JP2005080616A - Physiologically active substance komodoquinone a and komodoquinone b, method for producing the same and use thereof - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To obtain physiologically active substances, komodoquinone A and komodoquinone B, produced by a microbial strain belonging to Actinomycete found in marine sediment, and obtain an anticancer agent and a nerve-protecting agent produced by using the substances. <P>SOLUTION: This invention provides a physiologically active substance komodoquinone A expressed by formula (I), a physiologically active substance komodoquinone B expressed by formula (II), and pharmacologically permissible salts of the substances. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to bioactive substances komodoquinone A and komodoquinone B produced by one strain belonging to actinomycetes found in marine sediments, and anticancer agents and neuroprotective agents using them.

Conventionally, as shown in Non-Patent Document 1, adriamycin, cisplatin, taxol, vincristine and the like are known as anticancer agents. In particular, anthracycline compounds such as adriamycin are widely used clinically as representative anticancer agents, but there are cases in which sufficient treatment cannot be performed due to side effects such as cardiotoxicity and bone marrow suppression and the emergence of drug-resistant cancer cells. It has increased.
Taxol, vincristine and the like also have a side effect of neuropathy.

Tsukagoshi Shigeru, Transition of Cancer Chemotherapy, Cancer and Chemotherapy, Japan, Cancer and Chemotherapy, 1999, Vol. 26, Supplement 1, p. 23-31

  Therefore, there is no satisfactory anticancer agent so far in the clinical field, and a new anticancer agent is demanded. Further, a low molecular weight compound having an action like nerve growth factor (NGF) that protects nerves from the neurotoxicity of existing anticancer agents against nerve cells is awaited.

  As a result of various searches for microbial metabolites in order to solve the above problems, the present inventors have found bioactive substances komodoquinone A and komodoquinone B produced by one strain belonging to actinomycetes, and have completed the present invention. .

That is, the present invention provides (1) the following formula (I)

A physiologically active substance komodoquinone A represented by the following formula (II)

A physiologically active substance komodoquinone B represented by: or a pharmacologically acceptable salt thereof;

(2) The physiologically active substance komodoquinone A or komodoquinone B having the following physicochemical properties, or a pharmacologically acceptable salt thereof a) komodoquinone A
1) Appearance: Red 2) Molecular formula: C ₂₇ H ₃₁ NO ₁₀ (measured by high resolution mass spectrum method)
3) Molecular weight: 529 (measured by FAB-MS method (M) ⁻ = 529, measured by HRFAB-MS method (M) ⁻ = 529.1948)
4) Ultraviolet absorption spectrum (solvent methanol): 233 nm (ε19200), 252 nm (ε18800), 289 nm (ε9600), 492 nm (ε5300), 525 nm (ε3200)
5) Infrared absorption spectrum (KBr method): 3337, 2935, 1653, 1614, maximum at 1585 cm ⁻¹ 6) Hydrogen nuclear magnetic resonance spectrum (solvent DMSO-d ₆ )
δ (multit., J (Hz))
7.93 (d, 7.1), 7.83 (dd, 8.2, 7.1), 7.77 (d, 8.2), 5.95 (br s), 4.95 (br s), 4.32 (d, 10.1), 4.12 (br s), 3.97 (q, 6.3), 3.82 (d, 10.1), 2.99 (d, 18.9), 2.89 (6H, s), 2.52 (d, 18.9), 2.02 (d, 13.9), 1.82 (br d, 13.9), 1. 29 (3H, s), 1.02 (3H, d, 6.3)
7) Carbon nuclear magnetic resonance spectrum (solvent DMSO-d ₆ )
187.1, 185.9, 158.3, 156.6, 155.8, 137.2, 136.2, 135.8, 135.0, 123.1, 121.8, 121.4, 110. 5, 110.0, 99.8, 69.1, 68.2, 67.5, 65.4, 62.2, 41.2, 40.9, 38.0, 36.2, 29.1, 15.1
8) Solubility: Soluble in water, acetone and methanol

