CN104987319B - Marine fungus-derived depside compounds and application thereof in treatment of type 2 diabetes - Google Patents
Marine fungus-derived depside compounds and application thereof in treatment of type 2 diabetes Download PDFInfo
- Publication number
- CN104987319B CN104987319B CN201510205871.1A CN201510205871A CN104987319B CN 104987319 B CN104987319 B CN 104987319B CN 201510205871 A CN201510205871 A CN 201510205871A CN 104987319 B CN104987319 B CN 104987319B
- Authority
- CN
- China
- Prior art keywords
- depsidcs
- preparation
- compound
- culture
- compounds
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 241000233866 Fungi Species 0.000 title claims abstract description 13
- 150000001875 compounds Chemical class 0.000 title abstract description 18
- 208000001072 type 2 diabetes mellitus Diseases 0.000 title abstract description 13
- YTJJRAWFHJBAMT-UHFFFAOYSA-N depside Natural products OC(=O)CC1=C(O)C=C(O)C=C1OC(=O)C1=CC=C(O)C(O)=C1 YTJJRAWFHJBAMT-UHFFFAOYSA-N 0.000 title abstract 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- 238000002360 preparation method Methods 0.000 claims description 15
- 238000000855 fermentation Methods 0.000 claims description 12
- 238000011218 seed culture Methods 0.000 claims description 12
- 230000004151 fermentation Effects 0.000 claims description 11
- 241000839313 Meyerozyma sp. Species 0.000 claims description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 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 claims description 6
- 239000008103 glucose Substances 0.000 claims description 6
- 239000001963 growth medium Substances 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 239000002609 medium Substances 0.000 claims description 6
- 238000004321 preservation Methods 0.000 claims description 5
- FRXSZNDVFUDTIR-UHFFFAOYSA-N 6-methoxy-1,2,3,4-tetrahydroquinoline Chemical compound N1CCCC2=CC(OC)=CC=C21 FRXSZNDVFUDTIR-UHFFFAOYSA-N 0.000 claims description 4
- 238000004587 chromatography analysis Methods 0.000 claims description 4
- 239000012531 culture fluid Substances 0.000 claims description 4
- 230000002829 reductive effect Effects 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 240000007594 Oryza sativa Species 0.000 claims description 3
- 235000007164 Oryza sativa Nutrition 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 3
- 238000010828 elution Methods 0.000 claims description 3
- 238000011534 incubation Methods 0.000 claims description 3
- 235000009566 rice Nutrition 0.000 claims description 3
- 235000002639 sodium chloride Nutrition 0.000 claims description 3
- 239000011780 sodium chloride Substances 0.000 claims description 3
- 239000003208 petroleum Substances 0.000 claims description 2
- 238000010898 silica gel chromatography Methods 0.000 claims description 2
- 102100024295 Maltase-glucoamylase Human genes 0.000 abstract description 10
- 108010028144 alpha-Glucosidases Proteins 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 7
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 abstract description 5
- 239000003888 alpha glucosidase inhibitor Substances 0.000 abstract description 5
- 229940126214 compound 3 Drugs 0.000 abstract description 5
- 229940125898 compound 5 Drugs 0.000 abstract description 5
- 239000003112 inhibitor Substances 0.000 abstract description 5
- 229940125904 compound 1 Drugs 0.000 abstract description 4
- 229940125782 compound 2 Drugs 0.000 abstract description 4
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 abstract description 3
- 229960002632 acarbose Drugs 0.000 abstract description 3
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 abstract description 3
- 239000013641 positive control Substances 0.000 abstract description 3
- 230000036963 noncompetitive effect Effects 0.000 abstract description 2
- 238000011160 research Methods 0.000 abstract description 2
- 229940079593 drug Drugs 0.000 abstract 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 15
- 102000004190 Enzymes Human genes 0.000 description 8
- 108090000790 Enzymes Proteins 0.000 description 8
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 6
- 239000000499 gel Substances 0.000 description 6
- XELZGAJCZANUQH-UHFFFAOYSA-N methyl 1-acetylthieno[3,2-c]pyrazole-5-carboxylate Chemical compound CC(=O)N1N=CC2=C1C=C(C(=O)OC)S2 XELZGAJCZANUQH-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 230000005764 inhibitory process Effects 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- 229960001866 silicon dioxide Drugs 0.000 description 5
- 239000000758 substrate Substances 0.000 description 5
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 description 4
