WO2016052656A1 - Nouveau composé, son procédé de production et utilisation associée - Google Patents

Nouveau composé, son procédé de production et utilisation associée Download PDF

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Publication number
WO2016052656A1
WO2016052656A1 PCT/JP2015/077822 JP2015077822W WO2016052656A1 WO 2016052656 A1 WO2016052656 A1 WO 2016052656A1 JP 2015077822 W JP2015077822 W JP 2015077822W WO 2016052656 A1 WO2016052656 A1 WO 2016052656A1
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structural formula
compound represented
rentztrehalose
compound
results
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PCT/JP2015/077822
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English (en)
Japanese (ja)
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和田　俊一
雅之 五十嵐
由美子 久保田
竜一 澤
俊一 大庭
和樹 波多野
まや 梅北
千草 林
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公益財団法人微生物化学研究会
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Priority to JP2016552140A priority Critical patent/JP6660301B2/ja
Publication of WO2016052656A1 publication Critical patent/WO2016052656A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria

Definitions

  • the present invention includes a novel compound, a method for producing the novel compound, a compound-containing composition and a sweetener containing the novel compound, an autophagy-inducing agent containing the novel compound and its analogs, and the novel compound. Relates to antioxidants.
  • Trehalose is a compound found in many animals and plants and microorganisms.
  • the trehalose works as a nutrient source, a moisturizer, or a cell wall component depending on the species. For example, it is known that insects are the main component of blood sugar, and mushrooms account for 1% to 17% of the dry weight.
  • the trehalose is decomposed by trehalase into glucose. The mammal itself does not have the trehalose but has the trehalase.
  • the trehalose is added to many foods, and is also used for cosmetics, a protective solution for organ transplantation, and the like.
  • the trehalose has been reported to have autophagy-inducing activity in experiments using a mouse Alzheimer's disease model or a mouse amyotrophic lateral sclerosis model (see, for example, Non-Patent Documents 1 and 2). .
  • the amount of trehalose administered in the above report is large, and there is a problem that there is a concern that it may lead to obesity and diabetes.
  • the present invention has been made in view of the above-described prior art, and an object thereof is to achieve the following object. That is, the present invention has an excellent autophagy-inducing activity, and an autophagy-inducing agent that is excellent in safety, a novel compound that can be used as at least one of the autophagy-inducing agent, sweetener, and antioxidant, It aims at providing the manufacturing method of the said novel compound, and a compound containing composition, sweetener, and antioxidant using the said novel compound.
  • ⁇ 1> A compound represented by the following structural formula (A) (hereinafter sometimes referred to as “rentztrehalose A”), a compound represented by the following structural formula (B) (hereinafter referred to as “rentztrehalose B”). And an autophagy-inducing agent comprising at least one of compounds represented by the following structural formula (C) (hereinafter sometimes referred to as “rentztrehalose C”).
  • ⁇ 3> A compound represented by the following structural formula (C).
  • a method for producing at least one of a compound represented by the following structural formula (B) and a compound represented by the following structural formula (C), A culture step of culturing a microorganism belonging to the genus Lentzea and having the ability to produce at least one of a compound represented by the following structural formula (B) and a compound represented by the following structural formula (C); And a collection step of collecting at least one of a compound represented by the following structural formula (B) and a compound represented by the following structural formula (C) from the culture obtained in the culturing step, This is a method for producing the compound.
  • a compound-containing composition comprising at least one of a compound represented by the following structural formula (B) and a compound represented by the following structural formula (C).
  • a sweetener comprising at least one of a compound represented by the following structural formula (B) and a compound represented by the following structural formula (C).
  • An antioxidant comprising a compound represented by the following structural formula (B).
  • At least one of the autophagy-inducing agent, the autophagy-inducing agent, the sweetener, and the antioxidant that can achieve the object has an excellent autophagy-inducing activity, and is excellent in safety. It is possible to provide a novel compound that can be used in any way, a method for producing the novel compound, and a compound-containing composition, a sweetener, and an antioxidant that utilize the novel compound.
  • FIG. 1A is an infrared spectrum chart of the compound represented by the structural formula (A) measured by the KBr tablet method.
  • Vertical axis transmittance (%), horizontal axis: wave number (cm ⁇ 1 ).
  • FIG. 1B is a chart of an ultraviolet absorption spectrum of the compound represented by the structural formula (A).
  • Vertical axis absorbance (Abs), horizontal axis: wavelength (nm).
  • FIG. 1C is a chart of a proton nuclear magnetic resonance spectrum at 600 MHz measured at 25 ° C. in deuterated methanol of the compound represented by the structural formula (A).
  • Horizontal axis ppm unit.
  • FIG. 1D is a chart of carbon-13 nuclear magnetic resonance spectrum at 150 MHz, measured at 25 ° C.
  • FIG. 2A is an infrared spectrum chart of the compound represented by the structural formula (B) measured by the KBr tablet method. Vertical axis: transmittance (%), horizontal axis: wave number (cm ⁇ 1 ).
  • FIG. 2B is a chart of an ultraviolet absorption spectrum of the compound represented by the structural formula (B). Vertical axis: absorbance (Abs), horizontal axis: wavelength (nm).