b) komodoquinone B
1) Appearance: Red 2) Molecular formula: C ₁₉ H ₁₆ O ₇ (measured by high resolution mass spectrum method)
3) Molecular weight: 356 (measured by FAB-MS method (M + Na) ⁺ = 379, measured by HRFAB-MS method (M + Na) ⁺ = 379.0794)
4) Ultraviolet absorption spectrum (solvent methanol): 234 nm (ε15600), 245 nm (ε1200), 292 nm (ε3700), 492 nm (ε6200), 526 nm (ε4500),
5) Infrared absorption spectrum (KBr method): 3362, 2924, 1736, maximum at 1599 cm ⁻¹ 6) Hydrogen nuclear magnetic resonance spectrum (solvent CDCl ₃ )
δ (multit., J (Hz))
13.50 (s), 13.00 (s), 12.19 (s), 7.99 (d, 6.8), 7.32 (d, 8.0), 7.22 (dd, 8 0.0, 6.8), 5.27 (d, 5.5), 2.61 (d, 18.9), 2.38 (d, 18.9), 2.36 (d, 14.9). ), 1.93 (dd, 14.9, 5.5), 1.51 (3H, s)
7) Carbon nuclear magnetic resonance spectrum (solvent CDCl ₃ )
188.9, 186.1, 162.3, 157.2, 156.0, 137.6, 137.5, 136.7, 133.2, 124.2, 119.8, 116.0, 110. 2, 110.0, 68.2, 62.0, 40.3, 38.4, 29.8
8) Solubility: Soluble in acetone and ethyl acetate, hardly soluble in water and methanol;

(3) A pharmaceutical comprising as an active ingredient the physiologically active substance komodoquinone A or komodoquinone B described in (1) or (2) above, or a pharmacologically acceptable salt thereof;
(4) a cell growth inhibitor comprising as an active ingredient the physiologically active substance komodoquinone A or komodoquinone B described in (1) or (2) above, or a pharmacologically acceptable salt thereof;
(5) An anticancer agent comprising as an active ingredient the physiologically active substance komodoquinone A or komodoquinone B described in (1) or (2) above, or a pharmacologically acceptable salt thereof;

(6) A neurite outgrowth extender comprising as an active ingredient the physiologically active substance komodoquinone A or komodoquinone B described in (1) or (2) above, or a pharmacologically acceptable salt thereof;
(7) A neuroprotective agent comprising as an active ingredient the physiologically active substance komodoquinone A or komodoquinone B described in (1) or (2) above, or a pharmacologically acceptable salt thereof;

(8) A microorganism belonging to the genus Streptomyces and having the ability to produce the physiologically active substance komodoquinone A and / or komodoquinone B according to claim 1 or 2, is cultured in a nutrient medium, and the physiologically active substance is contained in the culture. A method for producing komodoquinone A and / or komodoquinone B, characterized in that komodoquinone A and / or komodoquinone B is produced and accumulated and collected.
(9) Streptomyces sp. KS3 (National Institute of Advanced Industrial Science and Technology, Patent Organism Depositary, Deposit No. FERM P-19514) or a mutant thereof;
About.

  The komodoquinone A or komodoquinone B of the present invention, or a pharmacologically acceptable salt thereof, can be used as an anticancer agent, particularly a chemotherapeutic agent for cancer exhibiting multidrug resistance. The compound can also be used as a protective agent against neuropathy, which is a side effect of anticancer agents.

  The komodoquinone A of the present invention has the above physicochemical properties, the structural formula of the above formula (I), and the komodoquinone B has the above physicochemical properties, and has the structural formula of the above formula (II). In terms of molecular weight in the physicochemical properties, FAB-MS represents mass spectrometry by the fast atom bombardment method, and HRFAB-MS represents high-resolution FAB-MS.