- 230000002255 enzymatic effect Effects 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- REAYFGLASQTHKB-UHFFFAOYSA-N [2-[3-(1H-pyrazol-4-yl)phenoxy]-6-(trifluoromethyl)pyridin-4-yl]methanamine Chemical compound N1N=CC(=C1)C=1C=C(OC2=NC(=CC(=C2)CN)C(F)(F)F)C=CC=1 REAYFGLASQTHKB-UHFFFAOYSA-N 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 241000862501 Kandelia candel Species 0.000 description 2
- 240000002044 Rhizophora apiculata Species 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000008399 tap water Substances 0.000 description 2
- 235000020679 tap water Nutrition 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 1
- IFBHRQDFSNCLOZ-IIRVCBMXSA-N 4-nitrophenyl-α-d-galactoside Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1OC1=CC=C([N+]([O-])=O)C=C1 IFBHRQDFSNCLOZ-IIRVCBMXSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- 102000003886 Glycoproteins Human genes 0.000 description 1
- 108090000288 Glycoproteins Proteins 0.000 description 1
- 229940122069 Glycosidase inhibitor Drugs 0.000 description 1
- 102000005744 Glycoside Hydrolases Human genes 0.000 description 1
- 108010031186 Glycoside Hydrolases Proteins 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- 235000009392 Vitis Nutrition 0.000 description 1
- 241000219095 Vitis Species 0.000 description 1
- 240000006365 Vitis vinifera Species 0.000 description 1
- 235000014787 Vitis vinifera Nutrition 0.000 description 1
- FZNCGRZWXLXZSZ-CIQUZCHMSA-N Voglibose Chemical compound OCC(CO)N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O FZNCGRZWXLXZSZ-CIQUZCHMSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- WQZGKKKJIJFFOK-DVKNGEFBSA-N alpha-D-glucose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-DVKNGEFBSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000008033 biological extinction Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000006957 competitive inhibition Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 229940000406 drug candidate Drugs 0.000 description 1
- 235000006694 eating habits Nutrition 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 239000003316 glycosidase inhibitor Substances 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 235000002532 grape seed extract Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 201000001421 hyperglycemia Diseases 0.000 description 1
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000003914 insulin secretion Effects 0.000 description 1
- TWNIBLMWSKIRAT-VFUOTHLCSA-N levoglucosan Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@H]2CO[C@@H]1O2 TWNIBLMWSKIRAT-VFUOTHLCSA-N 0.000 description 1
- 229940127017 oral antidiabetic Drugs 0.000 description 1
- 239000003538 oral antidiabetic agent Substances 0.000 description 1
- AICOOMRHRUFYCM-ZRRPKQBOSA-N oxazine, 1 Chemical compound C([C@@H]1[C@H](C(C[C@]2(C)[C@@H]([C@H](C)N(C)C)[C@H](O)C[C@]21C)=O)CC1=CC2)C[C@H]1[C@@]1(C)[C@H]2N=C(C(C)C)OC1 AICOOMRHRUFYCM-ZRRPKQBOSA-N 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000000870 ultraviolet spectroscopy Methods 0.000 description 1
- 229960001729 voglibose Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D321/00—Heterocyclic compounds containing rings having two oxygen atoms as the only ring hetero atoms, not provided for by groups C07D317/00 - C07D319/00
- C07D321/02—Seven-membered rings
- C07D321/10—Seven-membered rings condensed with carbocyclic rings or ring systems
-
- 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
- C12P17/08—Oxygen as only ring hetero atoms containing a hetero ring of at least seven ring members, e.g. zearalenone, macrolide aglycons
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Wood Science & Technology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Zoology (AREA)
- Biotechnology (AREA)
- Microbiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- General Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The invention belongs to the field of medicinal compounds, and concretely discloses marine fungus-derived depside compounds and an application thereof in treatment of type 2 diabetes. The structure of the depside compounds is represented by formula (I). The compounds 1-6 can substantially inhibit the activity of alpha-glucosidase, the IC50 value of the compound 1 is 10.4[mu]M, the IC50 value of the compound 2 is 13.3[mu]M, the IC50 value of the compound 3 is 2.1[mu]M, the IC50 value of the compound 4 is 12.4[mu]M, the IC50 value of the compound 5 is 9.8[mu]M, and the IC50 value of the compound 6 is 11.7[mu]M, wherein the IC50 value of positive control acarbose is 553.7[mu]M. Kinetic researches of the alpha-glucosidaseinhibition effect show that the compounds 1, 3 and 5 are noncompetitive inhibitors. The compounds can be used for preparing alpha-glucosidase inhibitor medicines in order to prevent and treat the type 2 diabetes.
