PL242339B1 - Method for the production of 3'4'-dihydroxy-5,7-dimethoxyflavone - Google Patents
Method for the production of 3'4'-dihydroxy-5,7-dimethoxyflavone Download PDFInfo
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- PL242339B1 PL242339B1 PL435580A PL43558020A PL242339B1 PL 242339 B1 PL242339 B1 PL 242339B1 PL 435580 A PL435580 A PL 435580A PL 43558020 A PL43558020 A PL 43558020A PL 242339 B1 PL242339 B1 PL 242339B1
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- dimethoxyflavone
- dihydroxy
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- 238000000034 method Methods 0.000 title claims abstract description 12
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 6
- 241000188153 Isaria fumosorosea Species 0.000 claims abstract description 9
- 239000000758 substrate Substances 0.000 claims abstract description 7
- 239000003960 organic solvent Substances 0.000 claims abstract description 5
- 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
- 230000009466 transformation Effects 0.000 claims description 4
- 230000008569 process Effects 0.000 claims description 3
- 238000000746 purification Methods 0.000 claims description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 claims 1
- 238000012746 preparative thin layer chromatography Methods 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 abstract description 6
- 108090000790 Enzymes Proteins 0.000 abstract description 3
- 102000004190 Enzymes Human genes 0.000 abstract description 3
- 230000033444 hydroxylation Effects 0.000 abstract description 3
- 238000005805 hydroxylation reaction Methods 0.000 abstract description 3
- 238000000605 extraction Methods 0.000 abstract 1
- 244000005700 microbiome Species 0.000 abstract 1
- JRFZSUMZAUHNSL-UHFFFAOYSA-N chrysin 5,7-dimethyl ether Chemical compound C=1C(OC)=CC(OC)=C(C(C=2)=O)C=1OC=2C1=CC=CC=C1 JRFZSUMZAUHNSL-UHFFFAOYSA-N 0.000 description 18
- IAFBOKYTDSDNHV-UHFFFAOYSA-N (2S)-(-)-5,7-dimethoxyflavanone Natural products O1C2=CC(OC)=CC(OC)=C2C(=O)CC1C1=CC=CC=C1 IAFBOKYTDSDNHV-UHFFFAOYSA-N 0.000 description 9
- 241000196324 Embryophyta Species 0.000 description 6
- 229930003935 flavonoid Natural products 0.000 description 6
- 235000017173 flavonoids Nutrition 0.000 description 6
- 230000003110 anti-inflammatory effect Effects 0.000 description 5
- 150000002215 flavonoids Chemical class 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- RTIXKCRFFJGDFG-UHFFFAOYSA-N chrysin Chemical compound C=1C(O)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=CC=C1 RTIXKCRFFJGDFG-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 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 2
- 241000395050 Kaempferia parviflora Species 0.000 description 2
- MWUXSHHQAYIFBG-UHFFFAOYSA-N Nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
- 240000003969 Piper caninum Species 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- -1 flavonoid compounds Chemical class 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 230000007407 health benefit Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 150000008442 polyphenolic compounds Chemical class 0.000 description 2
- 235000013824 polyphenols Nutrition 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 208000001076 sarcopenia Diseases 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- NYCXYKOXLNBYID-UHFFFAOYSA-N 5,7-Dihydroxychromone Natural products O1C=CC(=O)C=2C1=CC(O)=CC=2O NYCXYKOXLNBYID-UHFFFAOYSA-N 0.000 description 1
- PXDHVVMDKPESHE-UHFFFAOYSA-N 5,7-dimethoxy-3,4-dihydro-2h-naphthalen-1-one Chemical compound C1CCC(=O)C2=CC(OC)=CC(OC)=C21 PXDHVVMDKPESHE-UHFFFAOYSA-N 0.000 description 1
- NOQJBXPAMJLUSS-UHFFFAOYSA-N 6-methyl-2-phenylchromen-4-one Chemical compound C=1C(=O)C2=CC(C)=CC=C2OC=1C1=CC=CC=C1 NOQJBXPAMJLUSS-UHFFFAOYSA-N 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 108010004539 Chalcone isomerase Proteins 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 244000060701 Kaempferia pandurata Species 0.000 description 1
- 235000013412 Kaempferia pandurata Nutrition 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
- 241000220225 Malus Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- QCBVVYLBNAZDPE-UHFFFAOYSA-N OC=1C=C(C=2OC3=CC(=CC(=C3C(C=2)=O)OC)OC)C=CC=1 Chemical compound OC=1C=C(C=2OC3=CC(=CC(=C3C(C=2)=O)OC)OC)C=CC=1 QCBVVYLBNAZDPE-UHFFFAOYSA-N 0.000 description 1