  • FIG. 2C is a chart of a proton nuclear magnetic resonance spectrum at 600 MHz measured at 25 ° C. in deuterated methanol of the compound represented by the structural formula (B). Horizontal axis: ppm unit.
  • FIG. 2A is an infrared spectrum chart of the compound represented by the structural formula (B) measured by the KBr tablet method. Vertical axis: transmittance (%), horizontal axis: wave number (cm ⁇ 1 ).
  • FIG. 2B is a chart of an ultraviolet absorption spectrum of the compound represented by the structural formula (B). Vertical
  • FIG. 2D is a chart of a carbon-13 nuclear magnetic resonance spectrum at 150 MHz, measured at 25 ° C. in deuterated methanol of the compound represented by the structural formula (B).
  • Horizontal axis ppm unit.
  • FIG. 3A is an infrared spectrum chart of the compound represented by the structural formula (C) measured by the KBr tablet method. Vertical axis: transmittance (%), horizontal axis: wave number (cm ⁇ 1 ).
  • FIG. 3B is a chart of an ultraviolet absorption spectrum of the compound represented by the structural formula (C). Vertical axis: absorbance (Abs), horizontal axis: wavelength (nm).
  • FIG. 3C is a chart of a proton nuclear magnetic resonance spectrum at 600 MHz measured at 25 ° C.
  • FIG. 4A is a diagram collectively showing the results of Trehalose, Rentztrehalose A, Rentztrehalose B, and Rentztrehalose C in Test Example 1.
  • FIG. 4B is a diagram showing the results of Rentstrehalose A in Test Example 1.
  • FIG. 4C is a diagram showing the results of Rentztrehalose B of Test Example 1.
  • FIG. 4D is a diagram showing the results of Rentstrehalose C of Test Example 1.
  • FIG. 5A is a diagram showing the results of Test Example 2-1.
  • FIG. 5B is a diagram showing the results of Test Example 2-2.
  • FIG. 5C is a diagram showing the results of Test Example 2-3.
  • FIG. 5D is a diagram showing the results of Test Example 2-4.
  • FIG. 5E is a diagram showing the results of Test Example 2-5.
  • FIG. 5F is a diagram showing the results of Test Example 2-6.
  • FIG. 6A is a diagram showing the results of treating human cultured melanoma strain Mewo of Test Example 3-1 with trehalose or lentztrehalose A.
  • FIG. 6B is a diagram showing the results of treating the human cultured melanoma strain Mewo of Test Example 3-1 with Rentstrehalose B or Rentstrehalose C.
  • FIG. 6C shows the results of treating human cultured ovarian cancer cell line OVK18 of Test Example 3-1 with trehalose or lentztrehalose A.
  • FIG. 6D is a diagram showing the results of treatment of human cultured ovarian cancer cell line OVK18 of Test Example 3-1 with Rentztrehalose B or Rentztrehalose C.
  • FIG. 6E is a diagram showing the results of Test Example 3-2.
  • FIG. 7A is a diagram showing the results of trehalose in Test Example 4-1.
  • FIG. 7B is a diagram showing the results of Rentztrehalose B of Test Example 4-1.
  • FIG. 7C is a diagram showing a result of Trolox in Test Example 4-1.
  • FIG. 7D is a diagram showing a result of dissolving Rentztrehalose B of Test Example 4-2 in water.
  • FIG. 7E is a diagram showing the results when Rentztrehalose B of Test Example 4-2 was dissolved in H 2 O 2 water.
  • UV absorption spectrum The ultraviolet absorption in the aqueous solution is end absorption as shown in FIG. 2B ( ⁇ value at 200 nm is 7155 in water).
  • Proton nuclear magnetic resonance spectrum The results measured at 25 ° C. in heavy methanol at 600 MHz are as shown in FIG. (9)
  • Carbon-13 nuclear magnetic resonance spectrum The results measured at 25 ° C. in deuterated methanol at 150 MHz are as shown in FIG.
  • UV absorption spectrum The ultraviolet absorption in the aqueous solution is end absorption as shown in FIG. 3B ( ⁇ value at 200 nm is 68 in water).
  • Proton nuclear magnetic resonance spectrum The results measured at 25 ° C. in heavy methanol at 600 MHz are as shown in FIG. 3C and Table 2.
  • Carbon-13 nuclear magnetic resonance spectrum The results measured at 25 ° C. in deuterated methanol at 150 MHz are as shown in FIG. 3D and Table 2.
  • the compound has the structure represented by the structural formula (B) or the structure represented by the structural formula (C) can be confirmed by various analysis methods selected as appropriate. Examples thereof include analysis methods such as mass spectrometry, infrared spectroscopy, ultraviolet spectroscopy, proton nuclear magnetic resonance spectroscopy, and carbon-13 nuclear magnetic resonance spectroscopy. In addition, some errors may occur in the measurement values obtained by the respective analysis methods. However, those skilled in the art will recognize that the compound is represented by the structure represented by the structural formula (B) or the structural formula (C). Having the structure represented can be easily identified.
  • the compound represented by the structural formula (B) is usually a hydrate.
  • the compound represented by the structural formula (C) is usually a hydrate.
  • the compound represented by the structural formula (B) and the compound represented by the structural formula (C) are the compound represented by the structural formula (B) and the compound represented by the structural formula (C). Although it may be obtained from a microorganism that produces at least one of the above or may be obtained by chemical synthesis, it is preferably obtained by the method for producing the compound of the present invention described later.
