JP4730879B2 - Kigamycinones, method for producing the same, and medicinal composition containing the kigamycinones - Google Patents

Description

  TECHNICAL FIELD The present invention relates to kigamynons that exhibit antibacterial activity / antitumor activity or anticancer activity and are useful as antibiotics, anticancer agents and the like, a method for producing the same, and a medicinal composition containing the kigamycinones.

Conventionally, various antitumor agents and antibacterial agents have been screened and used for cancer chemotherapy and treatment of bacterial infections (see Patent Documents 1 to 4). However, in cancer chemotherapy and treatment of bacterial infections, cancer cells, bacteria, etc. have acquired drug resistance, and the development of drug resistance is that antitumor agents and antibacterial agents that have been used until now are ineffective. It has become a big problem.
However, it is not easy to search for and screen for new antitumor agents and antibacterial agents. However, if the development of the new antitumor agents and antibacterial agents is delayed, it will be difficult to treat cancer and treat infectious diseases. There is a problem of causing trouble.
For this reason, it is necessary to further search and screen for new antitumor agents and antibacterial agents each time the drug resistance develops. In the cancer chemotherapy and the treatment of the bacterial infection, known compounds It has always been desired to discover or create new compounds having a chemical structure different from that of the compound and exhibiting excellent activity.

Japanese Patent Application Laid-Open No. 8-14369 JP-A-8-239379 JP-A-9-249647 JP-A-11-212263

  An object of the present invention is to solve the conventional problems in response to the above-mentioned demands and achieve the following object. That is, the present invention provides kigamynonones that show antibacterial activity / antitumor activity or anticancer activity and are useful as antibiotics, anticancer agents, and the like, a method for producing the same, and medicinal compositions containing the kigamycinones. For the purpose.

As a result of intensive studies by the present inventors in order to solve the above problems, the following knowledge has been obtained. That is, with the knowledge that kigamycinone derived from kigamycin, which is an antibiotic produced by a novel microorganism, the genus Amycolatopsis, exhibits antibacterial activity, antitumor activity or anticancer activity and is useful as an antibiotic, anticancer agent, is there.
This invention is based on the said knowledge by the present inventors, and the means for solving the said subject are as follows. That is,
<1> Kigamycinones, which are any of the compounds represented by the following general formula and derivatives thereof.
In said general formula, R < ¹ >, R < ² >, R < ³ >, R < ⁴ > and R < ⁵ > represent a hydrogen atom or a substituent.
<2> Kigamycinones, which are either a compound represented by the following structural formula (1) or a derivative thereof.
<3> The kigamycinones according to any one of <1> to <2>, wherein the derivative is either an inorganic salt or an organic salt.
<4> The kigamycinones according to any one of <1> to <3>, wherein the inorganic salt is selected from alkali metal salts, and the organic salt is selected from quaternary ammonium salts.
<5> The kigamycinones according to any one of <1> to <4>, which exhibit antibacterial activity against at least one of Gram-positive bacteria and Gram-negative bacteria, and exhibit growth inhibitory activity against cancer cells. .
<6> The kigamycinones according to any one of <8> to <9>, which are used at a concentration of 0.01 μM or more with respect to a target site requiring medicinal effect.
<7> The kigamycinones according to any one of <8> to <9>, which are used at a concentration of 0.1 μM or more with respect to a target site requiring medicinal effect.
<8> The kigamycinones according to any one of <6> to <7>, which are used for cancer cells.
<9> Amycolatopsis ML630-mF1 strain having an accession number of FERM P-15442 is cultured, and kigamycins according to any one of <1> to <8> are separated from the culture, It is a method for producing kigamycinones characterized by carrying out an incubation treatment in an aqueous solution.
<10> The method for producing kigamycinones according to <9>, wherein the culture is liquid shaking culture.
<11> A medicinal composition comprising the kigamycinone according to any one of <1> to <8>.
<12> The medicinal composition according to <11>, which is used as either an antibacterial agent or an antitumor agent.
<13> The medicinal composition according to any one of <11> to <12>, wherein kigamycinones are contained at a concentration such that the concentration in a target site requiring medicinal effect is 0.01 μM or more.
<14> The medicinal composition according to any one of <11> to <12>, wherein kigamycinones are contained at a concentration such that the concentration at a target site requiring medicinal effect is 0.01 μM or more.