The two-dimensional nuclear magnetic resonance spectrum of komodoquinone A shows the following correlation. No. Is the carbon atom number, δC is the chemical shift value of the carbon nuclear magnetic resonance spectrum with tetramethylsilane as the internal standard (ppm), and δ is the chemical shift value of the hydrogen nuclear magnetic resonance spectrum with tetramethylsilane as the internal standard (ppm) ), HMBC is a correlation result by ¹ H-detected Heteronuclear Multiple Bond Connectivity.
No. δC δ HMBC
1 121.4 7.93 C-3, C-4a, C-12
2 136.2 7.83 C-4, C-12a
3 123.1 7.77 C-1, C-4a
4 158.3
4a 121.8
5 187.1
5a 110.5
6 156.6
6a 137.2
7 62.2 4.95 C-6a
8 41.2 2.02
1.82
9 67.5
10 38.0 2.99 C-6, C-9, C-10a, C-11
2.52
10a 135.8
11 155.8
11a 110.0
12 185.9
12a 135.0
13 29.1 1.29
1 '99.8 5.95 C-2', C-5 '
2 '65.4 4.32
3 '36.2 3.82
4 '68.2 4.12 C-2'
5 '69.1 3.97
6 '15.1 1.02 C-4', C-5 '
_{N-CH 3 40.9 2.89 C-} 3 ', N-CH 3

The two-dimensional nuclear magnetic resonance spectrum of komodoquinone B shows the following correlation. No. , ΔC, and δ represent the same meaning as described above. As shown, a multiple line in a hydrogen nuclear magnetic resonance spectrum is indicated by a commonly used abbreviation, and J represents a spin coupling constant (Hz).
(Solvent CDCl ₃ )
No. δC δ (multi., J (Hz))
1 119.8 7.9 (d, 6.8)
2 137.6 7.22 (dd, 8.0, 6.8)
3 124.2 7.32 (d, 8.0)
4 162.3
4a 116.0
5 188.9
5a 110.2
6 156.0
6a 136.7
7 62.0 5.27 (d, 5.5)
8 40.3 2.36 (d, 14.9)
1.93 (dd, 14.9, 5.5)
9 68.2
10 38.4 3.28 (d, 18.9)
2.61 (d, 18.9)
10a 137.5
11 157.2
11a 110.0
12 186.1
12a 133.2
13 29.8 1.51 (3H, s)
4-OH 12.19 (s)
6-OH 13.00 (s)
11-OH 13.50 (s)

(Solvent DMSO-d ₆ )
No. δC δ (multi., J (Hz))
1 119.0 7.73 (d, 7.4)
2 137.7 7.80 (dd, 7.7, 7.4)
3 125.0 7.36 (d, 7.7)
4 162.2
4a 116.8
5 188.9
5a 111.9
6 157.8
6a 139.0
7 62.3 4.93 (br s)
8 41.2 2.04 (d, 13.8)
1.86 (br d, 13.8)
9 68.2
10 38.2 3.01 (d, 18.7)
2.53 (d, 18.7)
10a 137.6
11 157.0
11a 110.3
12 186.1
12a 133.7
13 30.5 1.32 (3H, s)

  Komodoquinone A has a structure in which an amino sugar is dehydrated and condensed with the phenolic hydroxyl group of the aromatic ring at the terminal of komodoquinone B.

  A representative example of the producer of komodoquinone A and komodoquinone B of the present invention is, for example, Streptomyces sp. Belonging to the genus Streptomyces isolated from marine sediment. Examples include the KS3 strain. The mycological properties of this strain are shown below.

1) Morphological properties As a result of culturing on a yeast / malt agar medium, the colony was a grayish yellow pin and exhibited a medium gray with sporulation. No soluble pigment is observed, the basal hyphae are branched, the width is 0.5-1.0 μm and does not divide. The spore formed a spiral spore chain at the tip of the spore handle branched from the aerial hyphae. As a result of observation by an electron microscope, the spore was a long cylindrical shape having a length of 0.8 to 1.2 μm and a width of 0.5 to 1.0 μm, and its surface was smooth. Neither sporangia nor sclerotia were observed.