  • the compound represented by the structural formula (B) is a highly safe compound having excellent autophagy-inducing activity and excellent antioxidant activity, as shown in Test Examples described later. It can also be used as a sweetener component. Therefore, the compound represented by the structural formula (B) can be suitably used as an active ingredient such as a compound-containing composition, an autophagy-inducing agent, an antioxidant, and a sweetener of the present invention described later. . Moreover, since the compound represented by the structural formula (B) has autophagy-inducing activity and antioxidant activity, it is more expected as an active ingredient of a preventive or therapeutic agent for amyotrophic lateral sclerosis.
  • the compound represented by the structural formula (C) is a highly safe compound having excellent autophagy-inducing activity as shown in the test examples described later. It can also be used as a sweetener component. Therefore, the compound represented by the structural formula (C) can be suitably used as an active ingredient such as a compound-containing composition, an autophagy-inducing agent, and a sweetener of the present invention described later.
  • the production method of at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C) of the present invention includes at least a culture step and a collection step, and if necessary And other steps.
  • the culturing step cultivates a microorganism belonging to the genus Lentzea and having the ability to produce at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C). It is a process to do.
  • microorganism As the microorganism, as long as it belongs to the genus Lentzea and has the ability to produce at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C), There is no limitation, and it can be appropriately selected according to the purpose. However, the Lentzea sp. ML457-mF8 strain (NITE BP-01586) isolated by the present inventors is preferable. In addition, other strains capable of producing at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C) can be isolated from the natural world by a conventional method. It is.
  • a bacterium producing at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C), including the Lentzea sp. ML457-mF8 strain By subjecting to irradiation or other mutation treatment, it is also possible to increase the productivity of at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C). . Furthermore, it is possible to produce at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C) by a genetic engineering technique.
  • Examples of a method for analyzing that the microorganism has the ability to produce at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C) include, for example, A method for analyzing autophagy-inducing activity or antioxidant activity of components in a culture, preferably a culture supernatant after liquid culture or a solid medium after solid culture, and the structural formula (B) And a method for detecting at least one of the compound represented by the structural formula (C).
  • Lentzea sp. ML457-mF8 strain The Lentzea sp. ML457-mF8 strain is an actinomycete isolated from soil in Sado City, Niigata Prefecture at the Microbial Chemistry Research Institute of the Microbial Chemistry Society of Japan. It is as follows.
  • Morphology ML457-mF8 strain extends straight or curved aerial hyphae from the branched basic hyphae.
  • a mature spore chain links 10-20 columnar spores.
  • the spore size is about 0.4 to 0.5 ⁇ 1.1 to 1.5 microns, and the spore surface is smooth.
  • Physiological properties (1) Growth temperature range Using yeast starch agar medium (soluble starch 1%, yeast extract 0.2%, string agar 2.6%, pH 7.0), 10 ° C, 20 ° C, 27 ° C, As a result of testing at each temperature of 30 ° C., 37 ° C., 42 ° C., and 50 ° C., no growth was observed at 10 ° C. and 50 ° C., and it grew in the range of 20 ° C. to 42 ° C. The optimum temperature for growth is around 30 ° C.
  • Cellular component 2,6-Diaminopimelic acid in the cell wall is meso -type.
  • the ML457-mF8 strain extends straight and curved aerial hyphae from the branched basic hyphae. Its tip is linked to columnar spores. In various media, white to gray white aerial hyphae are grown on the development of light yellow to light blue. The optimum temperature for growth is around 30 ° C. 2,6-Diaminopimelic acid in the cell wall of the ML457-mF8 strain is meso -type. When the partial base sequence of 16S rRNA gene of ML457-mF8 strain was analyzed and compared with the data of known strains, it showed high homology with Streptomyces spp.
  • the ML457-mF8 strain is considered to belong to the genus Lentzea . Accordingly, the ML457-mF8 strain is designated as Lentzea sp. ML457-mF8.
  • the ML457-mF8 strain was applied for deposit at the Patent Microorganism Deposit Center of the National Institute of Technology and Evaluation on April 9, 2013 and was consigned domestically as NITE P-01586 on April 9, 2013. Later, on August 13, 2015, a request for transfer to an international deposit based on the Budapest Treaty was received and deposited internationally under the deposit number NITE BP-01586.
  • the culture may be referred to as a production bacterium that produces at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C) (hereinafter simply referred to as “compound-producing bacterium”). And a compound represented by the structural formula (B) and / or a compound represented by the structural formula (C).
  • the production is carried out by culturing at a good temperature.
  • the nutrient source added to the nutrient medium is not particularly limited and can be appropriately selected according to the purpose.
  • inorganic salts such as sodium chloride and calcium carbonate can be added to the medium for use, and in addition, a trace amount of metal salt can be added to the medium for use.
  • These materials may be used as long as they are useful for the production of at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C) by the compound-producing bacteria. Any known culture material can be used.
  • the pre-culture solution for production of at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C) is not particularly limited and is appropriately selected depending on the purpose.
  • a growth product obtained by culturing the above-mentioned compound-producing microorganism on a medium such as a liquid medium, a plate medium, a slant medium, a half slant medium, or the like can be used.
  • the culture method is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include shaking culture, static culture, and tank culture.
