and a solubilizing agent according to a conventional method. The tablets or pills may be coated with sugar coating or a gastric or enteric coating, if necessary.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc. and include commonly used inert solvents such as purified water, ethanol . The composition may contain, in addition to the inert solvent, auxiliaries such as solubilizing agents, wetting agents and suspending agents, sweetening agents, flavoring agents, fragrances and preservatives.
Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Aqueous solvents include, for example, distilled water for injection and physiological saline. Examples of the non-aqueous solvent include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80 (trade name). Such compositions may further comprise a tonicity agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizer, and a solubilizing agent. These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide or irradiation. In addition, these can be used by preparing a sterile solid composition, dissolving and suspending in sterile water or a sterile injection solvent before use.

  In general, in the case of oral administration, 0.1 to 500 mg orally and 0.01 to 100 mg parenterally are appropriate for an adult per day, and these are administered once or more than once a day. The dose is appropriately determined depending on the individual case in consideration of symptoms, age, sex, and the like. Since the dosage varies under various conditions, an amount smaller than the above dosage range may be sufficient.

  Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

A medium (pH 6.5) containing 30 g of glucose, 10 g of corn steep liquor, 5 g of dry yeast, 5 g of pharma media, 5 g of SIII meat, 2 g of calcium carbonate, and 1 L of distilled water is dispensed in 100 ml aliquots into 500 ml Erlenmeyer flasks at 120 ° C. Sterilized for 20 minutes. The Beauveria felina QN22047 strain that had grown well on a potato dextrose agar medium was scraped and inoculated, and shake-cultured at 24 ° C. and 200 rpm for 5 days to obtain a seed culture solution. Next, a medium (pH 6.5) containing 30 g of glucose, 20 g of glycerol, 10 g of dextrin, 10 g of malt extract, 2 g of yeast extract, 1 g of tryptone, 1 g of ammonium nitrate, 1 g of potassium dihydrogen phosphate, and 1 L of distilled water in 100 ml aliquots of 500 ml each was used. Dispensed into flasks and sterilized at 120 ° C. for 20 minutes. The medium was inoculated with 3 ml of each of the seed cultures, and shaking culture was performed at 24 ° C. and 200 rpm for 6 days.
The bacterial cells and the supernatant were separated by an aspirator for 2 L of the culture solution cultured in this manner. The supernatant was extracted with ethyl acetate, dehydrated by adding sodium sulfate, and then concentrated to dryness under reduced pressure. The oily crude extract was subjected to silica gel column chromatography, developed with chloroform-methanol (10: 1), and the active fraction was concentrated. Next, it was subjected to Toyopearl HW-40 column chromatography, eluted with methanol, and the active fraction was concentrated. Finally, the resultant was subjected to thin-layer chromatography, developed with chloroform-methanol (5: 1), the peak showing activity was collected, and 32.1 mg of QN22047-5A substance was isolated.

The isolated QN22047-5A substance was identified as 4- (2,3-dihydroxy-5-methylphenoxy) -2-hydroxy-6-methylbenzoic acid based on the following physicochemical properties.
(1) Color and shape: white amorphous translucent solid (2) Acidic, neutral, basic classification: acidic (3) Solubility: soluble in methanol, insoluble in water and hexane (4) ultraviolet Absorption spectrum (solvent: methanol): shows an absorption maximum at 258, 215 nm. (5) Molecular weight: 290.27
(6) Molecular formula: C ₁₅ H ₁₄ O ₆
(7) HPLC analysis:
Column: DOCOSIL B (Sensyu Science; 4.6φ × 250mm)
Elution solvent: mixed solution of acetonitrile-65mM aqueous ammonium acetate (30:70) Outflow rate: 0.7ml / min
Detection wavelength: 210nm
Detection time: 7.0 minutes (8) ¹ H-NMR spectrum (500 MHz, CDCl ₃ ): as shown in FIG. 1 (9) ¹³ C-NMR spectrum (125 MHz, CDCl ₃ ): as shown in FIG.

  150 μl of anhydrous dichloromethane was added to 5 mg of the QN22047-5A substance, and 50 μl of anhydrous methanol and 17 μl of 2M TMS-diazomethane were added while stirring under ice cooling. The mixture was further stirred at room temperature for 2 hours, and the reaction solution was extracted with ethyl acetate, dehydrated by adding sodium sulfate, and then concentrated to dryness under reduced pressure. The obtained reaction product is subjected to thin layer chromatography, developed with hexane-ethyl acetate (2: 1), the peak of the desired product is separated, and 3.3 mg of the methyl ester of QN22047-5A substance is obtained. Obtained.

(1) Ultraviolet absorption spectrum (solvent: methanol): shows an absorption maximum at 262, 214 nm (2) Molecular weight: 304.0964
(3) Molecular formula: C ₁₆ H ₁₆ O ₆
(4) ¹ H-NMR spectrum (500 MHz, CDCl ₃ ): as shown in FIG.