Description
Technical field
The present invention relates to medical compoundss field, and in particular to the medical compoundss in marine fungi source, more specifically, relating to
And one class marine fungi source depsidcs and its treatment type ii diabetes application.
Background technology
At present, the type ii diabetes number of patients in global range is more than 3.7 hundred million people, and the number of patient is also fast
Speed increases.The growth is reduced and other with economic development, aged tendency of population, increasingly urbanization, dietary habit change, physical exertion
Living-pattern preservation is relevant.Thus, type ii diabetes are considered as that 21 century world community public health security is most severe
One of challenge.In type ii diabetes, body can produce insulin, but because of insulin secretion relative deficiency or effect defect
(also referred to as insulin resistant), causes blood glucose rise.And alpha-glucosidase is a kind of important for the treatment of early stage type ii diabetes
Target.It is that a class can be from the total of the alpha-glucose-based enzyme of the non-reducing end catalyzing hydrolysis containing phlorose glycosidic bond substrate
Claim.Alpha-glucosidase is distributed widely in organism, participates in food digestion, the biosynthesiss of glycoprotein, and polysaccharide and sugar are compound
Many bioprocesss such as the synthesis of thing and catabolism.Alpha-glucosidase inhibitor is a class to delay intestinal carbohydrate
Absorb and reach the oral antidiabetic drug for the treatment of diabetes, its action principle is：Competitive inhibition is located at the various α-Fructus Vitis viniferaes of small intestinal
Glycosidase, slows down the speed for being decomposed into glucose, so as to slow down the absorption of glucose in intestinal, improves the height of post-prandial glycemia
Peak.Research confirms that alpha-glucosidase inhibitor can prevent and treat post prandial hyperglycemia and alleviate hyperinsulinemia, while can be with
Improve carbohydrate tolerance.Currently, the alpha-glucosidase inhibitor of clinical application mainly has Acarbose and voglibose.In order to keep away
Exempt from or reduce the adverse side effect or drug resistance of current medical, while providing more drug candidates, therefore find new α-Fructus Vitis viniferae
Glycosidase inhibitor and to develop into medicine be very necessary.
The content of the invention
Present invention aims to the defect that at present type ii diabetes medicine is present, there is provided a class marine fungi
The depsidcs in source.
It is a further object to provide the preparation method of the depsidcs in class marine fungi source.
The depsidcs for being to provide class marine fungi source in a purpose of the present invention are preparing treatment II
Application in patients with type Ⅰ DM medicine.
To achieve these goals, the present invention is achieved by the following technical programs：
The depsidcs in one class marine fungi source, its structural formula is as shown in formula I：
The depsidcs 1-6 are to separate to obtain from the fermentation liquid of marine fungi Meyerozyma sp.HZ-Y2
；The marine fungi Meyerozyma sp.HZ-Y2 were deposited in China typical culture collection on April 6th, 2015
The heart, preservation address is Wuhan University of Wuhan, China city, and deposit number is CCTCC NO：M 2015203.
Preferably, the preparation method of above-mentioned depsidcs is as follows：
S1. by marine fungi Meyerozyma sp.HZ-Y2Seed culture medium is accessed, shaking table culture obtains seed culture
Liquid；
S2. seed culture fluid is accessed in fermentation medium, quiescent culture；
S3. tunning is filtrated to get into thalline, thalline is soaked with methanol, concentrating under reduced pressure, obtains extractum, then Jing chromatographies point
From obtaining depsidcs 1-6.
Used as a kind of preferred version, in above-mentioned preparation method, the component of seed culture medium described in step S1 is：Rhizoma Solani tuber osi
200g, glucose 20g, water 1L.