  • the culture temperature is at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C) without substantially inhibiting the growth of the compound-producing bacteria. As long as it can be produced, it is not particularly limited and can be appropriately selected according to the producing bacteria to be used, but is preferably 25 ° C to 35 ° C.
  • the culture pH is at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C) without substantially inhibiting the growth of the compound-producing bacteria.
  • the culture period is not particularly limited and may be appropriately selected according to the accumulation of at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C). it can.
  • the collecting step is a step of collecting at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C) from the culture obtained in the culturing step. Since at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C) has the physicochemical properties described above, it may be collected from the culture according to the properties. it can.
  • the culture is not particularly limited as long as it contains at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C) obtained in the culturing step.
  • it can be appropriately selected according to the purpose, and examples include cells, culture supernatant after liquid culture, solid medium after solid culture, and mixtures thereof.
  • the compound represented by the structural formula (B) and the structure can be obtained by an extraction method using an appropriate organic solvent or an elution method by disrupting the cells.
  • At least one of the compounds represented by the formula (C) may be extracted from the cells and subjected to separation and / or purification.
  • the collection method is not particularly limited, and a method used for collecting a metabolite produced by a microorganism can be appropriately selected.
  • a solvent extraction method a method using a difference in adsorption affinity for various adsorbents, a chromatographic method, and the like can be mentioned.
  • the solvent used in the solvent extraction method is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include ethanol, methanol, acetone, butanol, and acetonitrile.
  • the adsorbent is not particularly limited and can be appropriately selected from known adsorbents according to the purpose. Examples thereof include polystyrene-based adsorbent resins.
  • the chromatographic method is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include a thin layer chromatographic method, a high-performance liquid chromatograph for fractionation using a normal phase or reverse phase column (preparation). HPLC) method and the like. There is no restriction
  • the method for eluting at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C) from the adsorbent or the carrier in the chromatographic method there is no particular limitation on the method for eluting at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C) from the adsorbent or the carrier in the chromatographic method.
  • the adsorbent and the carrier can be selected as appropriate according to the type and properties of the carrier.
  • a method of elution using water-containing alcohol, water-containing acetone or the like as an elution solvent can be mentioned.
  • the compound-containing composition of the present invention contains at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C), and, if necessary, further other components. including.
  • the content of at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C) in the compound-containing composition is not particularly limited and is appropriately determined depending on the purpose. You can choose.
  • the compound-containing composition may be at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C).
  • pharmacologically acceptable carrier a compound represented by the following structural formula (A) Etc. These may be used individually by 1 type and may use 2 or more types together. Specific examples of the pharmacologically acceptable carrier include additives, adjuvants, and water.
  • the additive or the adjuvant is not particularly limited and may be appropriately selected depending on the intended purpose.
  • examples thereof include bactericides, preservatives, binders, thickeners, fixing agents, binders, and coloring agents. , Stabilizers, pH adjusters, buffers, isotonic agents, solvents, antioxidants, UV inhibitors, crystal precipitation inhibitors, antifoaming agents, physical property improvers, preservatives, and the like.
  • the bactericidal agent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include cationic surfactants such as benzalkonium chloride, benzethonium chloride and cetylpyridinium chloride.
  • the preservative is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include p-hydroxybenzoates, chlorobutanol, and cresol.
  • the binder, the thickener, or the sticking agent is not particularly limited and may be appropriately selected depending on the intended purpose.
  • the binder is not particularly limited and may be appropriately selected depending on the intended purpose.
  • examples include propyl starch, methyl cellulose, ethyl cellulose, shellac, calcium phosphate, and polyvinyl pyrrolidone.
  • the colorant is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include titanium oxide and iron oxide.
  • the stabilizer is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include tragacanth, gum arabic, gelatin, sodium pyrosulfite, ethylenediaminetetraacetic acid (EDTA), thioglycolic acid, and thiolactic acid. Is mentioned.
  • the pH adjusting agent or the buffering agent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include sodium citrate, sodium acetate, and sodium phosphate.
  • the isotonic agent is not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include sodium chloride and glucose.
  • the compound-containing composition contains at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C), the compound-containing composition has excellent autophagy-inducing activity and excellent anti-resistance. It has at least one of oxidative activity, has sweetness, and is highly safe.
  • it can be suitably used as a pharmaceutical composition, autophagy-inducing agent, antioxidant, food, food additive, etc. It is.
  • the compound-containing composition may be used alone, or may be used in combination with a medicine containing other ingredients as active ingredients. Moreover, the said compound containing composition may be used in the state mix
  • the autophagy-inducing agent of the present invention comprises at least one of a compound represented by the following structural formula (A), a compound represented by the structural formula (B), and a compound represented by the structural formula (C). It contains at least, and other ingredients as necessary.
  • UV absorption spectrum Ultraviolet absorption in the aqueous solution is hardly seen as shown in FIG. 1B ( ⁇ value at 200 nm is 202 in water and 192 in 0.005M HCl).
  • Proton nuclear magnetic resonance spectrum The results measured at 25 ° C. in heavy methanol at 600 MHz are as shown in FIG. 1C and Table 3.
  • Carbon-13 nuclear magnetic resonance spectrum The results measured at 25 ° C. in deuterated methanol at 150 MHz are as shown in FIG. 1D and Table 3.