- 230000006750 UV protection Effects 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 229940121375 antifungal agent Drugs 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
- 230000008901 benefit Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 239000011942 biocatalyst Substances 0.000 description 1
- 238000004178 biological nitrogen fixation Methods 0.000 description 1
- 230000036983 biotransformation Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 235000015838 chrysin Nutrition 0.000 description 1
- 229940043370 chrysin Drugs 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000000378 dietary effect Effects 0.000 description 1
- QGGZBXOADPVUPN-UHFFFAOYSA-N dihydrochalcone Chemical class C=1C=CC=CC=1C(=O)CCC1=CC=CC=C1 QGGZBXOADPVUPN-UHFFFAOYSA-N 0.000 description 1
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 1
- 229960002986 dinoprostone Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 230000000967 entomopathogenic effect Effects 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- QPMJENKZJUFOON-PLNGDYQASA-N ethyl (z)-3-chloro-2-cyano-4,4,4-trifluorobut-2-enoate Chemical compound CCOC(=O)C(\C#N)=C(/Cl)C(F)(F)F QPMJENKZJUFOON-PLNGDYQASA-N 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 150000002212 flavone derivatives Chemical class 0.000 description 1
- 150000002213 flavones Chemical class 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000013595 glycosylation Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 244000005709 gut microbiome Species 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 230000000055 hyoplipidemic effect Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 231100000957 no side effect Toxicity 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 1
- 150000002940 palladium Chemical class 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 230000019612 pigmentation Effects 0.000 description 1
- 230000008121 plant development Effects 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 238000004237 preparative chromatography Methods 0.000 description 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
- 150000003180 prostaglandins Chemical class 0.000 description 1
- 230000004844 protein turnover Effects 0.000 description 1
- 238000011552 rat model Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 238000005556 structure-activity relationship Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000000844 transformation Methods 0.000 description 1
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- 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
- C07D311/30—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 not hydrogenated in the hetero ring, e.g. flavones
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- 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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Abstract
Wynalazek dotyczy sposobu wytwarzania 3'4'-dihydroksy-5,7-dimetoksyflawonu o wzorze 2. Postępując zgodnie z wynalazkiem, w wyniku działania układu enzymatycznego zawartego w komórkach szczepu Isaria fumosorosea KCh J2, następuje regioselektywna hydroksylacja substratu. Uzyskany w ten sposób produkt wydziela się z wodnej kultury mikroorganizmu, znanym sposobem, przez ekstrakcję rozpuszczalnikiem organicznym niemieszającym się z wodą (octan etylu).The invention relates to a method for the production of 3'4'-dihydroxy-5,7-dimethoxyflavone of the formula 2. Following the invention, regioselective hydroxylation of the substrate occurs as a result of the activity of the enzyme system contained in the cells of the strain Isaria fumosorosea KCh J2. The product thus obtained is separated from the aqueous culture of the microorganism by a known method by extraction with a water-immiscible organic solvent (ethyl acetate).
Description
Opis wynalazkuDescription of the invention
Przedmiotem wynalazku jest sposób wytwarzania 3’4’-dihydroksy-5,7-dimetoksyflawonu.The subject of the invention is a method for producing 3'4'-dihydroxy-5,7-dimethoxyflavone.
Metoda, według wynalazku może znaleźć zastosowanie w przemyśle farmaceutycznym do otrzymywania preparatów stosowanych w prewencji chorób układu krążenia oraz w profilaktyce przeciwnowotworowej.The method according to the invention can be used in the pharmaceutical industry for the preparation of preparations used in the prevention of cardiovascular diseases and in the prevention of cancer.