  INDUSTRIAL APPLICABILITY According to the present invention, conventional problems can be solved, antibacterial activity / antitumor activity to anticancer activity, and useful as antibiotics, anticancer agents and the like, kigamynons, a method for producing the same, and the kigamycinone Can be provided.

(Kigamaishinones)
The kigamycinones of the present invention are either a compound represented by the following general formula or a derivative thereof.
In said general formula, R < ¹ >, R < ² >, R < ³ >, R < ⁴ > and R < ⁵ > represent a hydrogen atom or a substituent.

The substituent is not particularly limited and may be appropriately selected depending on the intended purpose. However, the substituent is decomposable in vivo and can be changed to a hydrogen atom in the body (that is, “OR ¹ in the general formula (1)”). ”,“ OR ² ”,“ OR ³ ”,“ OR ⁴ ”, and“ OR ⁵ ”can be changed to“ OH ”, for example, a group containing an alcoholate (alkoxide) bond, an acetal bond A group containing an ester bond, a group containing an acid amide bond, a group containing a urethane bond, a group containing a substituted silyl group, and the like. These substituents may be contained individually by 1 type, may contain 2 or more types, and may be further substituted by the other substituent.

Examples of the group containing an alcoholate (alkoxide) bond include an alkoxy group such as a methoxy group, an ethoxy group, and a propoxy group, and a phenyloxy group such as a benzyloxy group and a toluyloxy group. Examples of the group containing an acetal bond include an acetonide group. Examples of the group containing an ester bond include an acetyl group, a sulfonate ester, and a phosphate ester. Examples of the group containing an acid amide bond, for _example, -OCH 2 NHCOCH _3, and the like. Examples of the group containing a urethane bond include -OCONHR. Examples of the group containing a substituted silyl group include a trimethylsilyl group.

Among the kigamycinones represented by the general formula, kigamycinone represented by the following structural formula is more preferable.

In addition, even when it is not the kigamycinone itself, that is, when R ¹ , R ² , R ³ , R ⁴ and R ⁵ in the general formula (1) are not all hydrogen atoms, the R ¹ , R ² , R ³ , R ⁴ and R ⁵ are variable to a hydrogen atom in vivo (that is, “OR ¹ ”, “OR ² ”, “OR ³ ”, “OR ⁴ ” in the general formula (1), and Since “OR ⁵ ” is variable to “OH”, the kigamycins of the present invention have the same antibacterial activity and anticancer activity in vivo in any structure represented by the general formula (1). Shows activity.

There is no restriction | limiting in particular as said derivative | guide_body, According to the objective, it can select suitably, For example, either inorganic salt and organic salt are mentioned suitably.
As said inorganic salt, an alkali metal salt, alkaline-earth metal salt, etc. are mentioned suitably, for example. Examples of the alkali metal salt include sodium salt and potassium salt, and examples of the alkaline earth metal salt include magnesium salt.
Examples of the organic salt include quaternary ammonium salts and pyridinium salts.
Since the kigamycinones are acidic substances, preferred examples include salts with organic bases such as the quaternary ammonium salts and salts with alkali metals (metals) such as sodium.

Examples of the physicochemical properties of kigamycinone represented by the structural formula include the following A) to K).
A) Appearance and properties: yellow powder or crystals B) Melting point: 230-235 ° C. (decomposition)
C) Specific rotation [α] _D ²⁴ : -438 ° (c0.3, chloroform)
D) Retention time value by HPLC: 3.08 minutes 40% acetonitrile / 60% purified water as an elution solvent by high performance liquid chromatography in a capsule pack (type UG120 5 μm, 4.6 mm × 150 mm, manufactured by Shiseido) It is a case where it elutes and measures by.
E) ESI-mass spectrum (m / z): 551 (M + H) ⁺ , 574 (M + Na) ⁺
F) High resolution ESI-mass spectrum: experimental value 574.1336 (M + Na) ⁺ , calculated value: 574.1325 (as C ₂₈ H ₂₅ NO ₁₁ Na)
G) Molecular formula: C ₂₈ H ₂₅ NO ₁₁
H) Ultraviolet absorption spectrum: Measured at a kigamycinone concentration of 10 μg / ml (FIG. 1).
UV absorption spectrum measured in methanol solution. The main peaks are as follows. λ _max nm (ε) 219 (32,900), 253 (32,200), 355 (14,300)
I) Red external absorption spectrum (KBr tablet method): FIG.
ν _max (cm ⁻¹ ) 3495, 2885, 1645, 1610, 1465, 1440, 1275, 1200, 1090
J) ¹ H-NMR spectrum (CDCl ₃ / CD ₃ OD = 2: 1, TMS): FIG.
K) ¹³ C-NMR spectrum (CDCl ₃ / CD ₃ OD = 2: 1, TMS): FIG.