2) Growth in various media

3) Physiological properties Growth temperature range (Bennett medium): 18-39 ° C
Optimal growth temperature (Bennet medium): 25-28 ° C
Salt tolerance (Bennett medium): 0% ++
4% +
7% ±
10%-
Starch hydrolysis: +
Peptone conversion of skim milk: 28 ℃
37 ° C-
Tyrosinase reaction: −
Melanin-like pigment production: +

4) Availability of carbon source L-arabinose-
D-xylose ++
D-glucose ++
D-fructose +
Sucrose −
Inositol ++
L-rhamnose-
Raffinose −
D-mannitol-

5) Chemical properties of bacterial cell components Isoprenoid quinone: MK 9 (H6, H8)
Cell wall diaminopimelic acid: LL type 6) 16SrDNA nucleotide sequence 16SrDNA nucleotide sequence homology analysis shows that it does not match the known 16SrDNA nucleotide sequence, 97.1% for Streptomyces pseudogriseolus NRRL 3985, and Streptomyces mashuense DSM 40221T Showed 97.1% homology to Streptomyces griseocarneum DSM 40004T.

  Based on the above properties, in accordance with the 8th edition (1974) of B.E. Buffanan & N. Gibbons, Bergey's Manual of Determinative Bacteriology As a result of the search, it was found that the strain belongs to the genus Streptomyces. The strain has been deposited at the National Institute of Advanced Industrial Science and Technology Patent Biological Deposit Center under the deposit number FERM P-19514.

  Streptomyces sp. Any mutant strain obtained by mutating the KS3 strain with, for example, ultraviolet rays, X-rays, or a drug, and the like, which has the ability to produce the physiologically active substance komodoquinone A and / or komodoquinone B is included in the present invention. It can be used for the production of the physiologically active substance komodoquinone A and / or komodoquinone B.

  The present invention also includes a production method in which the physiologically active substances komodoquinone A and / or komodoquinone B are cultured from their producing bacteria to produce the compound and collected from this culture. The culture of the producing bacteria is carried out aerobically in a medium containing a nutrient source that can be utilized by actinomycetes.

  As a nutrient source, it is effective to use rice, but known sources that have been conventionally used for culturing actinomycetes can be used. For example, as a carbon source, glucose, glycerin, galactose, chickenpox, dextrin, sugar Claus, starch, molasses, animal / vegetable oil, etc. can be used alone or in combination. As the nitrogen source, soybean powder, wheat, wheat germ, corn steep liquor, meat extract, peptone, yeast extract, ammonium sulfate, sodium nitrate, urea, etc. can be used alone or in combination. In addition, it is effective to add inorganic salts capable of generating sodium, cobalt, chlorine, sulfuric acid, phosphoric acid and other ions as required. Seawater may be used as appropriate. Examples of seawater include artificial seawater aquamarine (manufactured by Hachishu Pharmaceutical Co., Ltd.).

  A solid culture method is suitable as the culture method. A suitable temperature for culturing is 18 to 39 ° C, preferably about 25 to 30 ° C. The production of the physiologically active substance komodoquinone A or komodoquinone B varies depending on the medium and culture conditions, but the accumulation usually reaches its maximum within 1 to 14 days. When the accumulated amount of the physiologically active substance komodoquinone A or komodoquinone B in the culture reaches the maximum, the culture is stopped and the target substance is separated from the culture solution.

  In addition to the above methods, methods commonly used for collecting substances, such as adsorption chromatography, gel filtration chromatography, thin layer chromatography, high performance liquid chromatography, etc., may be combined as appropriate, or may be repeated as necessary to restore komodoquinone. A or komodoquinone B can be isolated pure.

  The pharmacologically acceptable salt in the present invention is not particularly limited as long as it is a salt that can be usually taken. For example, a salt with an alkali metal, that is, a sodium salt, a potassium salt, or a salt with an acid, that is, hydrochloric acid. Salts, sulfates, phosphates and the like are preferred.

  Various conventionally known methods can be applied as a formulation and administration method when used as a pharmaceutical. That is, as an administration method, for example, injection, oral or rectal administration can be performed. As a formulation form, it can take forms, such as an injection, a powder, a granule, a tablet, a suppository, or a capsule, for example.