  • the compound has the structure represented by the structural formula (A) can be confirmed by various analysis methods selected as appropriate.
  • the mass spectrometry, the infrared spectroscopy, the ultraviolet Analysis methods such as spectroscopy, proton nuclear magnetic resonance spectroscopy, and carbon-13 nuclear magnetic resonance spectroscopy can be used.
  • some errors may occur in the measurement values obtained by the respective analytical methods, but those skilled in the art can easily identify that the compound has the structure represented by the structural formula (A). Is possible.
  • the compound represented by the structural formula (A) is usually a hydrate.
  • the compound represented by the structural formula (A) may be obtained from a microorganism that produces the compound represented by the structural formula (A), or may be obtained by chemical synthesis. Also good.
  • the compound represented by the structural formula (A) is a highly safe compound having excellent autophagy-inducing activity, as shown in Test Examples described later. It can also be used as a sweetener component.
  • the compound represented by the said structural formula (B), and the said structure It can be produced in the same manner as in the production method of at least one of the compounds represented by formula (C). That is, in the production method of at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C), a culturing step, a collecting step, and other steps as necessary. And can be manufactured in the same manner.
  • the compound represented by the structural formula (A), the compound represented by the structural formula (B), and the compound represented by the structural formula (C) may be used alone or in combination. More than one species may be used in combination.
  • the autophagy-inducing agent is at least one of the compound represented by the structural formula (A), the compound represented by the structural formula (B), and the compound represented by the structural formula (C). It may be.
  • the other components in the autophagy-inducing agent are not particularly limited and may be appropriately selected depending on the purpose.
  • the same components as those described in the item of other components of the compound-containing composition may be used. Can be mentioned. These may be used individually by 1 type and may use 2 or more types together.
  • the content of other components in the autophagy inducer is not particularly limited as long as the effects of the present invention are not impaired, and can be appropriately selected according to the purpose.
  • the autophagy-inducing agent includes at least one of the compound represented by the structural formula (A), the compound represented by the structural formula (B), and the compound represented by the structural formula (C). It has excellent autophagy-inducing activity, is highly safe, and is used for research reagents for autophagy and neurodegenerative diseases such as Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, prion disease, and Huntington's disease. It can be suitably used as an active ingredient of a preventive or therapeutic agent. Rapamycin and the like have been known as compounds having autophagy-inducing activity so far, but they are highly toxic and problematic in terms of safety.
  • the autophagy-inducing agent may be used alone, or may be used in combination with a medicine containing other ingredients as active ingredients. Moreover, the said autophagy inducer may be used in the state mix
  • ⁇ Dosage form> There is no restriction
  • the autophagy inducers of these dosage forms can be produced according to a conventional method.
  • the solid preparation is not particularly limited and may be appropriately selected depending on the intended purpose.
  • a suppository, a poultice, a plaster agent etc. are mentioned, for example.
  • liquid agent a syrup agent, a drink agent, a suspension agent, an alcoholic agent etc. are mentioned, for example.
  • a liquid agent, eye drops, an aerosol agent, a spray agent etc. are mentioned, for example.
  • administering There is no restriction
  • the administration method include parenteral administration methods such as local administration methods and enteral administration methods, and oral administration methods.
  • the dose is not particularly limited, and is appropriately selected in consideration of various factors such as the age, weight, constitution, symptom, and presence / absence of administration of a drug or drug containing other ingredients as active ingredients. be able to.
  • the animal species to be administered is not particularly limited and can be appropriately selected according to the purpose. For example, human, monkey, pig, cow, sheep, goat, dog, cat, mouse, rat, bird, etc. Among them, among these, it can be suitably used for humans.
  • the antioxidant of this invention contains the compound represented by the said structural formula (B) at least, and also contains another component as needed.
  • the compound represented by the structural formula (B) is a novel compound, as described in the item of the novel compound. Moreover, the compound represented by the said structural formula (B) can be suitably manufactured by the method described in the item of the manufacturing method of the said compound.
  • the content of the compound represented by the structural formula (B) in the antioxidant is not particularly limited and may be appropriately selected depending on the purpose. Further, the antioxidant may be the compound itself represented by the structural formula (B).
  • the other components in the antioxidant are not particularly limited and may be appropriately selected depending on the purpose.
  • the same components as those described in the item of other components of the compound-containing composition may be mentioned. It is done. These may be used individually by 1 type and may use 2 or more types together.
  • the content of other components in the antioxidant is not particularly limited as long as the effects of the present invention are not impaired, and can be appropriately selected according to the purpose.
  • the antioxidant contains the compound represented by the structural formula (B), it has excellent antioxidant activity, high safety, a research reagent for antioxidants, and amyotrophic lateral sclerosis. It can be suitably used as an active ingredient of a prophylactic or therapeutic drug for diseases.
  • the said antioxidant may be used independently and may be used in combination with the pharmaceutical which uses another component as an active ingredient. Moreover, the said antioxidant may be used in the state mix
  • the administration method, dosage, administration timing, and administration target of the antioxidant are not particularly limited and can be appropriately selected according to the purpose, as described in the item of administration of the autophagy inducer. The same can be said.
  • sweetener contains at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C), and further contains other components as necessary. .
  • the content of at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C) in the sweetener is not particularly limited and may be appropriately selected depending on the purpose. be able to.