By examining the physicochemical properties of the kigamycinones, for example, ultraviolet (UV) absorption spectrum, infrared (IR) absorption spectrum, ¹ H-NMR (proton nuclear magnetic resonance) spectrum, ¹³ C-NMR (carbon C ¹³ nuclear magnetic resonance) spectra, by measuring the like, can be readily identified or discriminated.

The kigamycinones of the present invention exhibit antibacterial activity against at least one of Gram positive bacteria and Gram negative bacteria.
Examples of the bacterium that exhibits antibacterial properties of the kigamycinones of the present invention include, for example, Staphylococcus, Micrococcus, Bacillus, Corynebacterium, Escherichia, Shigella, Salmonella, Proteus, Providencia, Serratia , Klebsiella genus, Klebsiella genus, Mycobacterium genus, Candida genus, and the like.
Among these, the kigamycinones of the present invention exhibit strong antibacterial properties against Staphylococcus, Micrococcus, Bacillus, Corynebacterium, Escherichia, Shigella, Salmonella, Providencia, and the like. It shows particularly strong antibacterial activity against Staphylococcus, Micrococcus, Bacillus, and Corynebacterium.

Specific examples of these bacteria include Stahirococcus aureus, Micrococcus luteus, Bacillus subtilis, Bacillus cereus, Corynebacterium bovis, Escherichia coli, Shigella decentelier, Shigella flexinelli, Shigella sonai, Preferred examples include Salmonella enteritidis, Proteus bulgaris, Proteus mirabilis, Providencia retgueri, Serratia marcescens, Klebsiella pneumoniae, Klebsiella pneumoniae, Mycobacterium smegmatis, Candida albicans, and the like.
Among these bacteria, kigamycinones of the present invention are Staphylococcus aureus, Micrococcus luteus, Bacillus subtilis, Bacillus cereus, Corynebacterium bovis, Escherichia coli, Shigella decenteria, Salmonella enteritidis, Specific antibacterial activity against Providencia retgeri and specific strains include, for example, Stahirococcus aureus FDA209P, Stahirococcus aureus smith, Stahirococcus aureus MS9610, Stahirococcus aureus MRSA No. . 5. Stahirococcus aureus MRSA No. 5 17, Stahirococcus aureus MS16526, Stahirococcus aureus TY-04282, Micrococcus luteus FDA16, Micrococcus luteus IFO3333, Micrococcus luteus PCI1001, Bacillus subtilis NRRL B-558, Bacillus subtilis PC1 subtilis PC -Strong antibacterial properties against Cereus ATCC 10702, Corynebacterium bovis 1810, Escherichia coli NIHJ, Escherichia coli BEM11, Escherichia coli BE1186, Shigella decenteriye JS11910, Salmonella enteritidis, Providencia reggeri GN466.

  Whether or not the kigamycinones of the present invention exhibit antibacterial activity against bacteria can be determined by a known method. For example, the antibacterial spectrum of the kigamycinones against various bacteria can be determined according to the Japan Chemotherapy Association Standard. Based on the method, it can be determined by measuring by a multiple dilution method on a Mueller Hinton agar medium.

Kigamycinones of the present invention exhibit growth inhibitory activity against cancer cells. This growth inhibitory activity against cancer cells is presumed to be due to the fact that the kigamycinones have the effect of selectively causing cell death against cancer-starved cancer cells that cannot catch up with angiogenesis. .
When the kigamycinone of the present invention is used as an anticancer agent, the concentration of the kigamycinone is preferably 0.01 μM or more, more preferably 0.1 μM or more with respect to a target site requiring medicinal effect. Is more preferable.

  As described above, the kigamycinones of the present invention are particularly useful as antibacterial agents, growth inhibitors against cancer cells, antitumor agents (anticancer agents) and the like.

(Manufacturing method of kigamycinones)
The method for producing kigamycinones of the present invention comprises culturing the Amycolatopsis ML630-mF1 strain having the accession number FERM P-15442, isolating the kigamycins of the present invention from the culture, Incubation treatment is included, and other treatments appropriately selected as necessary are included.