Used as a kind of preferred version, in above-mentioned preparation method, the component of fermentation medium described in step S2 is：Northeast rice
7000g, sea salt 210g, water 7L.
Used as a kind of preferred version, in above-mentioned preparation method, shaking table culture condition is described in step S1：Rotating speed 200rpm,
28 DEG C of temperature, incubation time 72h.
Used as a kind of preferred version, in above-mentioned preparation method, quiescent culture temperature described in step S2 is 25 DEG C, incubation time
For 28 days.
Used as a kind of preferred version, in above-mentioned preparation method, extractum is separated with silica gel column chromatography described in step S3, point
From the ethyl acetate/petroleum ether gradient elution with 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 100%.
During extractum Jing chromatography, the 6th component is chromatographed using polydextran gel Sephadex LH-20, is 1 with volume ratio：
1 methanol-chloroform carries out eluting for eluant, then with silica gel column layer, 25% ethyl acetate-light petrol is eluant, is changed
Compound 2 and 6.8th component using polydextran gel Sephadex LH-20 chromatograph, with volume ratio be methanol be that eluant is washed
It is de-, then with silica gel column layer, 30% ethyl acetate-light petrol is eluant, obtains compound 3 and 4.15th component adopts glucosan
Gel Sephadex LH-20 are chromatographed, and are 1 with volume ratio：1 methanol-chloroform carries out eluting for eluant, then is prepared with half anti-
Phase high performance liquid chromatography prepares compound 1 and 5.
The depsidcs 1-6 of the present invention has inhibitory action to alpha-glucosidase, can be used to prepare phlorose
Glycosides enzyme inhibitor medicine, treats type ii diabetes.Therefore, claimed depsidcs 1-6 is preparing treatment
Application in type ii diabetes medicine.In addition, the present invention also protects depsidcs 1-6 preparing alpha-glucosidase suppression
Application in preparation.
Compared with prior art, the present invention has the advantages that：
The present invention is separated from the root of Guangdong Huizhou marine site Kandelia candel mangrove and obtains a fungal strain Meyerozyma
sp.HZ-Y2, and first separation obtains a class depsidcs 1-6 from the fermentation liquid of the bacterial strain, these compounds have
Alpha-glucosidase activity is significantly inhibited, alpha-glucosidase inhibitor medicament is being prepared, is had in treatment type ii diabetes good
Good market prospect.In addition, the depsidcs 1-6 of the present invention derive from marine fungi, from funguses detached side is extracted
Method is simple, with low cost.
Description of the drawings
Fig. 1 is double inverse enzymatic kinetic curves of the alpha-glucosaccharase enzyme inhibition of compound 1.
Fig. 2 is double inverse enzymatic kinetic curves of the alpha-glucosaccharase enzyme inhibition of compound 3.
Fig. 3 is double inverse enzymatic kinetic curves of the alpha-glucosaccharase enzyme inhibition of compound 5.
Specific embodiment
The present invention is made with reference to Figure of description and specific embodiment further being elaborated, the embodiment
It is served only for explaining the present invention, is not intended to limit the scope of the present invention.Test method used in following embodiments is such as without spy
Different explanation, is conventional method；Material, reagent for being used etc., are the reagent for commercially obtaining if no special instructions
And material.
Embodiment 1
Marine fungi Meyerozyma sp.HZ-Y of the present invention2It is the root portion from Guangdong Huizhou marine site Kandelia candel mangrove
From obtaining, separation method refers to this area conventional separation methods.By marine fungi Meyerozyma sp.HZ-Y after separation2In
On April 6th, 2015 is deposited in China typical culture collection center, and preservation address is Wuhan University of Wuhan, China city, and preservation is compiled
Number be CCTCC NO：M 2015203.
From marine fungi Meyerozyma sp.HZ-Y2Fermentation liquid in separate and obtain depsidcs, concrete step
It is rapid as follows：
S1. seed culture：
S11. seed culture medium is prepared：Rhizoma Solani tuber osi 200g, glucose 20g, tap water 1L, average mark is loaded on 5 500mL cones
Shape bottle, 121 DEG C go out 30 minutes.
