CN101836975B - Application of isopentene group flavonoid compound used as pancreatic lipase inhibitor - Google Patents
Application of isopentene group flavonoid compound used as pancreatic lipase inhibitor Download PDFInfo
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- CN101836975B CN101836975B CN2009100477522A CN200910047752A CN101836975B CN 101836975 B CN101836975 B CN 101836975B CN 2009100477522 A CN2009100477522 A CN 2009100477522A CN 200910047752 A CN200910047752 A CN 200910047752A CN 101836975 B CN101836975 B CN 101836975B
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- pancreatic lipase
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Abstract
The invention belongs to the technical field of medicaments, and in particular relates to application of isopentene group flavonoid compound used as a pancreatic lipase inhibitor. The flavonoid compound has the following structural formula and has a chemical name of: (E)-2-(2,4-dihydroxy phenyl)-5,7-dihydroxy-3-(3-methyl-2-butenyl)-6-(3-methy-l-butenyl)-4H-chromene-4-ketone, and can be extracted from artocarpus nitidus. Pancreatic lipase activity tests and experiments of weight loss action in animals prove that the compound has obvious pancreatic lipase inhibitory activity and weight loss action, can be taken as the lead compound for developing novel medicaments for preventing or curing obesity and related metabolic diseases, and also can be used for preparing the medicaments for preventing and curing clinically common multiple obesity and the related metabolic disease.
Description
Technical field
The invention belongs to medical technical field, more specifically, the present invention relates to the purposes of a kind of isopentene group flavonoid compound that separation obtains from Artocarpus nitidus Trec. as pancreatic lipase inhibitor.
Background technology
In nearly 20 years, the whole world especially obesity sickness rate of developed country is increasing.Because improving constantly of rapid economy development and living standard, all the time there is the relative superfluous problem of hypomotility in modern's life mode with the energy of ingesting, this has caused the absorption of numerous modern's human body energies to surpass energy expenditure, understand in the superfluous energy some as depot fat in fatty tissue, because its accumulation can be causeed fat and relevant disease, as the generation of diabetes, cancer, heart disease, hyperlipemia and fatty liver etc.
At present, the treatment of obesity mainly is to develop medicine that increases energy expenditure or the medicine that reduces caloric intake.Wherein, the main method that reduces caloric intake be exactly reduce health digestion and assimilate food in nutrient substance, especially fat.Pancreatic lipase is that fat digestion absorbs necessary enzyme in the intestinal, fat in the food is hydrolyzed to monoacylglycerol and free fatty under the pancreatic lipase effect, after intestinal is reuptaked, synthctic fat once more in vivo, store as energy, cause athero, the generation of metabolic diseases such as the hyperlipemia that finally causes fat and accompany, diabetes.Pancreatic lipase inhibitor can effectively suppress in the intestinal pancreatic lipase to the catalyticing decomposition action of fat, reach to reduce fat absorption and the fat purpose of treatment, thereby the effective pancreatic lipase inhibitor of development and application is subjected to people's common concern.Existing market pancreatic lipase inhibitor salable is an orlistat, and it is active strong that orlistat has, characteristics such as good stability, but have simultaneously unmanageable intestinal symptom, oil just with shortcomings such as the vomiting abdomen rises.Therefore seeking new pancreatic lipase inhibitor has great importance to the control of metabolic diseases such as obesity and diabetes.
Bibliographical information is arranged, and Enos Tangke Arung etc. separates from Fructus Artocarpi Heterophylli platymiscium Fructus Artocarpi Heterophylli and obtains suc as formula the chemical compound norartocarpin shown in (I).This chemical compound has the synthetic biological activity of the melanin of inhibition (Planta Medica, 2006,72 (9): 847-850).Other there are some researches show, this chemical compound has inhibition testosterone-5 activity, suppress cell proliferation, suppress cyclooxygenase-2 activity, suppress the 5-lipoxygenase activity, it is international patent application (the Artocarpin derivative or artocarpin-like compound of WO 2008020490 A1 that related application has international publication number, and hair growth/restorationcomposition, skin-whitening cosmetic composition, pharmaceutical as anti-cancer, antiphlogistic/analgesic, antipyretic or antiallergic agent and pharmaceutical fortreatment of pigmented skin lesion each co
Summary of the invention
Therefore, the purpose of this invention is to provide the isopentene group flavonoid compound shown in a kind of following structural formula (I) purposes in preparation pancreatic lipase inhibitor medicine, the particularly purposes in the medicine of preparation prevention or treatment of obesity.
Isopentene group flavonoid compound shown in the structural formula (I) is to extract to obtain from Artocarpus nitidus Trec., the present invention adopts the chemical compound of structural formula (I) to carry out antiobesity action investigation in pancreatic lipase active testing and the animal body, the result shows that the chemical compound of structural formula (I) has tangible pancreatic lipase and suppresses activity and antiobesity action, can be used as the new prevention of development or the lead compound of treatment of obesity and correlated metabolism diseases medicine, also can be used for preparing prevention or treat the obesity of clinical common pilosity and the medicine of correlated metabolism diseases.