  • the sweetener may be at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C).
  • sweetener ingredients are not particularly limited and may be appropriately selected depending on the intended purpose. Examples thereof include the same components as those described in the item of other components of the compound-containing composition. . These may be used individually by 1 type and may use 2 or more types together.
  • the content of other components in the sweetener is not particularly limited as long as the effects of the present invention are not impaired, and can be appropriately selected according to the purpose.
  • the sweetener contains at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C), the sweetener has excellent sweetness and high safety, for example, It can be suitably used as an additive for diet foods.
  • the sweetener may be used alone or in combination with a sweetener containing other ingredients as active ingredients. Moreover, the said sweetener may be used in the state mix
  • -Sampling process 320 mL of methanol was added to the culture, mixed well, and then filtered through a paper filter to recover the liquid. 320 mL of methanol was added to the residue, and the liquid was recovered in the same manner, mixed with the first liquid, and dried to dryness using an evaporator.
  • the dried sample was dissolved in 1 L of water, 1 L of ethyl acetate was added thereto and mixed well, and then two-layer distribution was performed, and the aqueous layer was collected and dried with an evaporator.
  • the fraction containing the Rentztrehalose A, Rentztrehalose B, and Rentztrehalose C is separated by HPLC using a hydrosphere C18 column HS12S05-2520WT (manufactured by YMC Co., Ltd.) using a gradient solvent system from water to methanol. Then, a fraction containing Rentztrehalose A, a fraction containing Rentztrehalose B, and a fraction containing Rentztrehalose C were obtained.
  • the fraction containing Lenztrehalose A, the fraction containing Lenztrehalose B, and the fraction containing Rentztrehalose C are each dried and then dissolved in a small amount of water, and 9 times the amount of acetonitrile is added to the emulsion.
  • a Polyamine II column PB12S05-2510WT manufactured by YMC Co., Ltd.
  • the fraction was separated by HPLC using a gradient solvent system from 90% by volume acetonitrile to 50% by volume acetonitrile, and the fraction containing lentztrehalose A, lentztrehalose A A fraction containing B and a fraction containing Rentztrehalose C were obtained.
  • the fraction containing Lenztrehalose A, the fraction containing Lenztrehalose B, and the fraction containing Lenztrehalose C are each applied to a Sephadex LH-20 (manufactured by GE Healthcare Japan) column using methanol as a solvent. Objects were removed and dried with an evaporator.
  • the dried fraction containing Rentstrehalose A, the fraction containing Rentstrehalose B, and the fraction containing Rentstrehalose C are each passed through an activated carbon (made by Wako Pure Chemical Industries, Ltd.) column using water as a solvent.
  • the fraction passed through and the water-washed fraction were collected and lyophilized to obtain purified lentztrehalose A, lentztrehalose B, and lentztrehalose C.
  • the physicochemical properties of the obtained Rentztrehalose A are as follows, and from these, it was confirmed that the Rentztrehalose A is a compound having a structure represented by the following structural formula (A). It was. (1) Appearance: White bowl (2) Molecular formula: C 17 H 32 O 13 Incidentally, it is the dihydrate in a normal state, the elemental analysis, expressed as C 17 H 32 O 13 ⁇ 2H 2 O.
  • the physicochemical properties of the obtained Rentztrehalose B are as follows, and from these, it was confirmed that the Rentztrehalose B is a compound having a structure represented by the following structural formula (B). It was. (1) Appearance: White solid (2) Molecular formula: C 17 H 30 O 11 In addition, it becomes a monohydrate in a normal state, and is represented as C 17 H 30 O 11 ⁇ H 2 O in elemental analysis.
  • UV absorption spectrum The ultraviolet absorption in the aqueous solution was end absorption as shown in FIG. 2B ( ⁇ value at 200 nm was 7155 in water).
  • Proton nuclear magnetic resonance spectrum The results of measurement at 25 ° C. in deuterated methanol at 600 MHz were as shown in FIG. 2C and Table 5.
  • Carbon-13 nuclear magnetic resonance spectrum The result of measurement at 25 ° C. in deuterated methanol at 150 MHz was as shown in FIG. 2D and Table 5.
  • the physicochemical properties of the obtained Rentztrehalose C are as follows. From these, it was confirmed that the Rentztrehalose C is a compound having a structure represented by the following structural formula (C). It was. (1) Appearance: White solid (2) Molecular formula: C 17 H 30 O 12 In addition, it becomes a monohydrate in a normal state, and is represented as C 17 H 30 O 12 ⁇ H 2 O in elemental analysis.
  • UV absorption spectrum The ultraviolet absorption in the aqueous solution was end absorption as shown in FIG. 3B ( ⁇ value at 200 nm was 68 in water).
  • Proton nuclear magnetic resonance spectrum The results measured at 25 ° C. in deuterated methanol at 600 MHz are as shown in FIG. 3C and Table 6.
  • Carbon-13 nuclear magnetic resonance spectrum The result of measurement at 25 ° C. in deuterated methanol at 150 MHz was as shown in FIG. 3D and Table 6.