  The above-mentioned Amycolatopsis ML630-mF1 strain may be obtained from the National Institute of Advanced Industrial Science and Technology as a kigamycin-producing bacterium upon distribution of the strain with the accession number FERM P-15442, or in nature. It may be obtained by separating from a conventional method.

Examples of the kigamycins include those having the structures shown below.

In addition to the kigamycin itself, the kigamycins include derivatives of the kigamycin, salts of the kigamycin, and the like.
Examples of the kigamycin derivative include those described in the description of the kigamycinone derivative.
Examples of the salt of kigamycin include the same as those described in the description of the salt of kigamycinone.

The culture method is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include liquid culture and solid culture, but liquid culture is preferred, and among these, liquid shake culture is preferred. Particularly preferred.
Moreover, there is no restriction | limiting in particular about the conditions (for example, nutrient medium, temperature, inoculum, the number of days, a system, etc.) of the said culture | cultivation, According to the objective, it can select suitably.

There is no restriction | limiting in particular as said nutrient medium, According to the objective, it can select suitably, For example, a well-known bacteria (bacteria) culture medium etc. are mentioned. There is no restriction | limiting in particular as a nutrient source added to the said nutrient medium, According to the objective, it can select suitably according to the objective, For example, a nitrogen source, a carbon source, inorganic salts, trace metals, etc. are mentioned. .
Examples of the nitrogen source include commercially available peptone, meat extract, yeast extract, corn steep liquor, ammonium sulfate, ammonium chloride, corn, gluten, meal cotton, seed meal, toast soya, and the like. These may be used individually by 1 type and may use 2 or more types together.
Examples of the carbon source include glycerol, starch, glucose, galactose, dextrin, corn starch, maltose and other carbohydrates, fats, and the like. These may be used individually by 1 type and may use 2 or more types together.
Examples of the inorganic salts include sodium chloride and calcium carbonate.
Examples of the trace metal include manganese.

There is no restriction | limiting in particular as said temperature, According to the objective, it can select suitably, Usually, it is about the optimal temperature of actinomycetes, and 25-30 degreeC is preferable.
The inoculum is not particularly limited and may be appropriately selected depending on the intended purpose. For example, a slant culture or a liquid shaking culture of the above-mentioned Amycolatopsis ML630-mF1 strain is preferable. It is mentioned in. In addition, there is no restriction | limiting in particular as an inoculation amount of the said inoculum, According to the objective, it can select suitably.

  The number of days is not particularly limited and may be appropriately selected depending on the purpose. Usually, in about 3 to 6 days, the Amycolatopsis ML630-mF1 strain grows to a sufficient amount, and the kigamycinones are sufficient. Amount produced. It should be noted that whether or not a sufficient amount of the antitumor agent has been produced can be determined by measuring a change over time in the titer of the kigamycins in the culture solution of the Amycolatopsis ML630-mF1 strain. it can.

  The method may be, for example, an aerobic culture or an anaerobic culture, but the aerobic culture is preferable, and a solid (agar) culture such as a slant culture or a plate culture. Any of liquid culture may be used, but the liquid culture is preferable, and the liquid culture may be any of shaking culture, static culture, and stirring culture, but shake culture is preferable, and rotation Shaking culture is more preferred. In addition, when performing mass culture, you may culture using a fermenter etc.

The kigamycins are separated from the culture by, for example, centrifuging the culture (culture medium) and concentrating the precipitate, followed by liquid-liquid distribution chromatography, column chromatography (silica gel chromatography, etc.), etc. It can be carried out by a method for separating the kigamycins. In the silica gel chromatography or the like, the obtained distillate fraction is developed using, for example, a chloroform-methanol mixture and concentrated to dryness to obtain a solid containing the kigamycin. Can do.
In addition, the said centrifugation can be performed on the centrifugation conditions suitably selected using the well-known centrifuge.

The acid in the acid aqueous solution is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid, and organic acids such as acetic acid. These may be used individually by 1 type and may use 2 or more types together.
The acid aqueous solution may be used by mixing with other solutions, and examples of a solution that can be used in combination include dimethyl sulfoxide.

