PL244523B1 - Method for preparing 4'-hydroxyflavanone - Google Patents
Method for preparing 4'-hydroxyflavanone Download PDFInfo
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- PL244523B1 PL244523B1 PL439091A PL43909121A PL244523B1 PL 244523 B1 PL244523 B1 PL 244523B1 PL 439091 A PL439091 A PL 439091A PL 43909121 A PL43909121 A PL 43909121A PL 244523 B1 PL244523 B1 PL 244523B1
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- ZLHVIYHWWQYJID-UHFFFAOYSA-N 4'-hydroxyflavanone Chemical compound C1=CC(O)=CC=C1C1OC2=CC=CC=C2C(=O)C1 ZLHVIYHWWQYJID-UHFFFAOYSA-N 0.000 title claims abstract description 11
- 238000000034 method Methods 0.000 title claims description 11
- 239000003960 organic solvent Substances 0.000 claims abstract description 7
- 239000000758 substrate Substances 0.000 claims abstract description 7
- 230000009466 transformation Effects 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 7
- 241000188153 Isaria fumosorosea Species 0.000 claims abstract description 6
- HITISLKGAFZTFZ-UHFFFAOYSA-N 2-(4-methylphenyl)-2,3-dihydrochromen-4-one Chemical compound C1=CC(C)=CC=C1C1OC2=CC=CC=C2C(=O)C1 HITISLKGAFZTFZ-UHFFFAOYSA-N 0.000 claims abstract description 4
- 238000004587 chromatography analysis Methods 0.000 claims abstract description 4
- 241000233866 Fungi Species 0.000 claims abstract description 3
- 238000004519 manufacturing process Methods 0.000 claims abstract description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- 238000012746 preparative thin layer chromatography Methods 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 4
- 244000222996 Syzygium nervosum Species 0.000 description 3
- 150000002215 flavonoids Chemical class 0.000 description 3
- DBAAXPIMQWCLHT-KRWDZBQOSA-N (2s)-5,7-dihydroxy-2-(4-hydroxyphenyl)-8-methyl-6-(3-methylbut-2-enyl)-2,3-dihydrochromen-4-one Chemical compound C1([C@H]2OC3=C(C)C(O)=C(C(=C3C(=O)C2)O)CC=C(C)C)=CC=C(O)C=C1 DBAAXPIMQWCLHT-KRWDZBQOSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 241000827135 Eysenhardtia polystachya Species 0.000 description 2
- 102000005348 Neuraminidase Human genes 0.000 description 2
- 108010006232 Neuraminidase Proteins 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000000843 anti-fungal effect Effects 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 230000036983 biotransformation Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- 229930003935 flavonoid Natural products 0.000 description 2
- 235000017173 flavonoids Nutrition 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 244000005700 microbiome Species 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- SEHDRAXGPBPQKE-AWEZNQCLSA-N pisonivanone Chemical compound C1([C@@H]2CC(=O)C=3C(O)=CC(O)=C(C=3O2)C)=CC=CC=C1O SEHDRAXGPBPQKE-AWEZNQCLSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- MWEMUFLDDBSWRI-KRWDZBQOSA-N (2s)-5,7-dihydroxy-2-(4-hydroxyphenyl)-6-methyl-8-(3-methylbut-2-enyl)-2,3-dihydrochromen-4-one Chemical compound C1([C@@H]2CC(=O)C=3C(O)=C(C)C(O)=C(C=3O2)CC=C(C)C)=CC=C(O)C=C1 MWEMUFLDDBSWRI-KRWDZBQOSA-N 0.000 description 1
- HTDSMOBGCNRBHQ-RMKNXTFCSA-N (E)-4,2',4'-trihydroxy-6'-methoxy-3',5'-dimethylchalcone Chemical compound COC1=C(C)C(O)=C(C)C(O)=C1C(=O)\C=C\C1=CC=C(O)C=C1 HTDSMOBGCNRBHQ-RMKNXTFCSA-N 0.000 description 1
- HTDSMOBGCNRBHQ-UHFFFAOYSA-N (E)-4,2',4'-trihydroxy-6'-methoxy-3',5'-dimethylchalcone Natural products COC1=C(C)C(O)=C(C)C(O)=C1C(=O)C=CC1=CC=C(O)C=C1 HTDSMOBGCNRBHQ-UHFFFAOYSA-N 0.000 description 1
- JUZVHLGKYJTCKP-CMDGGOBGSA-N 2',4'-dihydroxy-3'-methyl-6'-methoxychalcone Chemical compound COC1=CC(O)=C(C)C(O)=C1C(=O)\C=C\C1=CC=CC=C1 JUZVHLGKYJTCKP-CMDGGOBGSA-N 0.000 description 1
- TZEQDSMFACWASC-MDZDMXLPSA-N 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone Chemical compound COC1=C(C)C(O)=C(C)C(O)=C1C(=O)\C=C\C1=CC=CC=C1 TZEQDSMFACWASC-MDZDMXLPSA-N 0.000 description 1
- SPWBEELZNSXNME-CMDGGOBGSA-N 2,2',4'-trihydroxy-6'-methoxy-3',5'-dimethylchalcone Chemical compound COC1=C(C)C(O)=C(C)C(O)=C1C(=O)\C=C\C1=CC=CC=C1O SPWBEELZNSXNME-CMDGGOBGSA-N 0.000 description 1