The GGPP synthase inhibitory activity of the QN22047-5A substance of the present invention and its methyl ester was confirmed by the following method.
First, an in vitro screening system was constructed to detect GGPP synthase inhibitory activity.
Human GGPP synthase cDNA was subcloned into pGEX-2T vector, transformed into E. coli JM109 strain, cultured overnight, and stimulated with IPTG (isopropyl-1-thio-β-D-galactopyranoside) to stimulate GST-GGPP synthase fusion. The protein was expressed. Thereafter, Escherichia coli was recovered by centrifugation, and the cells were disrupted by an ultrasonic disrupter, followed by centrifugation to obtain the target protein in the supernatant. This supernatant was mixed with GSH (glutathione) beads, and the mixture was rotated and stirred for 1 hour. After that, GST-GGPP synthase fusion was performed using an elution buffer (Elution Buffer: 50 mM Tris: pH 8.0, 20 mM reduced glutathione). The protein was eluted.
The GST-GGPP synthase fusion protein purified as described above was mixed with [ ¹⁴ C] IPP (isopentenyl pyrophosphate), FPP (falnesyl pyrophosphate) and an inhibitor sample in a reaction solution (0.1 M Tris-HCl pH 7.5, MnCl ₂ 0.3 mM). , MgCl ₂ 0.2 mM, BHT (2,6-di-t-butyl-4-methylphenol) 10 μg / ml) at 37 ° C. for 45 minutes. The generated [ ¹⁴ C] GGPP was extracted with 1-butanol, and the radioactivity of the 1-butanol layer was measured with a liquid scintillation counter.
As a result, the QN22047-5A substance of the present invention and its methyl ester both reduced the amount of [ ¹⁴ C] GGPP produced by GGPP synthase in the concentration range of 1 to 300 μM.

  The cell growth inhibitory activities of the QN22047-5A substances and B of the present invention were measured using a trypan blue extracellular exclusion test method (Sherwood SW (1995) Methods Cell Biol. 46: 77-97). In human colon cancer HT29 cells, human esophageal cancer EC109 cells, human esophageal cancer cells EC17 and human small cell lung cancer Ms-1 cells, QN22047-5A substance is at a concentration of 34.5 to 103.4 μM, and its methyl ester is at a concentration of 9.9 to 32.9 μM. Cell growth inhibitory activity in each region.

The activity of the QN22047-5A substance of the present invention and its methyl ester to suppress cancer cell invasion was measured using a transwell chamber assay.
Human melanoma highly metastatic cells B16BL6C2 were seeded on a 6-well plate and cultured overnight, and then the compound of the present invention was added thereto, and the cells were further cultured for 48 hours. The cells were trypsinized and detached, the serum concentration was adjusted to 0.5%, and the cells were spread on the upper layer of a Matrigel-coated chemotaxel chamber. The lower layer was filled with a culture solution containing 5% serum and infiltrated at 37 ° C for 12 hours.The cells were fixed with methanol, and the cells were stained with a hematoxylin stain to determine the number of cells infiltrating the lower layer. It was measured by microscopic observation.
As a result, the QN22047-5A substance showed a strong inhibitory activity against cancer cell invasion in the concentration range of 34.5 μM and its methyl ester in the concentration range of 9.87 μM.

¹ shows ¹ H-NMR spectrum of QN22047-5A substance. 3 shows the ¹³ C-NMR spectrum of QN22047-5A substance. ¹ shows the ¹ H-NMR spectrum of the methyl ester of QN22047-5A substance.

Claims (8)

4- (2,3-dihydroxy-5-methylphenoxy) -2-hydroxy-6-methylbenzoic acid or a salt or ester thereof. The 4- (2,3-dihydroxy-5-methylphenoxy) -2-hydroxy-6-methylbenzoic acid or a salt or ester thereof according to claim 1, wherein the ester is a C1-C4 alkyl ester. A microorganism belonging to the genus Beauveria and culturing a microorganism having an ability to produce 4- (2,3-dihydroxy-5-methylphenoxy) -2-hydroxy-6-methylbenzoic acid or a salt thereof, and culture thereof Isolating 4- (2,3-dihydroxy-5-methylphenoxy) -2-hydroxy-6-methylbenzoic acid or a salt thereof from 4- (2,3-dihydroxy-5-methylphenoxy) A method for producing phenoxy) -2-hydroxy-6-methylbenzoic acid or a salt thereof. The method according to claim 3, wherein the microorganism belonging to the genus Beauveria is Beauveria felina strain QN22047 (FERM P-19056). A medicament comprising the benzoic acid according to claim 1 or a salt or ester thereof as an active ingredient. The medicament according to claim 5, which is a geranylgeranyl pyrophosphate synthase inhibitor. The medicament according to claim 5, which is an antitumor agent. Beauveria felina QN22047 strain (FERM P-19056).

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