Na dzień dzisiejszy, szacuje się, że występuje ponad 9000 związków flawonoidowych pochodzenia roślinnego (Yonekura-Sakakibara, K.; Higashi, Y.; Nakabayashi, R. The Origin and Evolution of Plant Flavonoid Metabolism. Front. Plant Sci. 2019, 10, 1-16), które jako wtórne metabolity spełniają szereg funkcji m.in. regulujących ogólny rozwój roślin, pigmentację, czy zapewniających ochronę przed UV (Gall, M.; Thomsen, M.; Peters, C.; Pavlidis, I. V.; Jonczyk, P.; Grunert, P.P.; Beutel, S.; Scheper, T.; Gross, E.; Backes, M.; et al. Enzymatic Conversion of Flavonoids using Bacterial Chalcone Isomerase and Enoate Reductase. Angew. Chemie Int. Ed. 2014, 53, 1439-1442; Pathak, S.; Kesavan, P.; Banerjee, A.; Banerjee, A.; Celep, G.S.; Bissi, L.; Marotta, F. Metabolism of Dietary Polyphenols by Human Gut Microbiota and Their Health Benefits. In Polyphenols: Mechanisms of Action in Human Health and Disease; Elsevier, 2018; pp. 347-359 ISBN 9780128130063; Hassan, S.; Mathesius, U. Flavonoids Play Multiple Roles in Symbiotic Root-Rhizosphere Interactions. In Biological Nitrogen Fixation; 2015; Vol. 2-2, pp. 499-510 ISBN 9781119053095). Dodatkowo, ciągle są opisywane nowe właściwości biologiczne flawonów, które wykazują pozytywny wpływ na organizmy modelowe po ich spożyciu, w tym na organizm ludzki. Począwszy od często opisywanych zdolności antyoksydacyjnych, przeciwnowotworowych, przeciwzapalnych (Cao, H.; Chen, X.; Jassbi, A.R.; Xiao, J. Microbial biotransformation of bioactive flavonoids. Biotechnol. Adv. 2015, 33, 214-223; Xiao, Z.; Wang, Y.; Wang, J.; Li, P.; Ma, F. Structure-antioxidant capacity relationship of dihydrochalcone compounds in Malus. Food Chem. 2019, 275, 354-360), przeciwgrzybiczych, przeciwbakteryjnych czy przeciwwirusowych (Yao, L.H.; Jiang, Y.M.; Shi, J.; Tomas-Barberan, F. a; Datta, N.; Singanusong, R.; Chen, S.S. Flavonoids in food and their health benefits. Plant Foods Hum. Nutr. 2004, 59, 113-122) aż do wykorzystania tych związków do leczenia Choroby Alzheimera (Bei, D.; An, G. Pharmacokinetics and tissue distribution of 5,7-dimethoxyflavone in mice following single dose oral administration. J. Pharm. Biomed. Anal. 2016, 119, 65-70), czy obniżania poziomu glukozy we krwi (testowane na modelach szczurzych) (Xie, Y.; Zhang, Y.; Su, X. Antidiabetic and Hypolipidemic Effects of 5,7-Dimethoxyflavone in Streptozotocin-lnduced Diabetic Rats. Med. Sci. Monit. 2019, 25, 9893-9901), pokazują, że związki te można wykorzystać na bardzo szeroką skalę.As of today, it is estimated that there are over 9,000 flavonoid compounds of plant origin (Yonekura-Sakakibara, K.; Higashi, Y.; Nakabayashi, R. The Origin and Evolution of Plant Flavonoid Metabolism. Front. Plant Sci. 2019, 10, 1-16), which as secondary metabolites perform a number of functions, including regulating general plant development, pigmentation, or providing UV protection (Gall, M.; Thomsen, M.; Peters, C.; Pavlidis, I. V.; Jonczyk, P.; Grunert, P.P.; Beutel, S.; Scheper, T. ; Gross, E; Backes, M.; et al. Enzymatic Conversion of Flavonoids using Bacterial Chalcone Isomerase and Enoate Reductase. Angew. Chemie Int. Ed. 2014, 53, 1439-1442; Pathak, S.; Kesavan, P. ; Banerjee, A.; Banerjee, A.; Celep, G.S.; Bissi, L.; Marotta, F. Metabolism