S12. the culture of seed：By marine fungi Meyerozyma sp.HZ-Y2Bacterial strain access seed culture medium, 28
At a temperature of DEG C, put with the rotating speed of 200rpm on shaking table, culture obtains seed culture fluid in 72 hours.
S2. fermentation culture：
S21. fermentation medium is prepared：Northeast rice 7000g, sea salt 210g, tap water 7L, 121 DEG C go out 30 minutes.
S22. fermentation culture：Sterile working accesses seed liquor 5mL in the conical flask equipped with fermentation medium, quiet in 25 DEG C
Put culture 28 days.
S3. extract and separate：
Fermented product is soaked with methanol, and soak concentrating under reduced pressure at less than 50 DEG C obtains extractum 12.2g.Extractum Jing silicagel columns
Chromatography separated, respectively with 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 100% ethyl acetate-stone
Oily ether gradient elution, is divided into 30 components.Wherein the 6th component is chromatographed using polydextran gel Sephadex LH-20, uses volume ratio
For 1：1 methanol-chloroform carries out eluting for eluant, then with silica gel column layer, 25% ethyl acetate-light petrol is eluant, is obtained
Obtain compound 2 and 6.8th component using polydextran gel Sephadex LH-20 chromatograph, with volume ratio be methanol be that eluant enters
Row eluting, then with silica gel column layer, 30% ethyl acetate-light petrol is eluant, obtains compound 3 and 4.15th component adopts Portugal
Polysaccharide gel Sephadex LH-20 are chromatographed, and are 1 with volume ratio:1 methanol-chloroform carries out eluting for eluant, then is made with half
Standby reversed-phase high-performance liquid chromatography prepares compound 1 and 5.
Embodiment 2
Structural analyses test is carried out to the compound in embodiment 1, following physicochemical property data is obtained：
Compound 1：Pale yellow powder, 146-147 DEG C of fusing point (thermometer is not corrected), EI-MS (m/z)：288[M]+。
Compound 2：Faint yellow acicular crystal, 165-166 DEG C of fusing point (thermometer is not corrected), EI-MS (m/z)：300[M
]+。
Compound 3：White powder, 147-148 DEG C of fusing point (thermometer is not corrected), EI-MS (m/z)：302[M]+。
Compound 4：Pale yellow powder, 143-144 DEG C of fusing point (thermometer is not corrected), EI-MS (m/z)：316[M]+。
Compound 5：Pale yellow oil, EI-MS (m/z)：302[M]+。
Compound 6：Faint yellow acicular crystal, 169-170 DEG C of fusing point (thermometer is not corrected), EI-MS (m/z)：314[M
]+。
The NMR data of compound 1-3 is shown in Table the NMR data of Isosorbide-5-Nitrae-5 and is shown in Table 2.
The NMR data (100MHz/400MHz, TMS, ppm) of the compound 1-3 of table 1
The NMR data (100MHz/400MHz, TMS, ppm) of the compound 4-6 of table 2
According to data above, learn the structural formula of compound 1-6 as shown in formula I：
Embodiment 3
Alpha-glucosidase Inhibition test is carried out to the compound 1-6 in embodiment 1：
Adopt paranitrophenol-alpha-glucosaccharase (pNPG) for substrate, enter in 0.01M phosphate buffers (pH=7.0)
OK.PNPG is paranitrophenol by alpha-glucosidase enzymolysis, is measured at 400nm wavelength with ultraviolet-visible spectrophotometer
The change of its absorbance and calculate the activity of enzyme.Sample and positive control (Acarbose) are made into DMSO solution and (are 10 μ
Mol/mL), enzyme and substrate 0.01M phosphate buffers are made into suitable concentration solution, and 1mL primary response systems include 0.1unit
Enzyme, 20 μ L substrates, 20 μ L DMSO.Appropriate enzyme liquid is taken, the DMSO solution of blank DMSO solution or sample is added, is mixed, 37 DEG C
Under, constant temperature 20 minutes adds substrate, mixes, and detects the changing value of the absorbance of system in 1min at 400nm wavelength immediately.
Enzymatic activity is calculated with equation below：Suppression ratio (%)=[(B-S)/B] × 100%, wherein B is extinction when adding blank DMSO
Degree changing value, S is the absorbance change value of sample.The sample of 5 concentration is determined, dosage-suppression ratio curve is drawn, it is drawn
IC50Value.Each sample is repeated three times, and is as a result represented with meansigma methodss ± standard deviation.