There is no restriction | limiting in particular as the method of the said incubation process, According to the objective, it can select suitably, For example, the method of hold | maintaining and hold | maintaining in a thermostat etc. is mentioned suitably.
The incubation treatment conditions are not particularly limited and may be appropriately selected depending on the intended purpose. For example, the temperature is about 0 to 100 ° C, preferably 20 to 40 ° C, and preferably 30 to 40 ° C. More preferably, the time is about 1 minute to 100 hours.
The kigamycins are converted to the kigamycinones by the incubation treatment.

The method for fractionation (purification) of the kigamycinones thus obtained is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include solvent extraction using a solvent and adsorption affinity for various adsorbents. Adsorption separation method using the difference between the two, gel filtration method, column chromatography method, chromatography method using countercurrent distribution, and the like. These may be used alone or in combination of two or more.
As for kigamycinone thus purified, a purified powder of kigamycinone can be obtained by, for example, concentrating the fraction containing kigamycinone and passing it through a column filled with methanol: chloroform or the like.

  In addition, there is no restriction | limiting in particular as an identification method that what was fractionated by the above is the said kigamycinone, It can select suitably according to the objective, For example, a UV absorption spectrum, an infrared absorption spectrum, a high-speed It can be performed by an analytical method such as liquid chromatography (HPLC), NMR, mass spectrometry (MS), or the like.

  The kigamycinones of the present invention produced by the method for producing kigamycinones of the present invention may be used as they are, or may be used as the following medicinal composition of the present invention.

(Medicinal composition)
The medicinal composition of the present invention is not particularly limited except that it contains the kigamycinones of the present invention, and contains other components appropriately selected from known ones.

There is no restriction | limiting in particular as content of the said kigamycinone in the said medicinal composition, Although it can select suitably according to the objective, In the quantity from which the density | concentration in the object site | part which requires a medicinal effect is 0.01 micromol or more. It is preferable that the amount is 0.1 μM or more.
When the content of the kigamycinones in the medicinal composition is an amount that is less than 0.01 μM with respect to a target site that requires medicinal effects, antitumor or anticancer properties may not be sufficient. When the amount is 1 μM or more, the survival rate of cancer cells can be reduced, and when the amount is 0.01 μM or more, the survival rate of cancer cells can be extremely effectively reduced. It is advantageous.

There is no restriction | limiting in particular as a dosage form of the said medicinal composition, A powder medicine, a capsule medicine, a tablet medicine, a suppository, a liquid medicine, etc. are mentioned.
Suitable examples of the other components include pharmaceutically acceptable conventional solid or liquid carriers such as ethanol, water, and starch.
The medicinal composition can be suitably used as an antibacterial agent, an antitumor agent, etc., an antibacterial agent used for the treatment of bacterial infections, an antitumor agent or an anticancer agent having an activity of inducing cell death in cancer cells, Can be used particularly preferably.

  Examples of the present invention will be described below, but the present invention is not limited to these examples.

-Manufacture of kigamaicinones-
Potato starch 2% by weight, glucose 2% by weight, yeast extract 0.5% by weight, sodium chloride 0.25% by weight, toast soya meal 2% by weight, potassium carbonate 0.32% by weight, copper sulfate 0.0005% by weight, Dispense 110 ml of a liquid medium (adjusted to pH 7.4) containing 0.0005 mass% manganese chloride and 0.005 mass% zinc sulfate into an Erlenmeyer flask (500 ml volume) and sterilize at 120 ° C. for 20 minutes by a conventional method. The inoculated cells were inoculated with Amycolatopsis ML630-mF1 strain (FERM P-15442) cultured in an agar slant medium (inoculation amount: one platinum loop), and then cultured with shaking at 30 ° C. for 5 days. As a result, a seed culture solution was obtained.

  Next, a liquid containing 2% by mass of galactose, 2% by mass of dextrin, 1% by mass of soy peptone, 0.5% by mass of corn steep liquor, 1% by mass of glycerol, 0.02% by mass of ammonium sulfate, and 0.2% by mass of potassium carbonate Dispense 110 ml of medium (adjusted to pH 7.4) into Erlenmeyer flasks (500 ml) and sterilize them at 120 ° C. for 20 minutes by a conventional method, and inoculate 2 ml each of the seed culture solution obtained above. And cultured with shaking at 27 ° C. for 5 days. The culture solution obtained in the same manner using 12 liters of the medium was centrifuged to isolate the cells of Amycolatopsis ML630-mF1 strain.