  Various pharmaceutical additives used for pharmaceuticals, i.e., carriers and other auxiliary agents, as long as they do not adversely affect komodoquinone A or komodoquinone B or their pharmacologically acceptable salts during formulation. Stabilizers, preservatives, soothing agents, emulsifiers and the like may be used. In the preparation, the content of komodoquinone A, komodoquinone B or a pharmacologically acceptable salt thereof can vary widely depending on the form of the preparation, etc., and is generally 0.01 to 100% (weight), preferably 0. Contains 1 to 70% (by weight).

  A pharmaceutical agent containing komodoquinone A, komodoquinone B, or a pharmacologically acceptable salt thereof as an active ingredient can be preferably used as a cell growth inhibitor or a neurite extension agent. Alternatively, it is preferably used as an anticancer agent or a neuroprotective agent.

  Examples of the use as an anticancer agent include treatment of stomach cancer, lung cancer, colon cancer, pancreatic cancer, liver cancer, ovarian cancer, breast cancer, prostate cancer, brain tumor, leukemia and the like.

  In the present invention, the neurite extender has an activity related to differentiation induction of nerve cells like NGF, and maintains the presence or survival of nerve cells. When nerve cells are damaged due to internal or external factors, a neuroprotective agent having an activity of developing neurites prevents or reduces such damage or recovers from the damaged state. That is, as a neuroprotective agent, for example, neuropathy caused by a compound such as an anticancer drug, Mycobacterium tuberculosis bacteriostatic drug, an antiepileptic drug, and arsenic, cancer, infection, angiopathy, Sjogren's syndrome, Alzheimer's disease, genetic disease, etc. It can be used for neuropathy induced directly or indirectly by aging or aging, and for neuropathy caused by physical factors such as cerebral contusion, cerebral infarction, intracranial hemorrhage, cerebral ischemia. The neuroprotective agent can be used as a prophylactic or post-onset therapeutic agent. In particular, it is used for the prevention and treatment of neurological disorders known as side effects of anticancer agents.

  The dose of komodoquinone A, komodoquinone B or a pharmacologically acceptable salt thereof varies depending on the indication, symptoms, administration method, etc., but is about 0.01 to 800 mg per day per adult.

Test Example The physiological activities of komodoquinone A and komodoquinone B are described below.

(I) Cell growth inhibitory action Using an RPMI 1640 medium (Iwaki) supplemented with 10% fetal calf serum (manufactured by Moregate), human renal cancer cell UO-31, human breast cancer cell MDA-MB-231, or human Lung cancer cells NCI-H460 were cultured at 37 ° C. under 5% CO ₂ . These cells were seeded in a 96-well plate and cultured for 1 day, followed by addition of komodoquinone A. Adriamycin was added as a control. After further culturing for 3 days, floating cells were removed, fixed with methanol, and stained with methylene blue dye. After dyeing, the dye was extracted with 0.3% aqueous hydrochloric acid, the absorbance at 660 nm was measured, and the IC ₅₀ value was determined by the method described later.
Murine leukemia-derived cancer cells P388 or adriamycin resistant strain P388 / ADR were cultured at 37 ° C. under 5% CO ₂ using RPMI 1640 medium supplemented with 10% fetal bovine serum. The cells were seeded in a 96-well plate and cultured for 1 day, and then komodoquinone A or adriamycin was added. After further culturing for 2 days, 0.16 mg / mL of WST-1 and 3.3 μg / mL of 1-methyl-5-methylphenylsulfate were added to the culture solution and cultured for 4 hours. A value obtained by subtracting the absorbance at 660 nm from the absorbance at 450 nm was determined.

The growth inhibitory activity was expressed as the rate of decrease in absorbance of the compound addition group relative to the absorbance of cells not added with the compound. IC ₅₀ values were determined from the dose-response curves, and the values are shown in Table 2.