  • Trehalose hereinafter sometimes referred to as “TRH”
  • RVB Rentztrehalose A
  • LTA Rentztrehalose B
  • LTC Rentztrehalose C
  • porcine kidney trehalase Sigma-Aldrich Co. LLC, T8778
  • 135 mM citrate buffer pH 5.7
  • Reacted for 20 minutes 4 times the amount of porcine kidney trehalase (Sigma-Aldrich Co. LLC, T8778) dissolved in 135 mM citrate buffer (pH 5.7) at 0.24 unit / mL was added at 37 ° C. Reacted for 20 minutes.
  • glucose assay reagent Sigma-Aldrich Co. LLC, G3293
  • FIG. 4A is a diagram summarizing the results of trehalose, lentez trehalose A, lentez trehalose B, and lentez trehalose C.
  • FIGS. 4B to 4D show the results of lentez trehalose A, lentz trehalose B, and lentz trehalose C, respectively. It is the figure which showed the result. 4A to 4D, “ ⁇ ” represents the result of trehalose, “ ⁇ ” represents the result of Rentztrehalose A, “ ⁇ ” represents the result of Rentztrehalose B, and “ ⁇ ” represents the result of Rentztrehalose C. Indicates.
  • trehalose was degraded by trehalase and released the degradation product glucose depending on the amount of substrate.
  • Rentstrehalose A, Rentstrehalose B, and Rentstrehalose C were hardly decomposed by trehalase. Therefore, it was suggested that Rentstrehalose A, Rentstrehalose B, and Rentstrehalose C may exhibit biological activities similar to trehalose at lower concentrations than trehalose in mammals (eg, humans). .
  • Test Example 2 Acute toxicity test
  • Test Example 2-1 Intravenous injection of Rentztrehalose A> 4-week-old female ICR mice were intravenously injected with various concentrations of lenteztrehalose A dissolved in physiological saline, and then changes in body weight were observed for 2 weeks. The results are shown in FIG. 5A.
  • ⁇ Test Example 2-2 Oral administration of Rentztrehalose A> 4-week-old female ICR mice were orally administered with various concentrations of lenteztrehalose A dissolved in physiological saline, and thereafter, changes in body weight were observed for 2 weeks. The results are shown in FIG. 5B.
  • Example 2-3 Intravenous injection of Rentztrehalose B> 4-week-old female ICR mice were intravenously injected with various concentrations of lenteztrehalose B dissolved in physiological saline, and then changes in body weight were observed for 2 weeks. The results are shown in FIG. 5C.
  • Example 2-4 Oral administration of Rentztrehalose B> 4-week-old female ICR mice were orally administered with various concentrations of lenteztrehalose B dissolved in physiological saline, and thereafter, changes in body weight were observed for 2 weeks. The results are shown in FIG. 5D.
  • ⁇ Test Example 2-6 Oral administration of Rentztrehalose C> 4-week-old female ICR mice were orally administered with various concentrations of lenteztrehalose C dissolved in physiological saline, and thereafter, changes in body weight were observed for 2 weeks. The results are shown in FIG. 5F.
  • Test Example 3 Autophagy induction activity test
  • lenztrehalose A The autophagy-inducing activity of trehalose, lenztrehalose A, lenztrehalose B, and lenztrehalose C was tested as follows.
  • Human cultured melanoma strain Mewo obtained from JCRB Bioresource Bank, Incorporated Administrative Agency
  • human cultured ovarian cancer cell line OVK18 obtained from RIKEN Bioresource Center
  • DMEM Dulbecco's Modified Eagle with FBS It was suspended in Medium (DMEM, manufactured by Nissui Pharmaceutical Co., Ltd.) and seeded in a 96-well plate at 1.6 ⁇ 10 4 cells / 200 ⁇ L per well. After culturing at 37 ° C.
  • the amount of protein in the cell lysate in which the cells were lysed was measured by the BCA method, and 5 ⁇ g was applied to SDS-PAGE (12.5% precast gel, manufactured by Apro Science Co., Ltd.).
  • the electrophoretic product was transferred to a PVDF membrane (Merck KGaA) with a blotter (manufactured by Biocraft Co., Ltd.) at 12 V for 40 minutes.
  • the PVDF membrane was subjected to blocking treatment with 3% skim milk (manufactured by Snow Brand Megmilk Co., Ltd.) and Tris buffer solution (0.05% Tween-TBS, manufactured by Takara Bio Inc.) containing 0.05% Tween 20.
  • FIG. 6A shows the results of treating human cultured melanoma strain Mewo with trehalose (TRH) or lentez trehalose A (LTA), and FIG. 6B shows human cultured melanoma strain Mewo with lentez trehalose B (LTB) or lentz.
  • FIG. 6C shows the results of treatment with trehalose C (LTC).
  • FIG. 6C shows the results of treatment of human cultured ovarian cancer cell line OVK18 with trehalose (TRH) or Rentztrehalose A (LTA).
  • FIG. The result of having treated cultured ovarian cancer cell line OVK18 with Rentztrehalose B (LTB) or Rentztrehalose C (LTC) is shown.
  • 0 at the left end indicates the result when the treatment was not performed with trehalose, lentez trehalose A, lentez trehalose B, or lentez trehalose C (control). From the results shown in FIGS. 6A to 6D, Rentztrehalose A, Rentztrehalose B, and Rentztrehalose C all induce autophagy in each cancer cell line at about 100 mM, like trehalose. The expression level of a certain LC3 was increased.
