CN1169822C - Quercetin derivative and its medicinal use - Google Patents
Quercetin derivative and its medicinal use Download PDFInfo
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- CN1169822C CN1169822C CNB991202163A CN99120216A CN1169822C CN 1169822 C CN1169822 C CN 1169822C CN B991202163 A CNB991202163 A CN B991202163A CN 99120216 A CN99120216 A CN 99120216A CN 1169822 C CN1169822 C CN 1169822C
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- quercetin
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Abstract
The present invention relates to a quercetin derivant, a preparation method of the quercetin derivant, a medical composition with the quercetin derivant, and the purposes of the quercetin derivant and the medical composition for treating relevant diseases of 5HT1A, particularly preventing or treating depression or worriment.
Description
The present invention relates to quercetin derivative, and preparation method thereof, its pharmaceutical composition contained and they are as prevention or treatment and 5HT
1AThe purposes of diseases related, especially prevention or treatment depression or anxiety.
The non-toxic cotton seed that belongs to the cotton seed class is the seed of non-toxic cotton mature fruit, general feed as livestock.Non-toxic cotton seed is that painful (Malvaceve) plant of cotton certain herbaceous plants with big flowers is through genetic engineering modified big a kind of novel farm crop.Up to the present, do not see Quercetin chemical ingredients and bioactive report thereof in the cotton seed that comprises non-toxic cotton seed as yet.
Purpose of the present invention is a chemical monomer of seeking biologically active in the cotton seed comprise non-toxic cotton seed, and and then develops the medicinal use of this chemical monomer.
The present inventor is through extensively and profoundly research, now from for example extracting the quercetin derivative with formula I the non-toxic cotton seed.Found that it can be as 5HT
1AThe aglucon of acceptor, and demonstrate good curing and prevention and 5HT
1ADiseases associated and symptom are as: anti-gastric-ulcer, anti-duodenal ulcer, to the adjusting of heart and blood pressure and to the disease of cental system, as the activity of antidepressant, anxiety etc.The present invention is based on above discovery is accomplished.
The structural formula of formula I
The present invention relates to formula I Quercetin-3-O-α-D-apiose-(1 → 2)-(α-D-rhamnosyl-(1 → 6))-β-D-glycoside, it can be used as 5HT
1AThe aglucon of acceptor and demonstrate good preventing or treatment and 5HT
1ADiseases related, the especially activity of prevention or treatment depression or anxiety.
The invention still further relates to pharmaceutical composition, it comprises formula I compound and pharmaceutical carrier.
The invention still further relates to as prevention or treatment and 5HT
1AThe formula I compound of diseases associated or symptom, especially prevention or treatment depression or anxiety
The invention still further relates to as prevention or treatment and 5HT
1AThe pharmaceutical composition that contains formula I compound of diseases related or symptom, especially prevention or treatment depression and/or anxiety.
According to the present invention, formula I compound of the present invention or pharmaceutical composition can be by oral, non-enteron aisle or topical routes, and form of administration can be a tablet for example, capsule, solution, suspension, injection liquid, drip liquid etc.
According to the present invention, pharmaceutical composition of the present invention can prepare by means known in the art, for example formula I compound is mixed with pharmaceutical carrier.
According to the present invention, formula I compound: Quercetin-3-O-α-D-apiose-(1 → 2)-(α-D-rhamnosyl-(1 → 6))-β-D-glycoside is from for example obtaining the non-toxic cotton seed.Used organism solvent comprises alcohols such as methyl alcohol, ethanol, propyl alcohol, butanols etc.; Halo alkanes such as methylene dichloride, trichloromethane etc.; Ester class such as methyl acetate, ethyl acetate, propyl acetate etc.; And ethers such as sherwood oil, ether.
The following examples and biological activity test are to further describe of the present invention, but do not mean that any limitation of the invention.
Embodiment 1
The preparation of formula I Quercetin-3-O-α-D-apiose-(1 → 2)-(α-D-rhamnosyl-(1 → 6))-β-D-glycoside.
Non-toxic cotton seed 1kg is pulverized, cross 100 mesh sieves then, sieved the thing Petroleum ether extraction.Each with 5 liters of sherwood oils, extract 3 times.Dregs of a decoction extraction using alcohol is used 8 liters of ethanol at every turn, extracts 3 times, merges.Reduction vaporization is to weight.Obtain ethanol extraction 260g ethanol extraction water dissolution, it is being analyzed in n-butanol/water.Obtain n-butanol extract 10g, obtain water extract 200g.Propyl carbinol is got silica gel column chromatography separation on the thing, and developping agent is a propyl carbinol: acetic acid: water=7: 1: 2.Obtain formula I compound.
Formula I compound is a yellow powder.10%EtOH-H
2SO
4Be reddish black (heating), showing has sugar to exist.There is brilliant white fluorescence at ultraviolet 254nm place, shows it is flavonoid compound.IR spectrum (KBr): cm
-13412 (OH), 2925,1654 (C=O), 1608,1361,1201, showing has carbonyl and hydroxyl to exist; UV spectrum (MeOH): 256.2 (log ε 3.95), 354.6 (log ε 2.83) are typical flavonols ultraviolet feature.FAB-MS (m/z 743[M+H]
+), determine that its molecular weight is 742.The Compound I nuclear magnetic data sees Table one.