of Dietary Polyphenols by Human Gut Microbiota and Their Health Benefits. In Polyphenols: Mechanisms of Action in Human Health and Disease; Elsevier , 2018;pp. 347-359 ISBN 9780128130063; Hassan, S.;Mathesius, U. Flavonoids Play Multiple Roles in Symbiotic Root-Rhizosphere Interactions. In Biological Nitrogen Fixation;2015;Vol. 2-2, pp. 499-510 ISBN 9781119053095). In addition, new biological properties of flavones are constantly being described, which have a positive effect on model organisms after their consumption, including the human body. Starting from the often described antioxidant, anticancer, anti-inflammatory properties (Cao, H.; Chen, X.; Jassbi, A.R.; Xiao, J. Microbial biotransformation of bioactive flavonoids. Biotechnol. Adv. 2015, 33, 214-223; Xiao, Z .; Wang, Y.; Wang, J.; Li, P.; Ma, F. Structure-antioxidant capacity relationship of dihydrochalcone compounds in Malus. Food Chem. 2019, 275, 354-360), antifungal, antibacterial or antiviral ( Yao, L.H.; Jiang, Y.M.; Shi, J.; Tomas-Barberan, F. a; Datta, N.; Singanusong, R.; Chen, S.S. Flavonoids in food and their health benefits. Plant Foods Hum. Nutr. 2004, 59, 113-122) up to the use of these compounds for the treatment of Alzheimer's Disease (Bei, D.; An, G. Pharmacokinetics and tissue distribution of 5,7-dimethoxyflavone in mice following single dose oral administration. J. Pharm. Biomed. Anal 2016, 119, 65-70), or lowering blood glucose levels (tested on rat models) (Xie, Y.; Zhang, Y.; Su, X. Antidiabetic and Hypo lipidemic Effects of 5,7-Dimethoxyflavone in Streptozotocin-Induced Diabetic Rats. Med. sci. prompt. 2019, 25, 9893-9901), show that these compounds can be used on a very large scale.
5,7-Dimetoksyflawon jest wytwarzany przez rośliny stosowane w medycynie naturalnej: można go wyizolować m.in. z kłącza Boesenbergia pandurata (Roxb.), czyli w roślinie, która jest od dawna wykorzystywana w tajskiej medycynie tradycyjnej (Panthong, A.; Tassaneeyakul, W.; Kanjanapothi, D.; Tantiwac, P.; Reutrakul, V. Anti-Inflammatory activity of 5,7-dimethoxyflavone. Planta Medic 1989, 55, 133-136), z liści i nasion Piper caninum (Salleh, W.; Ahmad, F.; Yen, K. Chemical constituents from Piper caninum and antibacterial activity. J. Appl. Pharm. Sci. 2015, 5, 020-025) czy z liści Kaempferia parviflora (Yenjai, C.; Wanich, S.; Pitchuanchom, S.; Sripanidkulchai, B. Structural modification of 5,7-dimethoxyflavone from Kaempferia parviflora and biological activities. Arch. Pharm. Res. 2009, 32, 1179-1184). Co więcej, związek ten, przetestowany na szczurach wykazywał bardzo niską toksyczność, praktycznie bez skutków ubocznych (nawet w dawkach do 3 g/kg masy ciała) (Panthong, A.; Tassaneeyakul, W.; Kanjanapothi, D.; Tantiwac, P.; Reutrakul, V. Anti-Inflammatory activity of 5,7-dimethoxyflavone. Planta Medic 1989, 55, 133-136). Autorzy porównali tutaj właściwości przeciwzapalne 5,7-DMF z aspiryną i stwierdzili, iż związek ten jednocześnie hamuje wytwarzanie prostaglandyn (działanie p/zapalne) oraz w tym przypadku obniża (rektalną) temperaturę organizmu szczura. Dodatkowo wykazano również, iż 5,7-DMF działa jako inhibitor sarcopenii oraz powoduje jednocześnie rozwój masy i objętości mięśniowej na modelu mysim - czyli wykazuje właściwości bardzo zbliżone do wykorzystywanej w badaniach biologicznych chryzyny (5,7-dihydroksyflawonu) (Kim, C.; Hwang, J.