The specific embodiment
Isopentene group flavonoid compound among the present invention can extract from Artocarpus nitidus Trec. and obtain:
After the stem branch pulverizing with Artocarpus nitidus Trec. (Artocarpus nitidus Tr é c.), or/and water extraction prepares total extract, used organic solvent can adopt alcohols with organic solvent, as ethanol, methanol etc., wherein preferred 95% (volume ratio) ethanol.With total extract water-soluble after, with the extraction of petroleum ether, halogenated hydrocarbon solvent, get the halogenated hydrocarbon solvent extraction phase respectively, reclaim the solvent after drying, promptly obtain the halogenated hydrocarbon extract, used halogenated hydrocarbon solvent can be with chloroform or dichloromethane, wherein preferred chloroform.
The halogenated hydrocarbon extract is carried out silica gel column chromatography, with petroleum ether-acetone gradient elution; Wherein petroleum ether-acetone eluting partial concentration after is carried out silica gel column chromatography at 4: 1, with petroleum ether-isopropyl alcohol gradient elution; Wherein petroleum ether-isopropyl alcohol eluting partial concentration after is carried out silica gel column chromatography at 10: 1, behind chloroform-methanol (100: 1) eluting, obtain chemical compound (E)-2-(2, the 4-dihydroxy phenyl)-5,7-dihydroxy-3-(3-methyl-2-butene base)-6-(3-methyl-1-butene base)-4H-.alpha.-5:6-benzopyran-4-ketone, identify its structure with spectral method, as its structure shown in structural formula (I).
The present invention is further elaborated below in conjunction with specific embodiment, but do not limit the present invention.
Embodiment 1 extracts chemical compound (E)-2-(2, the 4-dihydroxy phenyl)-5 from Artocarpus nitidus Trec., 7-dihydroxy-3-(3-methyl-2-butene base)-6-(3-methyl-1-butene base)-4H-.alpha.-5:6-benzopyran-4-ketone
(1) extract: after the dry stem branch of 20 kilograms of Artocarpus nitidus Trec. powder essence, with percolation behind 100 liters of immersions of 95% aquiferous ethanol 12h, soak the back and add 95% aquiferous ethanol, collect 400 liters of percolates, concentrate drying obtains 1.5 kilograms of extractum.With the water-soluble back of this extractum chloroform extraction, the recovery solvent is concentrated into dried, gets chloroform extract 50 grams.
(2) separate: chloroform extract 10 grams are carried out silica gel column chromatography, and with petroleum ether-acetone (10: 1 → 7: 1 → 4: 1 → 2: 1) gradient elution, 1500 milliliters of each gradient consumptions are collected each eluent; Carry out silica gel column chromatography after wherein 4: 1 eluents of petroleum ether-acetone being concentrated, with petroleum ether-isopropyl alcohol (20: 1 → 10: 1 → 7: 1 → 4: 1) gradient elution, 500 milliliters of each gradient consumptions; Carry out silica gel column chromatography after wherein 10: 1 eluents of petroleum ether-isopropyl alcohol being concentrated, with obtaining chemical compound (E)-2-(2 behind chloroform-methanol (100: the 1) eluting, the 4-dihydroxy phenyl)-5,7-dihydroxy-3-(3-methyl-2-butene base)-6-(3-methyl-1-butene base)-4H-.alpha.-5:6-benzopyran-4-ketone is 100 milligrams.
The physicochemical property and the spectroscopic data of this chemical compound are as follows:
Molecular formula is C
25H
26O
6Molecular weight is 422; Character is yellow amorphous powder;
Ultraviolet spectra maximum absorption wave long value (methanol): 376,321,313,265,206nm;
Infrared spectrum absorption maximum frequency values (potassium bromide): 3500,2920,1650,1621,1525,1457,1358cm
-1
Electron impact mass spectra (mass-to-charge ratio): 422[M]
+
Proton nmr spectra (400MHz) data (chemical shift: ppm, coupling constant: Hz, solvent: deuterated acetone): 14.08 (1H, s, OH-5), (7.19 1H, d, J=8.4Hz, H-6 '), 6.76 (1H, dd, J=7.0,16.1Hz, H-17), 6.63 (1H, br d, J=16.1Hz, H-16), 6.55 (1H, d, J=2.2Hz, H-3 '), 6.50 (1H, dd, J=2.2,8.4Hz, H-5 '), 6.40 (1H, s, H-8), 5.11 (1H, br t, J=7.0Hz, H-12), 3.10 (2H, br d, J=7.0Hz, H-11), 2.43 (1H, br q, J=7.0Hz, H-18), 1.55 (3H, br s, H
3-14), 1.41 (3H, br s, H
3-15), 1.08 (6H, d, J=7.0Hz, H
3-19,20);
Carbon-13 nmr spectra (100MHz) data (chemical shift: ppm, solvent: deuterated acetone): 183.7 (C-4), 162.2 (C-2), 162.1 (C-7), 161.5 (C-4 '), 160.8 (C-5), (157.2 C-2 '), 157.0 (C-9), 141.8 (C-17), (132.3 C-6 '), 132.1 (C-13), 122.6 (C-12), 121.6 (C-3), 117.3 (C-16), 113.0 (C-1 '), 109.2 (C-6), 105.0 (C-10), 103.9 (C-3 '), (108.1 C-5 '), 93.8 (C-8), 33.9 (C-18), 25.8 (C-14), 24.6 (C-11), (23.1 C-19,20), 17.5 (C-15).
The chemical compound of embodiment 2 structural formulas (I) is to the inhibition determination of activity of pancreatic lipase
It is as follows that pancreatic lipase suppresses active assay method:
At first substrate acetic acid p-nitrophenyl acetate (p-Nitrophenyl acetate) (sigma company) is made into 1.35M with phosphate buffer (PBS, pH 7.4); Porcine pancreatic lipase (sigma company) is made into 10mg/ml with phosphate buffer (PBS, pH 7.4); (PBS pH7.4) is mixed with the solution of variable concentrations with phosphate buffer for the chemical compound of structural formula (I).In 96 orifice plates, add the substrate solution after 1000 times of enzymatic solution, the 40 μ l dilutions after 20 times of the 50 μ l dilutions and the given the test agent of 10 μ l variable concentrations then successively, mixing.25 ℃ were reacted 20 minutes down, detected the absorbance in every hole under 405nm every 2 minutes.
Calculate the maximum inhibition (%) of given the test agent according to the absorbance under 405nm, be contrast with the distilled water and be IC the concentration determination that the maximum inhibition (%) of enzyme reaches 50% o'clock inhibitor to pancreatic lipase
50Value.Maximum inhibition (%) can carry out according to following formula:
Maximum inhibition (%)=[(A-B)-(C-D)]/(A-B) * 100
In the following formula, A represents to react the absorbance of back blank well under 405nm,
B represents to react the preceding absorbance of blank well under 405nm,
C represents to react the absorbance of back sample well under 405nm,
D represents to react the preceding absorbance of sample well under 405nm.
The chemical compound of measuring structural formula (I) suppresses active to pancreatic lipase, as a result IC
50Be 1.79 ± 0.076 μ M, the chemical compound that shows structural formula (I) has very strong inhibitory action to the activity of pancreatic lipase.
Embodiment 3: the chemical compound of structural formula (I) is to the antiobesity action of Zucker obese rat
Zucker obese rat (heritability obese rat) is by the Animal House breeding of Shanghai medicine institute of the Chinese Academy of Sciences, and is male, 6 ages in week.Get 6 of normal Zucker rats, as the blank group.Fat Zucker rat is divided into 2 groups, i.e. model control group and administration group, 6 every group.The chemical compound 0.5%CMC-Na hydrotropy of structural formula (I), dosage is 120mg/kg; Blank and model control group gives the 0.5%CMC-Na of equal volume, two weeks of oral administration gavage administration.Regularly detect diet and body weight.
Result: see Table 1.
The chemical compound of table 1 structural formula (I) is to the influence of Zucker rat body weight and diet
Compare with model group,
*P＜0.05.
As can be seen from Table 1, the chemical compound of structural formula (I) has obviously suppressed Zucker obese rat weight increase, has antiobesity action, and diet is not had the significance influence, and rat feces shape no abnormality seen.
The fat Excessive Intake may be causeed fat and metabolism dysfunctional diseases such as diabetes relevant with obesity, hyperlipemia, fatty liver.Suppress pancreatic lipase and can suppress the decomposition of fat, thereby suppress the absorption of fat at small intestinal.The chemical compound of structural formula (I) is as pancreatic lipase inhibitor, and has antiobesity action, can be used for diseases such as prevention or treatment of obesity.
Claims (1)
1. the chemical compound shown in structural formula (I) is as the purposes of pancreatic lipase inhibitor in the medicine of preparation prevention or treatment of obesity,
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| CN102796112B (en) * | 2011-05-25 | 2014-10-29 | 复旦大学 | Prenylflavonoid compound and application thereof in preparation of pancrelipase inhibitor |
| CN103709130B (en) * | 2012-10-07 | 2015-05-13 | 复旦大学 | Synthetic methods and applications of natural products with pancrelipase inhibition activity |
| CN104147104B (en) * | 2014-08-27 | 2018-01-12 | 吉林省中医药科学院 | Subprostrate sophora flavone composition is being prepared with the application in reducing blood glucose while anti-curing hyperlipemia medicine |
| CN107418982B (en) * | 2017-09-25 | 2020-05-08 | 嘉必优生物技术（武汉）股份有限公司 | Low-chloropropanol microbial oil and preparation method thereof |
| CN110872267B (en) * | 2018-08-30 | 2022-07-08 | 复旦大学 | Compound extracted from paper mulberry and application of compound in preparation of protein tyrosine phosphatase 1B inhibitor |
| CN110025603A (en) * | 2019-05-15 | 2019-07-19 | 大连天星本草生物科技有限公司 | Application of the Bavachalcone compounds in the drug of preparation treatment obesity |
| CN111620917B (en) * | 2020-05-08 | 2021-06-15 | 广西壮族自治区中国科学院广西植物研究所 | Isovitexin-2' -O-beta-D-glucopyranoside, and preparation method and application thereof |
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