As a result measuring compound 1-6 can significantly inhibit the activity of alpha-glucosidase, its IC50Value is respectively 10.4 μM,
13.3 μM, 2.1 μM, 12.4 μM, 9.8 μM and 11.7 μM, the wherein IC of positive control Acarbose50For 553.7 μM.In addition 3 groups
As shown in Figures 1 to 3, response speed Vmax diminishes suppression double reciprocal curve under inhibitor concentration with inhibitor concentration increase,
And the Michaelis constant (Km) of alpha-glucosidase keeps constant under different inhibitor concentration, double reciprocal curve meets at abscissa
On, it is typical Noncompetition inhibition kinetic curve.Therefore, compound 1,3 and 5 is all noncompetitive inhibitor.
Claims (6)
1. a class marine fungi source depsidcs preparation method, it is characterised in that depsidcs 1-6
Structural formula such as formula（Ⅰ）It is shown：
Formula（Ⅰ）Depsidcs 1-6；
Depsidcs 1-6 are to separate to obtain from the fermentation liquid of marine fungi Meyerozyma sp.HZ-Y2；Institute
State marine fungi Meyerozyma sp.HZ-Y2 and be deposited in China typical culture collection center, preservation on April 6th, 2015
Address is Wuhan University of Wuhan, China city, and deposit number is CCTCC NO：M 2015203；
The preparation method of the depsidcs comprises the steps：
S1. by marine fungi Meyerozymasp.HZ-Y2Seed culture medium is accessed, shaking table culture obtains seed culture fluid；
S2. seed culture fluid is accessed in fermentation medium, quiescent culture；
S3. tunning is filtrated to get into thalline, thalline is soaked with methanol, and concentrating under reduced pressure obtains extractum, then Jing chromatography,
Obtain depsidcs 1-6.
2. preparation method according to claim 1, it is characterised in that the component of the seed culture medium is：Rhizoma Solani tuber osi
200g, glucose 20g, water 1L.
3. preparation method according to claim 1, it is characterised in that the component of the fermentation medium is：Northeast rice
7000g, sea salt 210g, water 7L.
4. preparation method according to claim 1, it is characterised in that shaking table culture condition is described in step S1：Rotating speed
200rpm, 28 DEG C of temperature, incubation time 72h.
5. preparation method according to claim 1, it is characterised in that quiescent culture temperature described in step S2 is 25 DEG C, training
The foster time is 28 days.
6. preparation method according to claim 1, it is characterised in that the silica gel column chromatography of extractum described in step S3 is carried out point
From, separate with 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 100% ethyl acetate/petroleum ether gradient elution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510205871.1A CN104987319B (en) | 2015-04-27 | 2015-04-27 | Marine fungus-derived depside compounds and application thereof in treatment of type 2 diabetes |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510205871.1A CN104987319B (en) | 2015-04-27 | 2015-04-27 | Marine fungus-derived depside compounds and application thereof in treatment of type 2 diabetes |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104987319A CN104987319A (en) | 2015-10-21 |
| CN104987319B true CN104987319B (en) | 2017-05-17 |
Family
ID=54299240
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510205871.1A Active CN104987319B (en) | 2015-04-27 | 2015-04-27 | Marine fungus-derived depside compounds and application thereof in treatment of type 2 diabetes |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104987319B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108925565B (en) * | 2018-06-20 | 2021-05-07 | 广东海洋大学深圳研究院 | Application of depside cyclic ether compound |
| CN108640841B (en) * | 2018-06-20 | 2021-04-02 | 广东海洋大学 | Depside cyclic ether compound and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008144982A1 (en) * | 2007-05-29 | 2008-12-04 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Compounds with 7-member cycle and the pharmaceutical use thereof for preventing and treating diabetes and metabolism syndrome |
| CN101376655A (en) * | 2008-10-11 | 2009-03-04 | 中国海洋大学 | Penicillazine derivative, and preparation and use thereof |
| EP2230235A1 (en) * | 2009-03-17 | 2010-09-22 | Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e.V. -Hans-Knöll-Institut- (HKI) | Botryosphaerones, novel depsidones and their use as medicaments |