-K. The 5,7-Dimethoxyflavone Suppresses Sarcopenia by Regulating Protein Turnover and Mitochondria Biogenesis-Related Pathways. Nutrients 2020, 12, 1079).5,7-Dimethoxyflavone is produced by plants used in natural medicine: it can be isolated, e.g. from the rhizome of Boesenbergia pandurata (Roxb.), a plant that has long been used in Thai traditional medicine (Panthong, A.; Tassaneeyakul, W.; Kanjanapothi, D.; Tantiwac, P.; Reutrakul, V. Anti-Inflammatory activity of 5,7-dimethoxyflavone. Planta Medic 1989, 55, 133-136), from leaves and seeds of Piper caninum (Salleh, W.; Ahmad, F.; Yen, K. Chemical constituents from Piper caninum and antibacterial activity. J Appl. Pharm. Sci. 2015, 5, 020-025) or from leaves of Kaempferia parviflora (Yenjai, C.; Wanich, S.; Pitchuanchom, S.; Sripanidkulchai, B. Structural modification of 5,7-dimethoxyflavone from Kaempferia parviflora and biological activities. Arch. Pharm. Res. 2009, 32, 1179-1184). Moreover, this compound, tested on rats, showed very low toxicity, with virtually no side effects (even at doses up to 3 g/kg of body weight) (Panthong, A.; Tassaneeyakul, W.; Kanjanapothi, D.; Tantiwac, P. ; Reutrakul, V. Anti-Inflammatory activity of 5,7-dimethoxyflavone. Planta Medic 1989, 55, 133-136). The authors here compared the anti-inflammatory properties of 5,7-DMF with aspirin and found that this compound simultaneously inhibits the production of prostaglandins (anti-inflammatory effect) and in this case lowers the (rectal) body temperature of the rat. In addition, it has also been shown that 5,7-DMF acts as an inhibitor of sarcopenia and at the same time causes the development of muscle mass and volume in a mouse model - i.e. it shows properties very similar to those of chrysin (5,7-dihydroxyflavone) used in biological research (Kim, C.; Hwang, J.-K. The 5,7-Dimethoxyflavone Suppresses Sarcopenia by Regulating Protein Turnover and Mitochondria Biogenesis-Related Pathways. Nutrients 2020, 12, 1079).
Szczep Isaria fumosorosea KCh J2 był wcześniej ujawniony w literaturze (Dymarska M., Grzeszczuk J., Urbaniak M., Janeczko T., Pląskowska E., Stępień Ł., Kostrzewa-Susłow E.; (2017) Glycosylation of 6-methylflavone by the strain Isaria fumosorosea KCH J2. Plos One. 12, e.0184885; Kozłowska E., Dymarska M., Kostrzewa-Susłow E.; Janeczko T., (2017) Isaria fumosorosea KCh J2 entomopathogenic strain as an effective biocatalyst for steroid compound transformations. Molecules, 22, 1511, doi:10.3390).The Isaria fumosorosea KCh J2 strain was previously disclosed in the literature (Dymarska M., Grzeszczuk J., Urbaniak M., Janeczko T., Pląskowska E., Stępień Ł., Kostrzewa-Susłow E.; (2017) Glycosylation of 6-methylflavone by the strain Isaria fumosorosea KCH J2. Plos One. 12, e.0184885, Kozłowska E., Dymarska M., Kostrzewa-Susłow E., Janeczko T., (2017) Isaria fumosorosea KCh J2 entomopathogenic strain as an effective biocatalyst for steroid compound transformations. Molecules, 22, 1511, doi:10.3390).
