CN106748778A - A kind of new bibenzyl natural drug with hypoglycemic effect and its production and use - Google Patents
A kind of new bibenzyl natural drug with hypoglycemic effect and its production and use Download PDFInfo
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- CN106748778A CN106748778A CN201611094254.XA CN201611094254A CN106748778A CN 106748778 A CN106748778 A CN 106748778A CN 201611094254 A CN201611094254 A CN 201611094254A CN 106748778 A CN106748778 A CN 106748778A
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- China
- Prior art keywords
- bibenzyl
- extract
- aglaia odorata
- aglaia
- odorata
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- Granted
Links
- 239000003814 drug Substances 0.000 title claims abstract description 16
- 229940079593 drug Drugs 0.000 title claims abstract description 8
- QWUWMCYKGHVNAV-UHFFFAOYSA-N 1,2-dihydrostilbene Chemical group C=1C=CC=CC=1CCC1=CC=CC=C1 QWUWMCYKGHVNAV-UHFFFAOYSA-N 0.000 title claims description 26
- 230000002218 hypoglycaemic effect Effects 0.000 title claims description 7
- 238000004519 manufacturing process Methods 0.000 title abstract 2
- 240000000595 Aglaia odorata Species 0.000 claims abstract description 37
- 235000010887 Aglaia odorata Nutrition 0.000 claims abstract description 37
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 208000008589 Obesity Diseases 0.000 claims abstract description 8
- 235000020824 obesity Nutrition 0.000 claims abstract description 8
- 241000730318 Aglaia abbreviata Species 0.000 claims abstract description 6
- 235000013402 health food Nutrition 0.000 claims abstract description 6
- 239000000284 extract Substances 0.000 claims description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 28
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 16
- 238000010828 elution Methods 0.000 claims description 15
- 239000003208 petroleum Substances 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 11
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 9
- 230000000694 effects Effects 0.000 claims description 9
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 8
- 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 claims description 6
- 239000000725 suspension Substances 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- 201000010099 disease Diseases 0.000 claims description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 5
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 5
- 239000002024 ethyl acetate extract Substances 0.000 claims description 3
- 239000000945 filler Substances 0.000 claims description 3
- 239000000499 gel Substances 0.000 claims description 3
- 238000001641 gel filtration chromatography Methods 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 238000010898 silica gel chromatography Methods 0.000 claims description 3
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 241000158728 Meliaceae Species 0.000 claims 1
- 230000002401 inhibitory effect Effects 0.000 abstract description 7
- 238000002474 experimental method Methods 0.000 abstract description 5
- 102000004169 proteins and genes Human genes 0.000 abstract description 5
- 108090000623 proteins and genes Proteins 0.000 abstract description 5
- 239000003801 protein tyrosine phosphatase 1B inhibitor Substances 0.000 abstract description 4
- 238000005516 engineering process Methods 0.000 abstract description 3
- 108090000371 Esterases Proteins 0.000 abstract description 2
- 101001087394 Homo sapiens Tyrosine-protein phosphatase non-receptor type 1 Proteins 0.000 abstract 2
- 102100033001 Tyrosine-protein phosphatase non-receptor type 1 Human genes 0.000 abstract 2
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 239000008280 blood Substances 0.000 abstract 1
- 210000004369 blood Anatomy 0.000 abstract 1
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 1
- 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 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 102000002727 Protein Tyrosine Phosphatase Human genes 0.000 description 6
- 108020000494 protein-tyrosine phosphatase Proteins 0.000 description 6
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- 102000004877 Insulin Human genes 0.000 description 5
- 108090001061 Insulin Proteins 0.000 description 5