-
2015
- 2015-04-27 CN CN201510205871.1A patent/CN104987319B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008144982A1 (en) * | 2007-05-29 | 2008-12-04 | Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences | Compounds with 7-member cycle and the pharmaceutical use thereof for preventing and treating diabetes and metabolism syndrome |
| CN101376655A (en) * | 2008-10-11 | 2009-03-04 | 中国海洋大学 | Penicillazine derivative, and preparation and use thereof |
| EP2230235A1 (en) * | 2009-03-17 | 2010-09-22 | Leibniz-Institut für Naturstoff-Forschung und Infektionsbiologie e.V. -Hans-Knöll-Institut- (HKI) | Botryosphaerones, novel depsidones and their use as medicaments |
Non-Patent Citations (3)
| Title |
|---|
| Botryorhodines A–D, antifungal and cytotoxic depsidones from Botryosphaeria rhodina, an endophyte of the medicinal plant Bidens pilosa;Randa Abdou et al.;《Phytochemistry》;20091111;第71卷;第110-116页 * |
| Metabolites from the Lichen Genus Psoroma;John A. Elix et al.;《Aust. J. Chem》;19821231;第35卷;第2325-2333页 * |
| New Depsidones from the Lichen Genus Erioderma;John A. Elix et al.;《Aust. J. Chem.》;19861231;第39卷;第719-722页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104987319A (en) | 2015-10-21 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108546306B (en) | Cordyceps militaris culture medium polysaccharide, and separation and purification method and application thereof | |
| CN104987316A (en) | Marine fungus-derived polyketone compound and application thereof in treatment of type 2 diabetes | |
| CN109970538A (en) | The Dimeric sesquiterpene compound in a kind of marine fungi source and preparation method thereof and application in preparing anti-inflammatory drugs | |
| CN103694209B (en) | The acetophenone compounds in one class thalassiomycetes source and preparation method thereof and application | |
| CN104987319B (en) | Marine fungus-derived depside compounds and application thereof in treatment of type 2 diabetes | |
| CN103880826B (en) | A kind of isobenzofuran ketonic compound and its preparation method and application | |
| CN102250170B (en) | Preparation method and application of two active flavonoid glycosides in okra fruits | |
| CN106188084B (en) | The naphthalene Spiroketals class compound in marine fungi source and its preparation method and application | |
| CN108315264A (en) | A kind of polyketide in sea paint endogenetic fungus source and its application in preparing anti-inflammatory drug | |
| CN104311526B (en) | The dinaphthalene analog derivative in thalassiomycetes source and preparation method thereof and the application in tuberculosis | |
| CN104311525A (en) | Use of marine fungus-derived Azaphilone compound in preparation of antituberculosis drugs | |
| CN103113489B (en) | Method of purifying polysaccharide of Xinjiang jun dates | |
| CN106636252B (en) | Wizened bacterium exopolysaccharide and its preparation method and application | |
| CN106138130B (en) | Mango seed flavone extract and preparation method thereof | |
| CN108383824B (en) | Benzopyrone dimer and extraction method and application thereof | |
| CN108948038B (en) | Neopteridine flavonoid compound and application thereof | |
| CN100509963C (en) | Method for preparing natural anthraquinone pigments using bamboo parasitic fungus fermentation | |
| CN109096056B (en) | Bisabolane sesquiterpenoids from mangrove endophytic fungi, preparation method and application in anti-type II diabetes drugs | |
| CN109810113A (en) | A kind of alkaloid compound and the preparation method and application thereof | |
| CN116121319A (en) | Extracellular polysaccharide and preparation method and application thereof | |
| CN108276467A (en) | A kind of Tea Saponin and its extraction process and application | |
| CN108079025A (en) | Application of the undaria pinnitafida extract in alpha-glucosidase restrainer is prepared | |
| CN106119313A (en) | A kind of liquid fermentation method of phellinus igniarius mycelium | |
| CN106565444A (en) | Extraction method and application of phenanthrene compounds from overground part of Chinese yam | |
| CN104230938A (en) | Marine fungus-derived piperazine derivative and application of derivative in preparation of antituberculosis drugs |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |