CN115010598B - Compound Villanovane VI, pharmaceutical composition thereof, preparation method and application thereof - Google Patents
Compound Villanovane VI, pharmaceutical composition thereof, preparation method and application thereof Download PDFInfo
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims abstract description 27
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 18
- 239000003814 drug Substances 0.000 claims abstract description 20
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 51
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 30
- 239000000284 extract Substances 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 16
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 15
- 239000003208 petroleum Substances 0.000 claims description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- 238000010898 silica gel chromatography Methods 0.000 claims description 10
- 230000002441 reversible effect Effects 0.000 claims description 7
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- 230000002401 inhibitory effect Effects 0.000 abstract description 16
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- 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 5
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- 239000000243 solution Substances 0.000 description 15
- -1 diterpenoid compounds Chemical class 0.000 description 10
- IFBHRQDFSNCLOZ-ZIQFBCGOSA-N 4-nitrophenyl alpha-D-glucoside 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-ZIQFBCGOSA-N 0.000 description 7
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- DNJVYWXIDISQRD-UHFFFAOYSA-N Cafestol Natural products C1CC2(CC3(CO)O)CC3CCC2C2(C)C1C(C=CO1)=C1CC2 DNJVYWXIDISQRD-UHFFFAOYSA-N 0.000 description 4
- DNJVYWXIDISQRD-JTSSGKSMSA-N cafestol Chemical compound C([C@H]1C[C@]2(C[C@@]1(CO)O)CC1)C[C@H]2[C@@]2(C)[C@H]1C(C=CO1)=C1CC2 DNJVYWXIDISQRD-JTSSGKSMSA-N 0.000 description 4
- 238000003032 molecular docking Methods 0.000 description 4
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- 239000000126 substance Substances 0.000 description 3
- BTJIUGUIPKRLHP-UHFFFAOYSA-N 4-nitrophenol Chemical compound OC1=CC=C([N+]([O-])=O)C=C1 BTJIUGUIPKRLHP-UHFFFAOYSA-N 0.000 description 2
- 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
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- IVZWRQBQDVHDNG-UHFFFAOYSA-N (-)-Kauran; alpha-Dihydrokauren Natural products C1CC2C3(C)CCCC(C)(C)C3CCC22CC(C)C1C2 IVZWRQBQDVHDNG-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
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- 108090000790 Enzymes Proteins 0.000 description 1
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- 241001465754 Metazoa Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
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- 235000021355 Stearic acid Nutrition 0.000 description 1
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
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- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
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- 239000003085 diluting agent Substances 0.000 description 1
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- 125000000567 diterpene group Chemical group 0.000 description 1
- IVZWRQBQDVHDNG-KUIXFMFUSA-N ent-kaurane Chemical compound C([C@@]1(C)[C@@H]2CC3)CCC(C)(C)[C@H]1CC[C@]21C[C@H](C)[C@H]3C1 IVZWRQBQDVHDNG-KUIXFMFUSA-N 0.000 description 1
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- 230000007062 hydrolysis Effects 0.000 description 1
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- 230000002218 hypoglycaemic effect Effects 0.000 description 1
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- 239000007924 injection Substances 0.000 description 1
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- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
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- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
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- LVTHXRLARFLXNR-UHFFFAOYSA-M potassium;1,1,2,2,3,3,4,4,4-nonafluorobutane-1-sulfonate Chemical compound [K+].[O-]S(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F LVTHXRLARFLXNR-UHFFFAOYSA-M 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C62/00—Compounds having carboxyl groups bound to carbon atoms of rings other than six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C62/30—Unsaturated compounds
- C07C62/32—Unsaturated compounds containing hydroxy or O-metal groups
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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Abstract
The invention provides an antipodal-coastal twin flower alkane type coffee diterpene (a compound Villanovane VI), a pharmaceutical composition thereof, a preparation method thereof and application thereof in preparing medicines and foods. Belongs to the technical field of medicines and foods. Novel compound Villanovane VI pairs of the inventionαGlucosidase inhibitory Activity IC 50 mu.M 9.2.+ -. 1.73, villanovane VI pairαGlucosidase inhibitory Activity ratio first-line clinicalαThe glucosidase inhibitory drug Acarbose is stronger. Can be used as medicine for treating diabetes related diseases. Can be used for lowering blood sugar. The preparation method has the advantages of easily obtained raw materials, easy operation and high yield, and is suitable for industrial production.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to an enantiomer-coastal twin-flower alkane type coffee diterpene (a compound Villanovane VI), a pharmaceutical composition thereof, a preparation method thereof and application thereof in preparing medicines.
Background
The coffee diterpene belongs to the diterpene of the enantiomer kaurane, is a very important secondary metabolite in coffee, and two main components are cafestol and cafestol, and due to the non-negligible existence of the coffee diterpene substances in coffee, a great deal of researches are carried out, including novel coffee diterpene structures and active functions. The existing coffee diterpenoid compounds have deeper anti-tumor activity research, and have antibacterial, antiviral and other activities besides the anti-tumor activity.
The present inventors have deeply excavated the novel structure of coffee diterpene and its activity, and have already disclosed coffee diterpene compounds and the like 13 C NMR, build coffee diterpene database; writing data matching grammar (DATAanalyte software) by Python, and performing crude extract 13 C NMR is compared with a database, the main diterpenoid compounds in the crude extract are rapidly analyzed, the crude extract is selectively purified, and the novel active diterpenoid compounds are rapidly discovered, isolated and identified. With this technology, more than 80 new coffee diterpene compounds were found from Yunnan coffee, including oxidized diterpene, rearranged diterpene, furane diterpene, lactam diterpene, lactone diterpene, Δ4,18 diterpene, degraded diterpene, veranova diterpene and althenne diterpene. Recently Minghua research team discovered ten novel enantiomer kaempferia diterpene derivatives from roasted beans of Yunnan coffee. Four of these showed moderate inhibition of alpha-glucosidase, and the two diterpenes Cafestol and kahwiol, which were highest in coffee, did not show inhibition of alpha-glucosidase, but were quite interesting: the main component of coffee diterpene shows moderate alpha-glucosidase inhibitory activity against dehydrochafestol and dehokahweol, corresponding to the dehydration products of Cafestol and kahwiol. This phenomenon suggests that the double bond between C-15 and C-16 is beneficial for the α -glucosidase inhibitory activity. The possible mechanism by which these diterpene derivatives exert activity was studied intensively through molecular docking experiments.
To date, no report has been made in the prior art on the novel compound Villanovane VI, nor on its activity and use.
The invention comprises the following steps:
the invention aims to provide a novel enantiomer-coastal twin flower alkane type coffee diterpene, a pharmaceutical composition thereof, a preparation method thereof and application thereof in preparing medicines.
The invention uses the analysis technology of coffee diterpenoid NMR characteristic database to separate and identify 60 compounds from Yunnan coffee cultivar S288 cooked beans, including 2 types of diterpenoid new skeletons and 32 new compounds. The alpha-glucosidase inhibitory activity experiment is carried out on the coffee diterpene obtained by separation, and the result shows that: the novel compound Villanovane VI shows an inhibitory activity significantly superior to that of acarbose and the like. The novel compound Villanovane VI structure belongs to enantiomer-coastal twin flower alkane diterpene, and the invention also separates the alpha-glucosidase inhibitory activity of the identified partial diterpene, and carries out configuration relation discussion through molecular butt joint.
In order to achieve the above object of the present invention, the present invention provides the following technical solutions:
a compound Villanovane VI shown in the following structural formula,
the invention also provides a preparation method of the compound Villanovane VI, which comprises the following steps: pulverizing Yunnan coffee, reflux-extracting with 3-5 times of methanol under heating for 10 hr and 3 hr respectively, mixing extractive solutions, recovering solvent under reduced pressure to obtain concentrated extract MeOHE, dispersing the extract in water phase, sequentially extracting with petroleum ether and ethyl acetate to obtain two partial extracts PEE and AcOEtE; carrying out flow segmentation on an AcOEtE extract by using petroleum ether/ethyl acetate with volume ratios of 15:1, 10:1, 2:1, 1:1 and 1:4 as mobile phases and chloroform/methanol with volume ratios of 50:1, 20:1, 10:1, 2:1, 1:1 and 0:1 as mobile phases to obtain eight component segments Fr.A-Fr.H; the Fr.B part is segmented by using a C18 reverse phase chromatographic column, water/methanol of 70:30 to 0:100 is used for carrying out fraction segmentation, 9 parts Fr.B-1 to Fr.B-9 are obtained by combining the same parts, wherein the Fr.B-6 part is treated by using normal phase silica gel column chromatography and petroleum ether/ethyl acetate of 4:1 to 0:1, 6 parts Fr.B-6-1 to Fr.B-6 are respectively obtained, the Fr.B-6-4 is purified by using reverse phase silica gel column chromatography and acetonitrile/water of 45:55, and a monomer compound Villanovane VI is obtained.
The invention also provides application of the compound Villanovane VI in preparing a medicament for treating diabetes.
The application of the compound Villanovane VI in preparing hypoglycemic medicine.
In addition, the invention also provides a pharmaceutical composition containing the compound Villanovane VI and a pharmaceutically acceptable carrier.
The preparation method of the pharmaceutical composition comprises the following steps: pulverizing Yunnan coffee, reflux-extracting with 3-5 times of methanol under heating for 10 hr and 3 hr respectively, mixing extractive solutions, recovering solvent under reduced pressure to obtain concentrated extract MeOHE, dispersing the extract in water phase, sequentially extracting with petroleum ether and ethyl acetate to obtain two partial extracts PEE and AcOEtE; carrying out flow segmentation on an AcOEtE extract by using petroleum ether/ethyl acetate with volume ratios of 15:1, 10:1, 2:1, 1:1 and 1:4 as mobile phases and chloroform/methanol with volume ratios of 50:1, 20:1, 10:1, 2:1, 1:1 and 0:1 as mobile phases to obtain eight component segments Fr.A-Fr.H; the Fr.B part is segmented by C18 reversed phase chromatographic column with water/methanol of 70:30 to 0:100, 9 parts Fr.B-1 to Fr.B-9 are obtained by combining the same parts, wherein the Fr.B-6 part is treated by normal phase silica gel column chromatography and petroleum ether/ethyl acetate of 4:1 to 0:1 to respectively obtain 6 parts Fr.B-6-1 to Fr.B-6, the Fr.B-6-4 is purified by reversed phase silica gel column chromatography and acetonitrile/water of 45:55 to obtain a monomer compound Villanovane VI, and then a pharmaceutically acceptable carrier is added.
The application of the pharmaceutical composition in preparing medicines for treating diabetes.
The application of the pharmaceutical composition in preparing hypoglycemic drugs.
When the compound of the present invention is used as a medicament, it may be used as it is or in the form of a pharmaceutical composition. The pharmaceutical composition contains 0.1-99%, preferably 0.5-90% of the compound of the invention, the balance being pharmaceutically acceptable, non-toxic and inert pharmaceutically acceptable carriers and/or excipients for humans and animals.
The pharmaceutically acceptable carriers or excipients are one or more solid, semi-solid and liquid diluents, fillers and pharmaceutical formulation adjuvants. The pharmaceutical composition of the present invention is used in the form of a unit weight dose. The medicine of the present invention may be administered in various forms, including liquid preparation, solid preparation, injection, external preparation, spray and compound preparation.
Compared with the prior art, the invention has the following advantages:
1. the invention provides a novel compound Villanovane VI, which fills the blank of the prior art.
2. The invention provides a method for preparing a novel compound Villanovane VI, which has the advantages of easily available raw materials, easy operation and high yield, and is suitable for industrial production.
3. The invention provides a pharmaceutical composition with a novel compound Villanovane VI as an active ingredient, and provides a novel medicament with better medicinal effect for novel anti-tumor medicaments.
4. Novel compounds of the invention, villanovane VI, have alpha-glucosidase inhibitory Activity IC 50 The (mu M) is 9.2+/-1.73, and the compound Villanovane VI has stronger alpha-glucosidase inhibition activity than the first-line clinical alpha-glucosidase inhibition drug Accarbose.
5. The novel compound Villanovane VI can be used as a medicament for treating diabetes related diseases.
Description of the drawings:
FIG. 1 shows the process flow for the preparation of Villanovane VI;
FIG. 2 Villanovane VI is a result of molecular docking with an alpha-glucosidase protein;
FIG. 3 chemical structure of the compound Villanovane VI is schematically shown.
The specific embodiment is as follows:
the following describes the embodiments of the present invention with reference to the drawings, but the present invention is not limited thereto.
Example 1
Preparation of an enantiomerically-coastal twin-flower alkane type coffee diterpene (compound Villanovane vi):
quantifying the roasted bean of Yunnan coffee S288, crushing the roasted bean, extracting with 3-5 times of methanol under reflux for two times, wherein each extraction time is respectively 10 hours and 3 hours, combining the extracting solutions, recovering the solvent under reduced pressure to obtain concentrated extract MeOHE (yield 20% -25%), dispersing the extract in water phase, extracting sequentially with petroleum ether and ethyl acetate to obtain two partial extracts PEE and AcOEtE (yield 6% -8%).
The AcOEtE extract is put on a normal phase silica gel column, petroleum ether/ethyl acetate is taken as a mobile phase (15:1, 10:1, 2:1, 1:1, 1:4, v/v) and chloroform/methanol is taken as a mobile phase (50:1, 20:1, 10:1, 2:1, 1:1, 0:1, v/v), and the eight component sections (Fr.A-Fr.H) are obtained by flow segmentation. Fractions of Fr.B (yield 0.2% -0.3%) were fractionated with water/methanol (70:30→0:100, v/v) using a C18 reverse phase chromatography column to obtain 9 fractions (Fr.B-1→Fr.B-9). Wherein the Fr.B-6 fraction (yield 0.1% -0.15%) was treated with normal phase silica gel column chromatography (petroleum ether/ethyl acetate, 4:1. Fwdarw.0:1, v/v) to obtain 6 fractions (Fr.B-6-1. Fwdarw.Fr.B-6-6), respectively. Fr.B-6-4 was purified by reverse phase silica gel column chromatography (acetonitrile/water, 45:55) to give the monomer compound Villanovane VI (yield 0.02% -0.04%).
The preparation process flow of the compound Villanovane VI comprises the following steps: according to the experimental summary, the preparation process flow of the target active molecule Villanovane VI is summarized in FIG. 1. Structural characterization of the active molecule of interest Villanovane VI:
1) Chemical structure of compound Villanovane vi:
2) Structural characterization of the compound Villanovane VI.
Villanovane VI: white amorphous powder. [ alpha ]] 28 D 96.54(c 0.26,MeOH)；UV(MeOH)λmax(logε):243.0(4.01),196.0(4.02)；HRESIMS m/z 339.1931[M+Na] + Given the formula C 20 H 28 O 3 (calculated value: C 20 H 28 O 3 Na + ,339.1931)；。
1 H NMR(CH 3 OD,600MHz,J in Hz)δ H :1.50(1H,m,H-1a),1.56(1H,m,H-1b),1.54(1H,m,H-2a),1.93(1H,m,H-2b),1.09(1H,m,H-3a),2.21(1H,m,H-3b),2.11(1H,d,J＝10.2Hz,H-5),6.11(1H,d,J＝10.2Hz,,H-6),5.88(1H,dd,d,J＝3,10.2Hz,H-7),1.33(1H,m,H-11a),1.85(1H,m,H-11b),1.66(2H,m,H-12),2.39(1H,m,H-13),1.58(1H,m,H-14a),1.76(1H,m,H-14b),5.17(1H,brs,H-15),2.63(1H,m,H-16),3.50(2H,d,J＝8.4Hz,H-17),1.30(3H,s,H-18),0.83(3H,s,H-20),xx(1H,s,COOH)。
13 C NMR(CH 3 OD,150MHz)δ C :32.2(CH 2 ,C-1),20.5(CH 2 ,C-2),38.7(CH 2 ,C-3),44.5(C,C-4),52.2(CH,C-5),128.4(CH,C-6),126.7(CH,C-7),144.7(C,C-8),53.8(C,C-9),39.1(C,C-10),32.9(CH 2 ,C-11),24.2(CH 2 ,C-12),35.9(CH,C-13),36.6(CH 2 ,C-14),123.2(CH,C-15),47.9(CH,C-16),64.4(CH 2 ,C-17),30.0(CH 3 ,C-18),181.2(C,C-19),17.5(CH 3 ,C-20).
Example 2
Alpha-glucosidase inhibitory Activity assay of Compound Villanovane VI with control:
1) Principle of experiment
The alpha-glucosidase can catalyze the hydrolysis of alpha-1, 4-glycosidic bond, so that oligosaccharides such as maltose, sucrose and the like in the small intestine are hydrolyzed. Inhibiting alpha-glucosidase activity, slowing down glucose production and absorption, reducing postprandial blood glucose peak, and regulating blood glucose level. Alpha-glucosidase inhibitors have become a focus of research in recent years in pharmaceutical chemistry. 4-nitrophenyl-alpha-D-glucopyranoside (PNPG), which is a specific substrate for alpha-glucosidase, is hydrolyzed by alpha-glucosidase to produce p-nitrophenol (yellow), which is characterized by absorption at 405 nm. The alpha-glucosidase inhibitory activity of the compounds can be determined by comparing the amount of p-nitrophenol produced in the system before and after the addition of the compound Villanovane VI of the present invention. Acarbose (Acarbose) was used as a positive control for the experiment.
2) Experimental method
i) Solution preparation
a) Phosphate buffer PBS (ph=6.86) the mixed phosphate powder was added to a 500mL volumetric flask and CO-free was added 2 Distilled water reaches scales, and is dissolved and shaken uniformly and then stored at 4 ℃ for standby.
b) PNPG (2.5 mM) as substrate solution was prepared by precisely weighing 37.6mg of PNPG, metering to 50mL with the above PBS, dissolving, shaking, and storing at 4deg.C.
c) 2.3mg (26U/mg) of glucosidase powder is precisely weighed, dissolved and prepared into 10U/mL by the PBS, and split-packed by a 10U/mL tube, and kept at-20 ℃ for standby. The samples were diluted 10-fold with PBS for each use.
d)Na 2 CO 3 Solution (0.2M) of anhydrous Na is weighed 2 CO 3 2.12g of the powder is placed in a 100mL volumetric flask, the volume is fixed to 100mL by using the PPBS, and the powder is dissolved and shaken uniformly and then stored at 4 ℃ for standby.
e) Sample solution, monomer compound mother liquor preparation concentration 20 mu mol/mL, positive medicine mother liquor preparation concentration 20 mu mol/mL. The mother liquor was diluted to the corresponding multiple at the time of measurement.
ii) determination of alpha-glucosidase inhibitory Activity
Sample group comprising adding 40. Mu.L PBS buffer solution, 10. Mu.L sample solution, 10. Mu.L alpha-glucosidase solution sequentially to 96 well plates, pre-incubating at 37deg.C for 10min, adding 50. Mu.L PNPG solution, incubating at 37deg.C for 60min, and adding 80. Mu.L Na 2 CO 3 A solution.
Background group 50. Mu.L PBS buffer solution, 10. Mu.L sample solution are sequentially added into a 96-well plate, pre-incubated for 10min at 37 ℃, 40. Mu.L PNPG solution is added, incubation is carried out for 60min at 37 ℃, and finally 80. Mu.L Na is added 2 CO 3 A solution.
Control group, 96-well plate, 40 μl PBS buffer, 10 μl acarbose solution, pre-incubation at 37deg.C for 10min, then 40 μl PNPG solution, incubation at 37deg.C for 60min, and finally 80 μl Na 2 CO 3 A solution.
Each group of experiments was performed three times in parallel, absorbance at 405nm was detected in a microplate reader, and the enzyme inhibition ratio of the sample was calculated according to the following formula%α -glucosidase inhibition = (OD) Background -OD Sample of )/OD Background ×100％。
Results:
IC of the inhibitory Activity of Villanovane VI on alpha-glucosidase 50
Villanovane Ⅵ IC 50 (μM)9.2±1.73
Accarbose IC in the same experiment 50 (μM)60.71±16.45
The experimental results show that: the compound Villanovane VI has stronger alpha-glucosidase inhibitory activity than the first-line clinical alpha-glucosidase inhibitory drug Accarbose.
Molecular docking of the active compound results:
the result of molecular docking of Villanovane VI with alpha-glucosidase protein (FIG. 2) shows that the carbonyl group on C-19 of Villanovane VI is respectively related to TRP81
And ASP 64->
Hydrogen bonds are formed.
Formulation examples:
1. taking a compound Villanovane VI, adding an excipient according to the weight ratio of the compound Villanovane VI to the excipient of 1:1, granulating and tabletting.
2. Taking a compound Villanovane VI, adding an excipient according to the weight ratio of the compound Villanovane VI to the excipient of 1:2, granulating and tabletting.
3. Taking the compound Villanovane VI, and preparing the compound Villanovane VI into capsules according to a conventional capsule preparation method.
4. The compound Villanovane VI is taken and made into tablets by the following method:
5. the capsule comprises the following components: 100mg of compound Villanovane VI, a proper amount of starch and a proper amount of stearic acid mould are taken, and the preparation method comprises the following steps: the compound is mixed with the auxiliary agent, sieved, mixed uniformly in a suitable container, and the resulting mixture is filled into hard gelatin capsules.
6. Taking 1 part of compound Villanovane VI and 10 parts of vegetable fat powder, uniformly mixing, and preparing the solid beverage according to a conventional method.
Claims (8)
1. A compound Villanovane VI shown in the following structural formula,
2. a process for the preparation of the compound Villanovane vi according to claim 1, characterised in that the process comprises the steps of: taking Yunnan coffee S288 roasted beans, crushing, heating and reflux-extracting with 3-5 times of methanol for two times, wherein each extracting time is respectively 10 hours and 3 hours, combining the extracting solutions, recovering the solvent under reduced pressure to obtain concentrated extract MeOHE, dispersing the extract in a water phase, extracting sequentially with petroleum ether and ethyl acetate to obtain two partial extracts PEE and AcOEtE respectively; carrying out flow segmentation on an AcOEtE extract by taking petroleum ether/ethyl acetate with volume ratios of 15:1, 10:1, 2:1, 1:1 and 1:4 as mobile phases and chloroform/methanol with volume ratios of 50:1, 20:1, 10:1, 2:1, 1:1 and 0:1 as mobile phases to obtain eight component segments Fr.A-Fr.H; the Fr.B part is segmented by using a C18 reverse phase chromatographic column according to the volume ratio of water/methanol of 70:30 to 0:100, 9 parts Fr.B-1 to Fr.B-9 are obtained by combining the same parts, wherein the Fr.B-6 part is treated by using normal phase silica gel column chromatography according to the volume ratio of petroleum ether/ethyl acetate of 4:1 to 0:1 to respectively obtain 6 parts Fr.B-6-1 to Fr.B-6, the Fr.B-6-4 is subjected to reverse phase silica gel column chromatography, and acetonitrile/water of 45:55 are purified to obtain a monomer compound Villanovane VI.
3. Use of the compound Villanovane vi according to claim 1 for the preparation of a medicament for the treatment of diabetes.
4. Use of the compound Villanovane vi according to claim 1 for the preparation of a hypoglycemic agent.
5. A pharmaceutical composition comprising the compound villinovane vi of claim 1 and a pharmaceutically acceptable carrier.
6. A process for the preparation of a pharmaceutical composition according to claim 5, characterized in that it comprises the following steps: taking Yunnan coffee S288 roasted beans, crushing, heating and reflux-extracting with 3-5 times of methanol for two times, wherein each extracting time is respectively 10 hours and 3 hours, combining the extracting solutions, recovering the solvent under reduced pressure to obtain concentrated extract MeOHE, dispersing the extract in a water phase, extracting sequentially with petroleum ether and ethyl acetate to obtain two partial extracts PEE and AcOEtE respectively; carrying out flow segmentation on an AcOEtE extract by taking petroleum ether/ethyl acetate with volume ratios of 15:1, 10:1, 2:1, 1:1 and 1:4 as mobile phases and chloroform/methanol with volume ratios of 50:1, 20:1, 10:1, 2:1, 1:1 and 0:1 as mobile phases to obtain eight component segments Fr.A-Fr.H; the Fr.B part is segmented by using a C18 reverse phase chromatographic column according to the volume ratio of water/methanol of 70:30 to 0:100, 9 parts Fr.B-1 to Fr.B-9 are obtained by combining the same parts, wherein the Fr.B-6 part is treated by using normal phase silica gel column chromatography according to the volume ratio of petroleum ether/ethyl acetate of 4:1 to 0:1 to respectively obtain 6 parts Fr.B-6-1 to Fr.B-6, the Fr.B-6-4 is purified by using reverse phase silica gel column chromatography and acetonitrile/water of 45:55 to obtain a monomer compound Villanovane VI, and then a pharmaceutically acceptable carrier is added.
7. The use of the pharmaceutical composition of claim 5 for the preparation of a medicament for the treatment of diabetes.
8. The use of the pharmaceutical composition of claim 5 in the preparation of a hypoglycemic agent.
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