- 241000222122 Candida albicans Species 0.000 description 1
- DQFBYFPFKXHELB-UHFFFAOYSA-N Chalcone Natural products C=1C=CC=CC=1C(=O)C=CC1=CC=CC=C1 DQFBYFPFKXHELB-UHFFFAOYSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- -1 Flavonoid compounds Chemical class 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 241001646725 Mycobacterium tuberculosis H37Rv Species 0.000 description 1
- 108700035964 Mycobacterium tuberculosis HsaD Proteins 0.000 description 1
- 241000932935 Pisonia Species 0.000 description 1
- 244000208734 Pisonia aculeata Species 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 230000002365 anti-tubercular Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 229940095731 candida albicans Drugs 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 150000001789 chalcones Chemical class 0.000 description 1
- 235000005513 chalcones Nutrition 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 150000004777 chromones Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 125000004387 flavanoid group Chemical group 0.000 description 1
- 229930003949 flavanone Natural products 0.000 description 1
- 150000002208 flavanones Chemical class 0.000 description 1
- 235000011981 flavanones Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 244000052637 human pathogen Species 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000033444 hydroxylation Effects 0.000 description 1
- 238000005805 hydroxylation reaction Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 208000037801 influenza A (H1N1) Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000002906 microbiologic effect Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 201000010740 swine influenza Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
- C12P17/02—Oxygen as only ring hetero atoms
- C12P17/06—Oxygen as only ring hetero atoms containing a six-membered hetero ring, e.g. fluorescein
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
- C12P7/00—Preparation of oxygen-containing organic compounds
- C12P7/02—Preparation of oxygen-containing organic compounds containing a hydroxy group
- C12P7/22—Preparation of oxygen-containing organic compounds containing a hydroxy group aromatic
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
- C12R2001/00—Microorganisms ; Processes using microorganisms
- C12R2001/645—Fungi ; Processes using fungi
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- Chemical Kinetics & Catalysis (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Biotechnology (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Przedmiotem zgłoszenia jest sposób wytwarzania 4'-hydroksyflawanonu polegający na tym, że do podłoża odpowiedniego dla grzybów strzępkowych wprowadza się szczep Isaria fumosorosea KCH J2, następnie po upływie co najmniej 72 godzin do hodowli wprowadza się substrat, którym jest 4'-metyloflawanon o wzorze 1, rozpuszczony w rozpuszczalniku organicznym mieszającym się z wodą, transformację prowadzi się w temperaturze od 20 do 30 stopni Celsjusza, przy ciągłym wstrząsaniu, co najmniej 96 godzin, po czym produkt ekstrahuje się rozpuszczalnikiem organicznym niemieszającym się z wodą i oczyszcza chromatograficznie, przy czym 4'-hydroksyflawanon o wzorze 2 znajduje się we frakcji o pośredniej polarności w trzecim paśmie od linii startu.The subject of the application is a method for producing 4'-hydroxyflavanone, which consists in introducing the Isaria fumosorosea KCH J2 strain into a medium suitable for filamentous fungi, and then, after at least 72 hours, the substrate, which is 4'-methylflavanone of formula 1, is introduced into the culture. , dissolved in an organic solvent miscible with water, the transformation is carried out at a temperature of 20 to 30 degrees Celsius, with constant shaking, for at least 96 hours, after which the product is extracted with an organic solvent immiscible with water and purified by chromatography, with 4' -hydroxyflavanone of formula 2 is found in the fraction of intermediate polarity in the third band from the starting line.
Description
Przedmiotem wynalazku jest sposób wytwarzania 4’-hydroksyflawanonu.The subject of the invention is a method for producing 4'-hydroxyflavanone.
4’-Hydroksyflawanon może znaleźć zastosowanie jako związek przeciwutleniający i przeciwdrobnoustrojowy w preparatach farmaceutycznych i kosmetycznych oraz produktach spożywczych.4'-Hydroxyflavanone can be used as an antioxidant and antimicrobial compound in pharmaceutical and cosmetic preparations and food products.
Związki flawonoidowe z grupami hydroksylowymi i metylowymi wykazują aktywność przeciwdrobnoustrojową. Chalkony z azjatyckiego drzewa Syzygium nervosum (Cleistocalyx operculatus): (E )-4,2’,4’-trihydroksy-6’-metoksy-3’,5’-dimetylochalkon, (E )-2’,4’-dihydroksy-6’-metoksy-3’,5’-dimetylochalkon, (E)-2’,4’-dihydroksy-6’-metoksy-3’-metylochalkon, (E)-2,2’,4’-trihydroksy-6’-metoksy-3’,5’-dimetylochalkon wykazywały silną inhibicję wobec enzymów pochodzących od dwóch szczepów wirusa grypy: H1N1 oraz H9N2. Blokowały one działanie neuraminidaz, umożliwiających wirusom opuszczanie zakażonych komórek poprzez rozkład ich błon komórkowych (Dao T. T. , Tung B. T, Nguyen P. H., Thuong P T, Yoo S. S., Kim E. H., Kim S. K., Oh W. K. C-methylated flavonoids form Cleistocalyx operculatus and their inhibitory effects on novel influenza A (H1N1 ) neuraminidase. Journal of Natural Products 2010, 73, 1636-1642).Flavonoid compounds with hydroxyl and methyl groups have antimicrobial activity. Chalcones from the Asian tree Syzygium nervosum (Cleistocalyx operculatus): (E)-4,2',4'-trihydroxy-6'-methoxy-3',5'-dimethylchalcone, (E)-2',4'-dihydroxy- 6'-methoxy-3',5'-dimethylchalcone, (E)-2',4'-dihydroxy-6'-methoxy-3'-methylchalcone, (E)-2,2',4'-trihydroxy-6 '-methoxy-3',5'-dimethylchalcone showed strong inhibition against enzymes from two strains of influenza virus: H1N1 and H9N2. They blocked the action of neuraminidases, which enable viruses to leave infected cells by breaking down their cell membranes (Dao T. T., Tung B. T., Nguyen P. H., Thuong P T, Yoo S. S., Kim E. H., Kim S. K., Oh W. K. C-methylated flavonoids form Cleistocalyx operculatus and their inhibitors effects on novel influenza A (H1N1) neuraminidase. Journal of Natural Products 2010, 73, 1636-1642).
Podobnie (2S)-5,7,2’-trihydroksy-8-metyloflawanon izolowany z krzewu Pisonia aculeate wykazywał aktywność przeciwdrobnoustrojową podczas badania in vitro z udziałem szczepu Mycobacterium tuberculosis H37Rv. Związek ten wywoływał inhibicję wzrostu bakterii przy minimalnym stężeniu hamującym wynoszącym 50 μg/cm3 (Wu M. C., Peng C. F., Chen I. S., Tsai I. L. Antitubercular chromones and flavanoids from Pisonia aculeata. Journal of Natural Products 2011, 74, 976-982).Similarly, (2S)-5,7,2'-trihydroxy-8-methylflavanone isolated from the Pisonia aculeate shrub showed antimicrobial activity when tested in vitro with the Mycobacterium tuberculosis H37Rv strain. This compound inhibited bacterial growth at a minimum inhibitory concentration of 50 μg/cm 3 (Wu MC, Peng CF, Chen IS, Tsai IL Antitubercular chromones and flavanoids from Pisonia aculeata. Journal of Natural Products 2011, 74, 976-982).
Aktywność antybakteryjną i antygrzybiczną potwierdzono również dla flawonoidów wyekstrahowanych z naziemnych części rośliny Eysenhardtia texana: (2S)-4’,5,7-trihydroksy-8-metylo-6-prenyloflawanonu oraz (2S)-4’,5,7-trihydroksy-6-metylo-8-prenyloflawanonu. Dowiedziono, że w stężeniu 0,1 mg/cm3 hamowały wzrost Staphylococcus aureus. (2S)-4’,5,7-trihydroksy-8-metylo-6-prenyloflawanon spowalniał również wzrost Candida albicans (Wachter G. A., Hoffmann J. J., Furbacher T. T, Blake M. E., Timmermann B. N. Antibacterial and antifungal flavanones from Eysenhardtia texana. Phytochemistry 1999, 52, 1469-1471).Antibacterial and antifungal activity was also confirmed for flavonoids extracted from the ground parts of the Eysenhardtia texana plant: (2S)-4',5,7-trihydroxy-8-methyl-6-prenylflavanone and (2S)-4',5,7-trihydroxy- 6-methyl-8-prenylflavanone. It was proven that at a concentration of 0.1 mg/ cm3 they inhibited the growth of Staphylococcus aureus. (2S)-4',5,7-trihydroxy-8-methyl-6-prenylflavanone also slowed down the growth of Candida albicans (Wachter GA, Hoffmann JJ, Furbacher T. T, Blake ME, Timmermann BN Antibacterial and antifungal flavanones from Eysenhardtia texana. Phytochemistry 1999, 52, 1469-1471).
Znany jest szczep Isaria fumosorosea KCH J2 ujawniony w zgłoszeniu patentowym o numerze P.416996.There is a known strain of Isaria fumosorosea KCH J2 disclosed in patent application number P.416996.
W ostatnich latach, w leczeniu różnych chorób i ich zapobieganiu, coraz większe znaczenie zyskują związki pochodzenia naturalnego oraz ich odpowiedniki uznawane za naturalne, które uzyskano na drodze przekształceń mikrobiologicznych. Dlatego istotne jest opracowywanie nowych metod wytwarzania związków aktywnych biologicznie na drodze biotransformacji, użytecznych dla przemysłu farmaceutycznego, kosmetycznego i spożywczego.In recent years, in the treatment and prevention of various diseases, compounds of natural origin and their equivalents considered as natural, obtained through microbiological transformations, have become increasingly important. Therefore, it is important to develop new methods for producing biologically active compounds by biotransformation, useful for the pharmaceutical, cosmetic and food industries.
Istotą wynalazku jest sposób otrzymywania 4’-hydroksyflawanonu.The essence of the invention is the method of obtaining 4'-hydroxyflavanone.
Istota sposobu polega na tym, że do podłoża odpowiedniego dla grzybów strzępkowych wprowadza się szczep Isaria fumosorosea KCH J2. Po upływie co najmniej 72 godzin do hodowli wprowadza się substrat, którym jest 4’-metyloflawanon, rozpuszczony w rozpuszczalniku organicznym mieszającym się z wodą. Transformację prowadzi się w temperaturze od 20 do 30 stopni Celsjusza, przy ciągłym wstrząsaniu, przez co najmniej 96 godzin. Następnie produkt ekstrahuje się rozpuszczalnikiem organicznym niemieszającym się z wodą oraz oczyszcza chromatograficznie. 4’-Hydroksyflawanon znajduje się we frakcji o pośredniej polarności, w trzecim paśmie od linii startu.The essence of the method is that the Isaria fumosorosea KCH J2 strain is introduced into a medium suitable for filamentous fungi. After at least 72 hours, the substrate, which is 4'-methylflavanone, dissolved in an organic solvent miscible with water, is introduced into the culture. The transformation is carried out at a temperature of 20 to 30 degrees Celsius, with constant shaking, for at least 96 hours. Then the product is extracted with an organic solvent immiscible with water and purified by chromatography. 4'-Hydroxyflavanone is found in the fraction of intermediate polarity, in the third band from the starting line.
Korzystnie jest, gdy stosunek masy dodawanego substratu do objętości hodowli wynosi 0,1 mg : 1 cm3.It is preferable when the ratio of the mass of the added substrate to the culture volume is 0.1 mg: 1 cm3 .
Korzystnie także jest, gdy proces prowadzi się w temperaturze 25 stopni Celsjusza.It is also preferable when the process is carried out at a temperature of 25 degrees Celsius.
Dodatkowo, korzystnie jest, gdy transformację prowadzi się przez 9 dni.Additionally, it is preferable if the transformation is carried out for 9 days.
Korzystnie również jest, gdy oczyszczanie prowadzi się, wykorzystując cienkowarstwową chromatografię preparatywną w układzie eluującym z chloroformem i metanolem w stosunku objętościowym 9 : 1.It is also preferable when purification is carried out using preparative thin-layer chromatography in an eluting system with chloroform and methanol in a volume ratio of 9: 1.
Postępując zgodnie z wynalazkiem, w wyniku działania układu enzymatycznego zawartego w komórkach szczepu Isaria fumosorosea KCH J2, następuje odszczepienie grupy metylowej oraz hydroksylacja przy C-4’. Uzyskany w ten sposób produkt wydziela się z wodnej kultury mikroorganizmu, znanym sposobem, przez ekstrakcję rozpuszczalnikiem organicznym niemieszającym się z wodą (octan etylu).Following the invention, as a result of the action of the enzymatic system contained in the cells of the Isaria fumosorosea KCH J2 strain, the methyl group is cleaved and hydroxylation at C-4' occurs. The product obtained in this way is isolated from the aqueous culture of the microorganism in a known method, by extraction with an organic solvent immiscible with water (ethyl acetate).
Zasadniczą zaletą wynalazku jest otrzymanie 4’-hydroksyflawanonu w temperaturze pokojowej i przy pH naturalnym dla szczepu oraz wykorzystując mikroorganizm niebędący patogenem ludzkim.The main advantage of the invention is the preparation of 4'-hydroxyflavanone at room temperature and pH natural for the strain and using a microorganism that is not a human pathogen.
PL 244523 BIPL 244523 BI
Wykorzystanie biotransformacji, zamiast syntezy chemicznej, umożliwia, w sposób przyjazny dla środowiska, uzyskanie związków o większej biodostępności i aktywności biologicznej niż użyte substraty.The use of biotransformation, instead of chemical synthesis, allows, in an environmentally friendly way, to obtain compounds with greater bioavailability and biological activity than the substrates used.
Wynalazek jest bliżej objaśniony na przykładzie wykonania.The invention is explained in more detail using an example embodiment.
Przykład. Do kolby stożkowej o pojemności 2000 cm3, w której znajduje się 500 cm3 sterylnej pożywki zawierającej 10 g aminobaku i 30 g glukozy, wprowadza się szczep Isaria fumosorosea KCH J2. Po 72 godzinach jego wzrostu dodaje się 50 mg 4’-metyloflawanonu o wzorze 1, rozpuszczonego w 1 cm3 dimetylosulfotlenku. Transformację prowadzi się w 25 stopniach Celsjusza przy ciągłym wstrząsaniu przez 9 dni. Następnie mieszaninę poreakcyjną ekstrahuje się dwukrotnie octanem etylu, osusza bezwodnym siarczanem magnezu i odparowuje rozpuszczalnik. Otrzymany ekstrakt oczyszcza się chromatograficznie z zastosowaniem jako eluentu mieszaniny chloroformu i metanolu w stosunku objętościowym 9:1. Produkt znajduje się we frakcji o pośredniej polarności, w trzecim paśmie od linii startu.Example. The Isaria fumosorosea KCH J2 strain is introduced into a 2000 cm 3 conical flask containing 500 cm 3 of sterile medium containing 10 g of aminobac and 30 g of glucose. After 72 hours of growth, 50 mg of 4'-methylflavanone of formula 1, dissolved in 1 cm 3 of dimethyl sulfoxide, are added. The transformation is carried out at 25 degrees Celsius with constant shaking for 9 days. The reaction mixture is then extracted twice with ethyl acetate, dried over anhydrous magnesium sulfate and the solvent is evaporated. The obtained extract is purified by chromatography using a mixture of chloroform and methanol in a volume ratio of 9:1 as the eluent. The product is located in the fraction of intermediate polarity, in the third band from the starting line.
Na tej drodze otrzymuje się 3,4 mg 4’-hydroksyflawanonu (wydajność 6,7%). Stopień konwersji substratu według HPLC >99%.In this way, 3.4 mg of 4'-hydroxyflavanone is obtained (yield 6.7%). The degree of substrate conversion according to HPLC is >99%.
Uzyskany produkt charakteryzuje się następującymi danymi spektralnymi.The obtained product is characterized by the following spectral data.
Opis sygnałów pochodzących z widma 1H NMR (601 MHz, Aceton-ds)Description of signals from the 1 H NMR spectrum (601 MHz, Acetone-ds)
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