  • DMEM manufactured by Nissui Pharmaceutical Co., Ltd.
  • “Mewo” represents a human cultured melanoma strain Mewo
  • “OVK18” represents a human cultured ovarian cancer cell line OVK18
  • “PC” represents a phase contrast image
  • “Cyto-ID” represents Cyto-ID.
  • An image in which a Green detection reagent is detected is represented.
  • “TRH” represents trehalose
  • “LTA” represents Rentztrehalose A
  • “LTB” represents Rentztrehalose B
  • “LTC” represents Rentztrehalose C.
  • Cyto-ID registered trademark
  • trehalose is rapidly degraded in the animal body to become glucose, so it is considered that the effect is immediately lost.
  • Rentstrehalose A, Rentstrehalose B, and Rentstrehalose C have the same autophagy-inducing activity as trehalose, they are considered to be more stable in the body because they are not degraded by trehalose. The effect at a lower concentration can be expected.
  • Rentstrehalose A, Rentstrehalose B, and Rentstrehalose C do not raise blood glucose levels and circulate in a non-reducing state, and are thus unlikely to cause obesity and vascular disorders.
  • Test Example 4 Antioxidant activity test
  • ORAC OxiSelect TM Oxygen Radical Antioxidant Capacity
  • Trolox which is a water-soluble vitamin E analog
  • the OxiSelect TM Oxygen Radical Antioxidant Capacity (ORAC) Activity Assay is a system in which degradation of a fluorescent substance by active oxygen is continuously observed in the presence of a target substance, and the antioxidant action of the substance is examined.
  • FIG. 7A The result of trehalose is shown in FIG. 7A
  • the result of Lenztrehalose B is shown in FIG. 7B
  • the result of Trolox is shown in FIG. 7C.
  • “ ⁇ ” indicates the result in the case of only water
  • “ ⁇ ” indicates the result in the case where the concentration of trehalose, Rentztrehalose B, or Trolox is 100 ⁇ M
  • “ ⁇ ” indicates trehalose
  • the results when the concentration of Rentstrehalose B or Trolox is 50 ⁇ M are shown
  • “ ⁇ ” shows the results when the concentration of Trehalose, Rentstrehalose B or Trolox is 25 ⁇ M. From the results of FIGS.
  • Lenztrehalose B showed an antioxidant effect (ORAC value 207.3 ( ⁇ mole TE / g)).
  • trehalose did not exhibit an antioxidant effect, but rather promoted decomposition of the fluorescent substance by active oxygen.
  • FIG. 7D shows the results obtained when Lenztrehalose B was dissolved in water
  • FIG. 7E shows the results obtained when Lenztrehalose B was dissolved in H 2 O 2 water.
  • Rentztrehalose B was stable in water at room temperature even after 6 days, and [M + Na] (433.18) and its Na salt peak (455.17) were detected.
  • In 15% H 2 O 2 water one having one O bonded (449.18), one having H 2 O 2 bonded (467.19), and one having another O bonded (483). .20) was detected.
  • Lenztrehalose B is likely to trap active oxygen, which is considered to be the main cause of antioxidant action.
  • the order of the samples was adjusted to be different for each evaluator. Give 0 points for water and 10 points for the sweetest sample and give a relative score for the other samples, or 0 points for water, 10 points for the first sample, and relative points for the other samples. Scored. The evaluation of each evaluator was converted so that sucrose would be 10 points. The average value of the converted points was calculated and used as an arbitrary sweetness level. The results are shown in Table 13.
  • Examples of the aspect of the present invention include the following. ⁇ 1> It includes at least one of a compound represented by the following structural formula (A), a compound represented by the following structural formula (B), and a compound represented by the following structural formula (C). Autophagy inducer. ⁇ 2> A compound represented by the following structural formula (B). ⁇ 3> A compound represented by the following structural formula (C).
  • a method for producing at least one of a compound represented by the following structural formula (B) and a compound represented by the following structural formula (C), A culture step of culturing a microorganism belonging to the genus Lentzea and having the ability to produce at least one of a compound represented by the following structural formula (B) and a compound represented by the following structural formula (C); And a collection step of collecting at least one of a compound represented by the following structural formula (B) and a compound represented by the following structural formula (C) from the culture obtained in the culturing step, This is a method for producing the compound.
  • a microorganism belonging to the genus Lentzea and having the ability to produce at least one of the compound represented by the structural formula (B) and the compound represented by the structural formula (C) is an accession number NITE BP.
  • a compound-containing composition comprising at least one of a compound represented by the following structural formula (B) and a compound represented by the following structural formula (C).
  • a sweetener comprising at least one of a compound represented by the following structural formula (B) and a compound represented by the following structural formula (C).
  • An antioxidant comprising a compound represented by the following structural formula (B).

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Abstract

L'invention concerne un agent induisant l'autophagie qui comprend au moins un élément choisi parmi un composé représenté par la formule structurale (A), un composé représenté par la formule structurale (B), et un composé représenté par la formule structurale (C).
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Publication number Priority date Publication date Assignee Title
WO2023032788A1 (fr) * 2021-09-06 2023-03-09 公益財団法人微生物化学研究会 Nouveau composé, son utilisation, son procédé de production, composition contenant le composé, procédé de production de la 4-tréhalosamine, et micro-organisme

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