10.3 liters of the obtained culture filtrate (cultured product) was adjusted to pH 2.0 by adding 1N hydrochloric acid, extracted with 10.3 liters of butyl acetate, and then with the butyl acetate. The butyl acetate layer was dried over anhydrous sodium sulfate. The butyl acetate layer was concentrated to dryness under reduced pressure to obtain 1.59 g. For this, a column (6.0 cm in total) packed with 240 g of silica gel 60N (for flash chromatography, manufactured by Kanto Chemical Co., Inc.) was charged to perform silica gel column chromatography.
Next, the distillate fraction obtained by the silica gel column chromatography was developed with a chloroform-methanol mixture. 133-170 was concentrated to dryness to obtain 325.2 mg of a solid. 171 to 301 were concentrated to dryness to obtain 256.2 mg of a solid.

  The silica gel column chromatography fraction No. From 133 to 170, elution was performed with 40% by volume acetonitrile water by high performance liquid chromatography (Pegasil ODS, total 30 × 250 mm) to obtain 31.6 mg of kigamycin C, 85.3 mg of kigamycin D, and 19.4 mg of kigamycin E. .

On the other hand, the silica gel column chromatography fraction No. 171 to 301 were eluted with 30% by volume acetonitrile in water using reverse phase silica gel chromatography (Senshu Scientific Co. Ltd. SSC-ODS-7515-12, 17 × 196 mm in total).
And the distillation (elution) fraction No. 74 to 85 were collected to obtain 25.8 mg of kigamycin A. Distillation (elution) fraction No. 55 to 60 were collected to obtain 7.9 mg of a mixture of kigamycin D and kigamycinone (mass of kigamycin D: mass of kigamycinone = 46: 54).

-Conversion of kigamycins to kigamycinone-
When 1.5 vol% dimethyl sulfoxide-0.1N hydrochloric acid aqueous solution of Kigamycin D 15 μg / ml was incubated at 37 ° C. for 30 minutes in a thermostatic bath, 28.6% by mass thereof was converted to kigamycinone.
Moreover, when the 0.01 N hydrochloric acid aqueous solution of Kigamycin D 15 μg / ml was incubated at 37 ° C. for 2 hours in a thermostat, 37.1% by mass was converted to kigamycinone.

-Conversion of Kigamycins to Kigamycinone-Purification-
The kigamycin D (589 mg) was dissolved in tetrahydrofuran (4 ml) and 0.2N hydrochloric acid (1.5 ml), and the mixture was stirred at room temperature for 20 hours to produce kigamycinone. Water (100 ml) was added to the reaction solution thus obtained, and the produced kigashinone was extracted using ethyl acetate (100 ml). Next, anhydrous sodium sulfate was added to the obtained extract, dried, filtered, and the extract was concentrated. Next, the concentrated kigamycinone was purified by passing the concentrated solution through an ODS column (50 ml) equilibrated with 40% by volume acetonitrile water and eluting with 40% by volume acetonitrile water. It was. Next, the fraction containing kigamycinone was concentrated and passed to Sephadex LH-20 packed with methanol: chloroform (volume ratio) = 5: 1. The fraction containing kigamycinone was concentrated to purify the kigamycinone. 120 mg of powder was obtained.

-Evaluation of physicochemical properties of kigamycinone-
The physicochemical properties of the obtained kigamycinone were measured and found to be as follows.
A) Appearance and properties: yellow powder or crystals B) Melting point: 230-235 ° C. (decomposition)
C) Specific rotation [α] _D ²⁴ : -438 ° (c0.3, chloroform)
D) Retention time value on HPLC: 3.08 minutes
This is a case where measurement was performed by elution with 40% by volume acetonitrile water as an elution solvent by high performance liquid chromatography of a capsule pack (type UG120 5 μm, 4.6 mm × 150 mm, manufactured by Shiseido).
E) ESI-mass spectrum (m / z): 552 (M + H) ⁺ , 574 (M + Na) ⁺
F) High resolution ESI-mass spectrum: experimental value = 5744.1336 (M + Na) ⁺ , calculated value = 5744.1325 (as C ₂₈ H ₂₅ NO ₁₁ Na)
G) Molecular formula: C ₂₈ H ₂₅ NO ₁₁
H) Ultraviolet absorption spectrum: Measured at a kigamycinone concentration of 10 μg / ml (FIG. 1). FIG. 1 is a UV absorption spectrum measured in a methanol solution, and main peaks are as follows. That is, λ _max nm (ε) 219 (32,900), 253 (32,200), 355 (14,300)
I) Red external absorption spectrum (KBr tablet method): Shown in FIG.
ν _max (cm ⁻¹ ) 3495, 2885, 1645, 1610, 1465, 1440, 1275, 1200, 1090
J) ¹ H-NMR spectrum (CDCl ₃ / CD ₃ OD = 2: 1, TMS): Shown in FIG.
K) ¹³ C-NMR spectrum (CDCl ₃ / CD ₃ OD = 2: 1, TMS): Shown in FIG.

-Evaluation of biological properties of kigamycinone-
A) Antibacterial activity The lowest growth inhibitory concentrations of the kigamycinones of the present invention against various bacteria were as shown in Table 1 below. This antibacterial spectrum was measured by a multiple dilution method on a Mueller Hinton agar medium based on the standard method of the Japanese Society of Chemotherapy.

B) Cancer Cell Growth Inhibitory Activity The kigamycinones are human pancreatic cancer cells PANC-1 cells, and have a stronger effect of causing cell death under nutrient starvation conditions than under normal cell culture conditions. The results are shown in FIG. Kigamycinone caused 50% cell death at a concentration of 10.7 μM when a normal medium was used (normal state), but 50% cell death was observed even at a concentration of 0.0195 μM in a nutrient-starved state. Evoked. In general, in solid cancer, it is considered that angiogenesis does not catch up with the nutritional starvation state. From the above results, the kigamycinone is more effective in the nutrition such as the solid cancer than the normal part (normal state) with good nutritional conditions. It is considered that selective activity is shown in the starved state and anticancer activity is shown.

  As is apparent from the results in Table 1, the kigamycinones of the present invention have antibacterial activity against various bacteria and are useful as antibacterial agents. Further, as is apparent from the results of FIG. 5, the kigamycinones of the present invention are useful as an antitumor agent or anticancer agent because they have antitumor activity or anticancer activity that suppresses the growth of cancer cells.

The kigamycinones of the present invention can be suitably used as antibacterial agents, antitumor agents and the like as they are, and can be suitably used as the medicinal composition of the present invention by mixing with other medicinal ingredients.
As a manufacturing method of kigamycinone of this invention, it can use suitably for manufacture of the said kigamycinone of this invention.
The medicinal composition of the present invention can be suitably used as an antibacterial agent and an antitumor agent, and particularly as an antibacterial agent used for the treatment of bacterial infections and an antitumor agent having an activity of inducing cell death in cancer cells. It can be preferably used.

FIG. 1 is an ultraviolet absorption spectrum diagram of kigamycinone (10 μg / ml) in a methanol solution. FIG. 2 is an infrared absorption spectrum of kigamycinone measured by the KBr tablet method. FIG. 3 is a proton nuclear magnetic resonance spectrum of kigamycinone measured with a deuterated chloroform solution (internal standard: tetramethylsilane). FIG. 4 is a carbon-13 nuclear magnetic resonance spectrum of kigamycinone measured with a deuterated chloroform solution (internal standard: tetramethylsilane). FIG. 5 is a comparative diagram (graph) of the cell-killing effect on PANC-1 human pancreatic cancer cells with different nutritional conditions for kigamycinone. In FIG. 5, “■” means culture under nutrient starvation conditions, and “◯” means normal culture.

Claims (8)

It is a compound represented by the following structural formula (1) or any one of inorganic salts and organic salts thereof, and exhibits antibacterial activity against at least one gram-positive bacterium and at least one gram-negative bacterium. Kigamaishinones.
The kigamycinones according to claim 1, wherein the inorganic salt is selected from alkali metal salts and the organic salt is selected from quaternary ammonium salts. The kigamycinones according to any one of claims 1 to 2, which exhibit growth inhibitory activity against cancer cells. A method for producing kigamycinones according to any one of claims 1 to 3, comprising culturing Amycolatopsis ML630-mF1 strain having a deposit number of FERM P-15442, separating kigamycins from the culture, A method for producing kigamycinones, comprising incubating kigamycins with an acid aqueous solution. The method for producing kigamycinones according to claim 4, wherein the culture is liquid shaking culture. A medicinal composition comprising the kigamycinones according to any one of claims 1 to 3. The medicinal composition according to claim 6, which is one of an antibacterial agent and an antitumor agent. The medicinal composition according to any one of claims 6 to 7, which contains kigamycinones in an amount such that the concentration at a target site requiring medicinal effect is 0.01 µM or more.