Results Table 2
Cell growth inhibitory effect of komodoquinone A and adriamycin Cell name IC50 (μM)
komodoquinone A Adriamycin UO-31 0.56 0.47
MDA-MB-231 2.0 0.095
NCI-H460 2.1 0.0061
P388 4.8 0.012
P388 / ADR 3.9 2.6
As is apparent from the above results, komodoquinone A has a cell growth inhibitory effect on mammalian cancer cells, and is almost the same as sensitive cells (P388) with respect to multidrug resistant cancer cells (P388 / ADR). Showed cell growth inhibitory action.

(Ii) Neurite extension effect Mouse neuroblast Neuro 2A was cultured at 37 ° C. under 5% CO ₂ using Dulbecco's modified MEM medium supplemented with 10% fetal bovine serum. The cells were seeded in a 24-well plate and cultured for 1 day, and then komodoquinone A or komodoquinone B was added. The drug treatment was performed for 2 days, and it was determined by microscopic examination whether neurite outgrowth was observed.

Results Komodoquinone A showed the appearance of remarkable neurites at 1 μg / mL, and komodoquinone B showed neurite outgrowth at 30 μg / mL or more.

  As is clear from the above results, komodoquinone A and komodoquinone B showed NGF-like activity to extend the process of nerve cells.

  Although the Example of this invention is shown below, this is only an illustration, Comprising: This invention is not limited, Various modifications are possible.

Production of Komodoquinone A and Komodoquinone B by Fermentation Method (1) Fermentation Culture Streptomyces sp. For the culture of the KS3 strain, a medium containing 25 g of rice per 50 mL of artificial seawater aquamarine (manufactured by Hachishu Pharmaceutical Co., Ltd.) containing 0.5% glucose and 2% yeast extract was used. In a 500 mL flask, the above medium and Streptomyces sp. 50 pieces of the KS3 strain were added and cultured at 30 ° C. for 2 weeks.

(2) Purification The culture was collected and extracted with 3 L of a solution in which 3 L of acetone, chloroform, methanol and acetone were mixed in a 1: 2: 4 ratio. The organic solvent was distilled off from the extract, and the resulting concentrate was partitioned in an ethyl acetate-water system. Diaion HP20 (manufactured by Mitsubishi Kasei) was added to the aqueous layer containing komodoquinone A, and the mixture was stirred for 15 minutes and then filtered. The compound was eluted from the recovered resin with methanol. The eluate was dried to obtain 4.2 g of residue.
The solvent was distilled off from the ethyl acetate layer containing komodoquinone B to obtain 4.2 g of a residue.
The fraction containing this komodoquinone A was subjected to silica gel chromatography using a lower layer of chloroform-methanol-water, and then HPLC (methanol-water-chloroform = 7: 3: 0) using a reverse phase column (Cosmosil 5Ph 10φ × 250 mm, manufactured by Cosmotech). .5) to obtain 20 mg of red komodoquinone A.
4.2 g of the residue of the ethyl acetate layer containing komodoquinone B was fractionated and purified by silica gel chromatography using n-hexane and ethyl acetate to obtain 110 mg of red komodoquinone B.

Claims (9)

Formula (I)

A physiologically active substance komodoquinone A represented by the following formula (II)