- 229940125396 insulin Drugs 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- XZKIHKMTEMTJQX-UHFFFAOYSA-N 4-Nitrophenyl Phosphate Chemical compound OP(O)(=O)OC1=CC=C([N+]([O-])=O)C=C1 XZKIHKMTEMTJQX-UHFFFAOYSA-N 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 230000001629 suppression Effects 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 241000588724 Escherichia coli Species 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 241000233855 Orchidaceae Species 0.000 description 2
- 240000007594 Oryza sativa Species 0.000 description 2
- 235000007164 Oryza sativa Nutrition 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 238000002114 high-resolution electrospray ionisation mass spectrometry Methods 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 235000009566 rice Nutrition 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 238000010998 test method Methods 0.000 description 2
- 208000035408 type 1 diabetes mellitus 1 Diseases 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- GXWUEMSASMVWKO-GNLHUFSQSA-N (4as,6ar,6as,6br,10s,12ar,14br)-10-[(2s,3r,4s,5s)-4,5-dihydroxy-3-[(2r,3r,4s,5s,6r)-3,4,5-trihydroxy-6-(hydroxymethyl)oxan-2-yl]oxyoxan-2-yl]oxy-2,2,6a,6b,9,9,12a-heptamethyl-1,3,4,5,6,6a,7,8,8a,10,11,12,13,14b-tetradecahydropicene-4a-carboxylic acid Chemical compound O([C@@H]1[C@@H](O)[C@@H](O)CO[C@H]1O[C@H]1CC[C@]2(C)[C@H]3CC=C4[C@@]([C@@]3(CCC2C1(C)C)C)(C)CC[C@]1(CCC(C[C@@H]14)(C)C)C(O)=O)[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O GXWUEMSASMVWKO-GNLHUFSQSA-N 0.000 description 1
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 1
- FYKHWKNFKLTGNX-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1.OC1=CC=C([N+]([O-])=O)C=C1 FYKHWKNFKLTGNX-UHFFFAOYSA-N 0.000 description 1
- 102000003746 Insulin Receptor Human genes 0.000 description 1
- 108010001127 Insulin Receptor Proteins 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 102000002072 Non-Receptor Type 1 Protein Tyrosine Phosphatase Human genes 0.000 description 1
- 108010015847 Non-Receptor Type 1 Protein Tyrosine Phosphatase Proteins 0.000 description 1
- 102000004160 Phosphoric Monoester Hydrolases Human genes 0.000 description 1
- 108090000608 Phosphoric Monoester Hydrolases Proteins 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102000018120 Recombinases Human genes 0.000 description 1
- 108010091086 Recombinases Proteins 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 210000000577 adipose tissue Anatomy 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012131 assay buffer Substances 0.000 description 1
- 239000002021 butanolic extract Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000005325 percolation Methods 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- DCWXELXMIBXGTH-QMMMGPOBSA-N phosphonotyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-QMMMGPOBSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 210000002027 skeletal muscle Anatomy 0.000 description 1
- 230000003595 spectral effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- -1 tyrosine ester Chemical class 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/56—Separation; Purification; Stabilisation; Use of additives by solid-liquid treatment; by chemisorption
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
- C07C67/58—Separation; Purification; Stabilisation; Use of additives by liquid-liquid treatment
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Abstract
The present invention relates to pharmaceutical technology field, it is related to extract new natural drug isolated, with function of blood sugar reduction from Chinese dark green Aglaia odorata Aglaia abbreviata C.Y.Wu blades, the medicine is Bibenzyl compound bibenzyl Aglaia odorata element A (aglaiabbrevin A).External PTP1B suppresses experiment and shows, compound for protein TYR esterase 1B (PTP1B) has certain inhibitory activity, therefore pharmaceutical preparation is can be made into as PTP1B inhibitor, for treating diabetes, obesity and its complication, it is also possible to which manufacture is beneficial to the health food of diabetic or obese patient.
Description
Technical field
The present invention relates to pharmaceutical technology field, relate in particular to a kind of isolated from Chinese dark green Aglaia odorata blade
, new Bibenzyl compound bibenzyl Aglaia odorata element A (aglaiabbrevin A) with hypoglycemic effect.The invention further relates to
The compound can be used to prepare PTP1B inhibitor, it can also be used to prepare treatment diabetes, the medicine of obesity and its complication or
Health food.
Background technology
Diabetes (diabetes mellitus) be one group caused by h and E factor interaction it is clinical comprehensive
Close disease.At present, diabetes are typically divided into two classes, I- patients with type Ⅰ DM (insulin-dependent diabetes mellitus, insulin-
Dependent diabetes mellitus, IDDM) and II- patients with type Ⅰ DM (Non-Insulin Dependent Diabetes Mellitus, non-
Insulin-dependent diabetes mellitus, NIDDM).90% above is II- patients with type Ⅰ DM in diabetes.
The characteristics of II- patients with type Ⅰ DM is that insulin sensitive tissues such as skeletal muscle, liver, adipose tissue are supported to insulin action
It is anti-.Protein-tyrosine-phosphatase (PTPases) GAP-associated protein GAP tyrosine phosphatase in insulin action path in statocyte
Effect in change level is increasingly taken seriously, the new way as treatment II- patients with type Ⅰ DM.PTPase includes big nation's cross-film
(receptor type) and intracellular (non-receptor type) enzyme, participates in a series of important life processes of regulation and control.At present, it is logical in insulin to PTPase
In road acceptor or acceptor metasomite influence Normal insulin effect research, be concentrated mainly on LAR-PTPase, SHPTP-2,
PTP1B。
PTP1B is first certified protein-tyrosine-phosphatase (protein tyrosine
Phosphatase), the experiment on mice rejected by PTP1B shows that PTP1B is acylated by the dephosphorization to insulin receptor, and then
Very important effect is played in regulation insulin sensitivity and fat metabolic process.Thus, it is selective, high activity
PTP1B inhibitor has important value in the treatment of II- patients with type Ⅰ DM, obesity and its complication.
The content of the invention
The present invention be extracted from Chinese dark green Aglaia odorata (A.abbreviata) blade it is isolated, with hypoglycemic
New Bibenzyl compound bibenzyl Aglaia odorata element A (aglaiabbrevin A) of effect.Show through pharmacological testing research, the chemical combination
Thing has certain inhibitory activity to protein tyrosine phosphate 1B (PTP1B).
Therefore, it is an object of the present invention to provide new Bibenzyl compound bibenzyl Aglaia odorata element A.
It is a further object to provide the preparation method of the bibenzyl Aglaia odorata element A.
The further object of the present invention is to provide the purposes of the bibenzyl Aglaia odorata element A.Specifically, the bibenzyl rice is young
Applications of the orchid element A in the medicine for preparing protein-tyrosine-phosphatase 1B (PTP1B) inhibitor, is further preparing treatment sugar
Application in the medicine or health food of urine disease, obesity and its complication.
First purpose of the invention, the present invention is found that a new bibenzyl from dark green Aglaia odorata blade first
Class compound bibenzyl Aglaia odorata element A, its chemical constitution is as follows：
Second purpose of the invention, the present invention provides the preparation method of the bibenzyl Aglaia odorata element A, and it is from green
It is isolated in green Aglaia odorata blade, comprise the following steps that：
1) extract medicinal extract is prepared
Dark green Aglaia odorata (A.abbreviata) the blade ethanol routinely seepage pressure effects that will be crushed, obtain extract solution, will
Extract solution is concentrated under reduced pressure to reclaim ethanol, obtains CE；
2) isolate and purify
(1) above-mentioned CE is dispersed in water into suspension, suspension is used into petroleum ether, ethyl acetate and positive fourth successively
Alcohol is extracted, and the concentration of gained extract respectively obtains petroleum ether and extracts medicinal extract, ethyl acetate extraction medicinal extract and n-butanol extraction medicinal extract；
(2) ethyl acetate extract is carried out into silica gel column chromatography, with petroleum ether/acetone gradient elution, is developed the color according to TLC and merged
Similar stream part obtains 4 components A, B, C, D；Wherein component B is petroleum ether/acetone volume ratio 8:2 and 7:3 elution fractions are passed through
Sephadex LH-20 gel filtration chromatography (chromatographic column specifications：4.0 (diameter) × 120 (length) cm；Sephadex LH-20 gels
Dry weight：150g), with methylene chloride/methanol volume ratio 1:1 wash-out, merges similar stream part and obtains 6 components according to TLC colour developings
(B1-B6)；Component B5, i.e. methylene chloride/methanol volume ratio 1:1 elution volume is 170~210mL elution fractions, then through preparing
Type HPLC, with acetonitrile/water 75:25 volume ratios are eluted, and obtain the compounds of this invention bibenzyl Aglaia odorata element A.
In above-mentioned preparation method, in extract medicinal extract step is prepared, the ethanol for using that extracts is 95% ethanol.
In above-mentioned preparation method, in separating step, the concentration of petroleum ether/acetone gradient elution is followed successively by volume ratio
100:0、90:10、80:20、70:30、50:50、30:70 and 0:100.
In above-mentioned preparation method, in separating step, the filler of the chromatographic column of the preparation HPLC is RP-18.
3rd purpose of the invention, PTP1B suppression is being prepared the invention provides the bibenzyl Aglaia odorata element A
Agent, diabetes medicament, the purposes of obesity drug, and prepare the use for diabetic or obese patient's health food
On the way.
In order to reach application purpose, tablet, capsule can be made, granule, oral liquid, sustained release preparation, controlled release preparation, received
The form such as metric system agent or injection.
The present invention has carried out external PTP1B to gained bibenzyl Aglaia odorata element A and has suppressed experiment, as a result shows the compound pair
PTP1B has certain inhibitory activity.Therefore, can be used to prepare PTP1B inhibitor, for diabetes, obesity and its concurrent
In disease drug or health food.
Brief description of the drawings
Fig. 1 PTP1B inhibitory activity test philosophies
Specific embodiment
Chemical structural formula (the Arabic numerals in structural formula of signified bibenzyl Aglaia odorata element A in examples below
It is the mark of carbon atom in chemical constitution)：
The preparation of bibenzyl Aglaia odorata element A described in embodiment 1
1. dark green Aglaia odorata leaf extract medicinal extract is prepared
(1) extract solution is prepared
Chinese dark green Aglaia odorata (A.abbreviata) blade (the picking up from In Xishuangbanna of Yunnan) 7.8kg (dry weight) that will be crushed
Extracted three times with the ethanol percolations of 40L 95% respectively, each diacolation 2 days, merge extract solution；
(2) extract medicinal extract is prepared
By said extracted liquid in temperature≤45 DEG C recovery ethanol concentrated under reduced pressure, CE 530g is obtained；
2. isolate and purify
1) above-mentioned CE is scattered in 6L water into suspension, suspension is used into petroleum ether (4L), ethyl acetate successively
(4L) and n-butanol (2L) are extracted three times respectively, and the gained extract petroleum ether that respectively obtains concentrated under reduced pressure extracts medicinal extract (58g), second
Acetoacetic ester extracts medicinal extract (186g) and n-butanol extracts medicinal extract (152g)；
2) ethyl acetate extract is carried out into silica gel column chromatography, with petroleum ether/acetone gradient elution；The concentration of gradient elution according to
Secondary is volume ratio 100:0、90:10、80:20、70:30、50:50、30:70 and 0:100, similar stream part is merged according to TLC colour developings
Obtain 4 components (A-D)；
3) component B is petroleum ether/acetone volume ratio 8:2 and 7:3 elution fractions are through Sephadex LH-20 gel filtration chromatographies
【Chromatographic column specification：4.0 (diameter) × 120 (length) cm；Sephadex LH-20 gel dry weights：150g】, with dichloromethane/first
Alcohol volume ratio 1:1 wash-out, merges similar stream part and obtains 6 components (B1-B6) according to TLC colour developings；
4) component B5, i.e. methylene chloride/methanol volume ratio 1:1 elution volume is 170~210mL elution fractions, then through system
Standby type HPLC (filler of chromatographic column is RP-18), with acetonitrile/water volume ratio 75:25 wash-outs, flow velocity is 3.5mL/min, during reservation
Between be 8.0min, obtain the compounds of this invention bibenzyl Aglaia odorata element A, be identified as noval chemical compound.
3. Structural Identification
Routinely through the various modern spectral technique such as NMR, HRESIMS, UV, IR and optically-active, it is determined that compound bibenzyl rice
The chemical constitution of young orchid element A, its physicochemical property is as follows：
Yellow powder, molecular formula is C21H24O5；
Ultraviolet spectra UV (MeOH) λmax(logε):230(3.52),265(3.20),312(2.96)nm；
Infrared spectrum IR (KBr) νmax:3312,1654,1598,1510,1420,1216cm–1；
High resolution mass spectrum HR-ESI-MS m/z 355.1544 [M-H]–(calcd for C21H23O5 –,355.1545)；
Proton nmr spectra1H NMR (400MHz) and carbon-13 nmr spectra13C NMR (100MHz) data are shown in Table one
Bibenzyl Aglaia odorata element A described in table one1H and13C NMR(ppm in CDCl3)
The test of the PTP1B inhibitory activity of embodiment 2：
Test philosophy：See Fig. 1.Using molecular biology method people's source protein TYR phosphoric acid is expressed in E. coli system
Esterase 1B (hPTP1B) catalyst structure domain, it is purified after hPTP1B recombinant proteins can hydrolyze substrate p-nitrophenyl phosphoric acid (p-
Nitrophenyl phosphate, pNPP) phosphatide key, obtain yellow soluble product p-nitrophenol (p-
Nitrophenol), the product has very strong light absorbs at 410nm, therefore can be with the change of light absorbs at direct detection 410nm
Change and observe the suppression situation of activity change and compound to enzymatic activity of enzyme.
The live body system of standard：10mM Tris.Cl tri- (methylol) aminomethane hydrochloride), pH 7.6,10mM
PNPP, 2%DMSO, 100nM hPTP1B.
Observation index：It is the light absorbs at 410nm that dynamic determines wavelength, and the time is 3 minutes, and its kinetic curve one-level is anti-
The slope answered as enzyme activity index.
Test method：Protein-tyrosine-phosphatase PTP1B for screening is from expression in escherichia coli and purifies
Gst fusion protein.Using ultraviolet suitable substrates p-nitrophenyl phosphoric acid (pNPP), active suppression of the observation various concentrations to recombinase
Make and use, with the medicinal effects of preliminary assessment compound.Before use by sample bibenzyl Aglaia odorata element A be dissolved in DMSO be made into it is appropriate dense
Degree, 3 times of dilutions, 7 dilution factors set three wells, take 2 μ L samples solution and add 96 orifice plates, are subsequently adding 88 μ L assay
Mix (assay buffer, pNPP, H2O), 10 μ L PTP1B are added.96 orifice plates are placed in dynamic detection ripple on VERSAmax
Absorbance value is detected at a length of 410nm, the time is 3 minutes.
The judge of experimental result and explanation：
The selection result is the percent inhibition to enzymatic activity when compound bibenzyl Aglaia odorata element A concentration is 20 μ g/ml, is suppressed
Rate be higher than 50% when, routinely screening (by inhibiting rate higher than 50% detected diluted chemical compound into different concentration, according to above-mentioned
Method of testing is reacted, and all experiments are respectively provided with multiple holes) draw IC50, the IC of positive control oleanolic acid50For 2.74 ±
0.20μM。
Experimental result：ICs of the compounds of this invention bibenzyl Aglaia odorata element A to PTP1B enzyme inhibition activities50It is 15.51 ± 1.54
μM。
Experiment conclusion：By molecular biology test, it can be seen that compound bibenzyl Aglaia odorata element A is to protein tyrosine ester
Enzyme 1B (PTP1B) has preferable inhibitory activity.Therefore, bibenzyl Aglaia odorata element A of the invention can be used to prepare diabetes, obesity
In the medicine of disease and its complication.
Claims (5)
1. a kind of new bibenzyl natural drug bibenzyl Aglaia odorata element A with hypoglycemic effect, it is characterised in that with followingization
Learn structure：
。
2. the new bibenzyl natural drug bibenzyl Aglaia odorata element A with hypoglycemic effect according to claim 1, its feature
It is that described compound is obtained from the dark green Aglaia odorata of Meliaceae plant, dark green Aglaia odorata scientific name is Aglaia
abbreviata C.Y.Wu。
3. there is the new bibenzyl natural drug bibenzyl Aglaia odorata element A of hypoglycemic effect, its preparation process is such as described in claim 1
Under：
1) extract medicinal extract is prepared
Dark green Aglaia odorata (A.abbreviata) the blade ethanol routinely seepage pressure effects that will be crushed, obtain extract solution, will extract
Liquid is concentrated under reduced pressure to reclaim ethanol, obtains CE；
2) isolate and purify
(1) above-mentioned CE is dispersed in water into suspension, suspension is extracted with petroleum ether, ethyl acetate and n-butanol successively
Take, the concentration of gained extract respectively obtains petroleum ether and extracts medicinal extract, ethyl acetate extraction medicinal extract and n-butanol extraction medicinal extract；
(2) ethyl acetate extract is carried out into silica gel column chromatography, with petroleum ether/acetone gradient elution, merges similar according to TLC colour developings
Stream part obtains 4 components A, B, C, D；Wherein component B is petroleum ether/acetone volume ratio 8:2 and 7:3 elution fractions are through Sephadex
LH-20 gel filtration chromatographies (chromatographic column specification：4.0 (diameter) × 120 (length) cm；Sephadex LH-20 gel dry weights：
150g), with methylene chloride/methanol volume ratio 1:1 wash-out, merges similar stream part and obtains 6 components (B1-B6) according to TLC colour developings；
Component B5 is methylene chloride/methanol volume ratio 1:1 elution volume is 170~210mL elution fractions, then through preparation HPLC, with
Acetonitrile/water 75:25 volume ratios are eluted, and obtain the compounds of this invention bibenzyl Aglaia odorata element A；
In extract medicinal extract step is prepared, the ethanol for using that extracts is 95% ethanol.
In separating step, the concentration of petroleum ether/acetone gradient elution is followed successively by volume ratio 100:0、90:10、80:20、70:
30、50:50、30:70 and 0:100.
In separating step, the filler of the chromatographic column of the preparation HPLC is RP-18.
4. bibenzyl Aglaia odorata element A according to claim 1 is preparing treatment diabetes, obesity as the active component of medicine
Application in disease and its complication medicine.
5. the bibenzyl Aglaia odorata element A described in claim 1 prepare for diabetic or obese patient's health food should
With.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113461532A (en) * | 2021-07-05 | 2021-10-01 | 南昌大学 | Black mulberry extract A with blood sugar reducing effect, and preparation method and application thereof |
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| US20020058701A1 (en) * | 2000-08-16 | 2002-05-16 | Inman Wayne D. | Compositions containing hypoglycemically active stilbenoids |
| US20020058708A1 (en) * | 2000-08-16 | 2002-05-16 | Inman Wayne D. | Compositions containing hypotriglyceridemically active stilbenoids |
| US20020058707A1 (en) * | 2000-08-16 | 2002-05-16 | Hopp David C. | Compositions containing hypoglycemically active stilbenoids |
| WO2014177593A1 (en) * | 2013-04-29 | 2014-11-06 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Amorfrutin analogs as ppargamma-modulators |
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| US20020058701A1 (en) * | 2000-08-16 | 2002-05-16 | Inman Wayne D. | Compositions containing hypoglycemically active stilbenoids |
| US20020058708A1 (en) * | 2000-08-16 | 2002-05-16 | Inman Wayne D. | Compositions containing hypotriglyceridemically active stilbenoids |
| US20020058707A1 (en) * | 2000-08-16 | 2002-05-16 | Hopp David C. | Compositions containing hypoglycemically active stilbenoids |
| WO2014177593A1 (en) * | 2013-04-29 | 2014-11-06 | MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. | Amorfrutin analogs as ppargamma-modulators |
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| CN113461532A (en) * | 2021-07-05 | 2021-10-01 | 南昌大学 | Black mulberry extract A with blood sugar reducing effect, and preparation method and application thereof |
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