Znana jest chemiczna metoda uzyskiwania 3’4’-dihydroksy-5,7-dimetoksyflawonu z 5,7-dimetoksy-1-tetralonu i boranylanupinakolu w wyniku zastosowania związków kompleksowych palladu (Ji-Young An, Hwi-Ho Lee, Ji-Sun Shin, Flyung-Seok Yoo, Jong Seon Park, Seung Hwan Son, Sang Won Kim, Jihyun Yu, Jun Lee, Kyung-Tae Lee, Nam-Jung Kim. Identification and structure activity relationship of novel flavone derivatives that inhibit the production of nitric oxide and PGE2 in LPS-induced RAW 264.7 cells. Bioorganic & Medicinal Chemistry Letters 27 (2017) 2613-2616). W literaturze nie ma doniesień dotyczących biotechnologicznego uzyskania 3’4’-dihydroksy-5,7-dimetoksyflawonu.There is a known chemical method of obtaining 3'4'-dihydroxy-5,7-dimethoxyflavone from 5,7-dimethoxy-1-tetralone and boranylanupinacol by using palladium complexes (Ji-Young An, Hwi-Ho Lee, Ji-Sun Shin , Flyung-Seok Yoo, Jong Seon Park, Seung Hwan Son, Sang Won Kim, Jihyun Yu, Jun Lee, Kyung-Tae Lee, Nam-Jung Kim. Identification and structure activity relationship of novel flavone derivatives that inhibit the production of nitric oxide and PGE2 in LPS-induced RAW 264.7 cells. Bioorganic & Medicinal Chemistry Letters 27 (2017) 2613-2616). There are no reports in the literature regarding the biotechnological obtaining of 3'4'-dihydroxy-5,7-dimethoxyflavone.
Istota wynalazku polega na tym, że do podłoża odpowiedniego dla grzybów strzępkowych wprowadza się szczep Isaria fumosorosea KCh J2. Po upływie co najmniej 48 godzin do hodowli wprowadza się substrat, którym jest 5,7-dimetoksyflawon o wzorze 1, rozpuszczony w rozpuszczalniku organicznym mieszającym się z wodą. Transformację prowadzi się w temperaturze od 15 do 35 stopni Celsjusza, przy ciągłym wstrząsaniu, co najmniej 7 dób. Kolejno produkt ekstrahuje się rozpuszczalnikiem organicznym niemieszającym się z wodą i oczyszcza chromatograficznie.The essence of the invention is that the strain Isaria fumosorosea KCh J2 is introduced into a substrate suitable for filamentous fungi. After at least 48 hours, the substrate, 5,7-dimethoxyflavone of the formula I, dissolved in a water-miscible organic solvent, is introduced into the culture. The transformation is carried out at a temperature of 15 to 35 degrees Celsius, with continuous shaking, for at least 7 days. Subsequently, the product is extracted with a water-immiscible organic solvent and purified by chromatography.
W wyniku regioselektywnej hydroksylacji otrzymuje się 3’-hydroksy-5,7-dimetoksyflawon, a reakcję prowadzi się w wodnej kulturze szczepu Isaria fumosorosea KCh J2.As a result of regioselective hydroxylation, 3'-hydroxy-5,7-dimethoxyflavone is obtained, and the reaction is carried out in an aqueous culture of the strain Isaria fumosorosea KCh J2.
Korzystnie jest, gdy stosunek masy dodawanego substratu do objętości hodowli wynosi 0,2 g:1 L.Preferably, the ratio of added substrate weight to culture volume is 0.2 g:1 L.
Korzystnie także jest, gdy proces prowadzi się w temperaturze 25 stopni Celsjusza.It is also preferred that the process is carried out at a temperature of 25 degrees Celsius.
Korzystnie także jest, gdy oczyszczanie prowadzi się wykorzystując cienkowarstwową chromatografię preparatywną w układzie eluującym chloroform: metanol w stosunku objętościowym 18:1.It is also preferred that the purification is carried out using thin-layer preparative chromatography in a system eluting with chloroform:methanol in a volume ratio of 18:1.
Postępując zgodnie z wynalazkiem, w wyniku działania układu enzymatycznego zawartego w komórkach szczepu Isaria fumosorosea KCh J2, następuje regioselektywna hydroksylacja substratu.Following the invention, regioselective hydroxylation of the substrate occurs as a result of the action of the enzyme system contained in the cells of the Isaria fumosorosea KCh J2 strain.
Zasadniczą zaletą wynalazku jest otrzymanie 3’4’-dihydroksy-5,7-dimetoksyflawon, z wydajnością izolowaną na poziomie 40% (konwersją według GC >50%), w temperaturze pokojowej i przy pH naturalnym dla szczepu.The main advantage of the invention is to obtain 3'4'-dihydroxy-5,7-dimethoxyflavone, with an isolated yield of 40% (conversion according to GC >50%), at room temperature and at the pH natural for the strain.
Wynalazek jest bliżej objaśniony na przykładzie wykonania.The invention is explained in more detail by means of an embodiment.
P rzy kła d. Do kolby Erlenmajera o pojemności 2000 cm3, w której znajduje się 500 cm3 sterylnej pożywki zawierającej 5 g aminobaku i 15 g glukozy, wprowadza się szczep Isaria fumosorosea KCh J2. Po 72 godzinach jego wzrostu dodaje się 100 mg 5,7-dimetoksyflawonu o wzorze 1, rozpuszczonego w 1 cm3 tetrahydrofuranu (THF). Transformację prowadzi się w 25 stopniach Celsjusza przy ciągłym wstrząsaniu przez 7 dni. Następnie mieszaninę poreakcyjną ekstrahuje się trzykrotnie octanem etylu, osusza bezwodnym siarczanem magnezu i odparowuje rozpuszczalnik. Otrzymany ekstrakt oczyszcza się chromatograficznie, używając jako eluentu mieszaniny chloroform i metanol 18:1.Example d Isaria fumosorosea KCh J2 strain is introduced into a 2000 cm 3 Erlenmajer flask containing 500 cm 3 of sterile medium containing 5 g of aminobac and 15 g of glucose. After 72 hours of growth, 100 mg of 5,7-dimethoxyflavone of the formula I, dissolved in 1 cm 3 of tetrahydrofuran (THF), are added. The transformation is carried out at 25 degrees Celsius with continuous shaking for 7 days. The reaction mixture is then extracted three times with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent is evaporated. The extract obtained is purified by chromatography using a 18:1 mixture of chloroform and methanol as eluent.
Na tej drodze otrzymuje się 3’4’-dihydroksy-5,7-dimetoksyflawon (konwersja według GC na poziomie >50%).In this way, 3'4'-dihydroxy-5,7-dimethoxyflavone is obtained (conversion according to GC >50%).
Uzyskany produkt charakteryzuje się następującymi danymi spektralnymi:The obtained product is characterized by the following spectral data:
1H NMR (600 MHz) (CDCb) δ (ppm): 3.82 (s, 3h, C-5-OCH3), 3.89 (s, 3H, C-7-OCH3), 6.46 (s, 1H, H-3), 6.49 (d, 1H, J = 2.3 Hz, H-6), 6.88 (d, 1H, J = 2.3 Hz, H-8), 6.87 (d, 1H, J = 8.9 Hz, H-5’), 7.34-7.37 (m, 2H, H-2’, H-6’). 1 H NMR (600 MHz) (CDCb) δ (ppm): 3.82 (s, 3h, C-5-OCH3), 3.89 (s, 3H, C-7-OCH3), 6.46 (s, 1H, H-3 ), 6.49 (d, 1H, J = 2.3 Hz, H-6), 6.88 (d, 1H, J = 2.3 Hz, H-8), 6.87 (d, 1H, J = 8.9 Hz, H-5') , 7.34-7.37 (m, 2H, H-2', H-6').
13C NMR (151 MHz, DMSO) δ = 55.94 (C-7-OCH3), 56.08 (C-5-OCH3), 93.21 (C-8), 96.17 (C-6), 106.18 (C-3), 108.26 (C-4a), 113.05 (C-2’), 115.92 (C-5’), 118.22 (C-6’), 121.74 (C-1’), 145.70 (C-3’), 148.96 (C-4’), 159.11 (C-8a), 160.26 (C-2 i C-5), 163.58 (C-7), 175.60 (C-4). 13 C NMR (151 MHz, DMSO) δ = 55.94 (C-7-OCH3), 56.08 (C-5-OCH3), 93.21 (C-8), 96.17 (C-6), 106.18 (C-3), 108.26 (C-4a), 113.05 (C-2'), 115.92 (C-5'), 118.22 (C-6'), 121.74 (C-1'), 145.70 (C-3'), 148.96 (C -4'), 159.11 (C-8a), 160.26 (C-2 and C-5), 163.58 (C-7), 175.60 (C-4).
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