A physiologically active substance komodoquinone B, or a pharmacologically acceptable salt thereof. The physiologically active substance komodoquinone A or komodoquinone B having the following physicochemical properties, or a pharmacologically acceptable salt thereof a) komodoquinone A
1) Appearance: Red 2) Molecular formula: C ₂₇ H ₃₁ NO ₁₀ (measured by high resolution mass spectrum method)
3) Molecular weight: 529 (measured by FAB-MS method (M) ⁻ = 529, measured by HRFAB-MS method (M) ⁻ = 529.1948)
4) Ultraviolet absorption spectrum (solvent methanol): 233 nm (ε19200), 252 nm (ε18800), 289 nm (ε9600), 492 nm (ε5300), 525 nm (ε3200)
5) Infrared absorption spectrum (KBr method): 3337, 2935, 1653, 1614, maximum at 1585 cm ⁻¹ 6) Hydrogen nuclear magnetic resonance spectrum (solvent DMSO-d ₆ )
δ (multit., J (Hz))
7.93 (d, 7.1), 7.83 (dd, 8.2, 7.1), 7.77 (d, 8.2), 5.95 (br s), 4.95 (br s), 4.32 (d, 10.1), 4.12 (br s), 3.97 (q, 6.3), 3.82 (d, 10.1), 2.99 (d, 18.9), 2.89 (6H, s), 2.52 (d, 18.9), 2.02 (d, 13.9), 1.82 (br d, 13.9), 1. 29 (3H, s), 1.02 (3H, d, 6.3)
7) Carbon nuclear magnetic resonance spectrum (solvent DMSO-d ₆ )
187.1, 185.9, 158.3, 156.6, 155.8, 137.2, 136.2, 135.8, 135.0, 123.1, 121.8, 121.4, 110. 5, 110.0, 99.8, 69.1, 68.2, 67.5, 65.4, 62.2, 41.2, 40.9, 38.0, 36.2, 29.1, 15.1
8) Solubility: Soluble in water, acetone and methanol b) komodoquinone B
1) Appearance: Red 2) Molecular formula: C ₁₉ H ₁₆ O ₇ (measured by high resolution mass spectrum method)
3) Molecular weight: 356 (measured by FAB-MS method (M + Na) ⁺ = 379, measured by HRFAB-MS method (M + Na) ⁺ = 379.0794)
4) Ultraviolet absorption spectrum (solvent methanol): 234 nm (ε15600), 245 nm (ε1200), 292 nm (ε3700), 492 nm (ε6200), 526 nm (ε4500),
5) Infrared absorption spectrum (KBr method): 3362, 2924, 1736, maximum at 1599 cm ⁻¹ 6) Hydrogen nuclear magnetic resonance spectrum (solvent CDCl ₃ )
δ (multit., J (Hz))
13.50 (s), 13.00 (s), 12.19 (s), 7.99 (d, 6.8), 7.32 (d, 8.0), 7.22 (dd, 8 0.0, 6.8), 5.27 (d, 5.5), 2.61 (d, 18.9), 2.38 (d, 18.9), 2.36 (d, 14.9). ), 1.93 (dd, 14.9, 5.5), 1.51 (3H, s)
7) Carbon nuclear magnetic resonance spectrum (solvent CDCl ₃ )
188.9, 186.1, 162.3, 157.2, 156.0, 137.6, 137.5, 136.7, 133.2, 124.2, 119.8, 116.0, 110. 2, 110.0, 68.2, 62.0, 40.3, 38.4, 29.8
8) Solubility: Soluble in acetone and ethyl acetate, hardly soluble in water and methanol A pharmaceutical comprising the physiologically active substance komodoquinone A or komodoquinone B according to claim 1 or 2 or a pharmacologically acceptable salt thereof as an active ingredient. A cell growth inhibitor comprising as an active ingredient the physiologically active substance komodoquinone A or komodoquinone B according to claim 1 or 2, or a pharmacologically acceptable salt thereof. An anticancer agent comprising the physiologically active substance komodoquinone A or komodoquinone B according to claim 1 or 2 or a pharmacologically acceptable salt thereof as an active ingredient. A neurite outgrowth extender comprising the physiologically active substance komodoquinone A or komodoquinone B according to claim 1 or 2 or a pharmacologically acceptable salt thereof as an active ingredient. A neuroprotective agent comprising the physiologically active substance komodoquinone A or komodoquinone B according to claim 1 or 2 or a pharmacologically acceptable salt thereof as an active ingredient. A microorganism belonging to the genus Streptomyces and having the ability to produce the bioactive substances komodoquinone A and / or komodoquinone B according to claim 1 or 2, is cultured in a nutrient medium, and the bioactive substances komodoquinone A and A method for producing the physiologically active substance komodoquinone A and / or komodoquinone B, characterized by producing and accumulating komodoquinone B and collecting it. Streptomyces sp. KS3 (National Institute of Advanced Industrial Science and Technology, Patent Biodeposition Center Deposit No. FERM P-19514) or a mutant thereof.