Table one: Compound I is in 400MHz
1H-NMR and
13The C-NMR data
| The position | δ H(JHz) | ?δ C |
| 2 3 4 5 6 7 8 9 10 1′ 2′ 3′ 4′ 5′ 6′ 1g 2g 3g 4g 5g 6g 1r 2r 3r 4r 5r 6r 1a 2a 3a 4a 5a | ---- ---- ---- ---- 6.12s ---- 6.30s ---- ---- ---- 7.57dd(2.0，1.6) ---- ---- 6.82dd(8.48，1.6) 7.72dd(8.84，2.0) 5.53d(7.6) 3.52d(7.6) ---- ---- ---- ---- 4.39s 3.11s ---- 3.09s ---- ---- 5.39s 3.84brs ---- 3.86s ---- | ?156.52 ?132.81 ?177.04 ?161.23 ?98.81 ?166.30 ?93.86 ?156.10 ?103.28 ?121.87 ?115.24 ?145.01 ?147.00 ?115.80 ?120.80 ?100.70 ?76.99 ?76.88 ?70.36 ?75.69 ?66.88 ?99.16 ?70.30 ?70.55 ?71.84 ?68.30 ?17.78 ?108.64 ?76.17 ?79.33 ?74.01 ?64.34 |
Embodiment 2
Formula I compound of the present invention: the antidepressant experiment of Quercetin-3-O-α-D-apiose-(1 → 2)-(α-D-rhamnosyl-(1 → 6))-β-D-glycoside.
1. to the influence of rat cerebral cortex adenylate cyclase activity
(1) method:
Male Wistar rat, body weight 200 ± 20g, sacrificed by decapitation is also separated pallium, presses 4 ℃ of literature methods and extracts synaptic membrane (referring to people such as Rasenick MM, Pro Natl Acad SciUSA, 1980; 77; 4628) and with damping fluid suspend, make protein concentration reach 3～5mg/ml.(adenylyl cyclase AC) is positioned on the synaptic membrane, so need be hatched with medicine and synaptic membrane in advance, method is as follows: each composition final concentration is in the reaction solution that to contain the corresponding cumulative volume for the treatment of the reagent substrate concentration be 100 μ l: 15mmol.L because adenylate cyclase
-1HEPES, PH7.5,5mmol.L
-1MgCl
2, 1mmol.L
-1EGTA, 1mmol.L
-1DTT, 60mmol.L
-1NaCl, lmmol.L
-1Aminophylline, 0.5mg/ml phosphocreatine, 0.14mg/ml creatine phosphokinase, each reaction tubes adds the synaptic membrane of 20 μ g respectively and puts immediately in 30 ℃ of water-baths and reacted 10 minutes, this reaction was linear in 20 minutes, immediately reaction tubes was placed boiling water to boil termination reaction 3 minutes then.Utilize cAMP test kit (available from Chinese atomics research institute) to measure cAMP generation in each reaction tubes, the mensuration process is all carried out in ice bath, reaction cumulative volume 130 μ l, press the test kit explanation and add all ingredients, after reaction finishes, centrifugal 7 minutes of 4000rpm, drawing supernatant 120 μ l puts in the measuring cup, add the 1.5ml dehydrated alcohol, add scintillation solution 3.5ml after shaking up again, cover completely, shake up, the back working sample cpm value on Wallac 1409 liquid scintillation instruments of spending the night is calculated the cAMP generation according to typical curve and cpm value.Result's ANOVA statistical study, relatively Dunnett ' s T check between group the results are shown in Table two and table three.
Table two. imipramine and buspirone are to the activation effect of AC
| Medicine | The cAMP generation (pmol/mg albumen/minute) | |||
| 25μM | ?100μM | 400μM | 1mM | |
| Imipramine | 15.07±4.91 | ?18.53±3.42 * | 30.32±5.63 *** | 79.79±21.38 *** |
| Buspirone | 19.52±5.46 * | ?19.71±5.57 * | 24.63±3.49 *** | 33.00±8.58 *** |
| Physiological saline | 13.47±1.92 | |||
Table three. the comparison of formula I compd A C activation effect
| Sample | The cAMP generation (pmol/mg albumen/minute) | |||
| 13.5μM | ?40.5μM | 135μM | 405μM | |
| Formula I compound | 23.27±4.95 * | 4.75±6.33 *** | 43.42±4.78 *** | 68.34±10.45 *** |
| Salt solution | 13.47±1.92 | ------ | ---- | ------ |
X ± SD Vs control group,
*P＜0.0,5,
*P＜0.01,
* *P＜0.001
(2) discuss:
Studies show that antidepressive has acute activation effect to synaptic membrane AC, this effect may be the important step of its mechanism of action, and as seen from Table 1, classical antidepressive imipramine and atypia antidepressive buspirone are dose-dependently ground and activate AC.Formula I compound just significantly activates AC when 13.5 μ M (0.01mg/ml), reach 23.27 ± 4.95pmol/mg albumen/minute, effect is all strong during than imipramine and buspirone 25 μ M.Formula I compound 404 μ M (0.3mg/ml) effects reach 68.34 ± 10.45pmol/mg albumen/minute, stronger 2～3 times than imipramine under the same dose and buspirone.Find out that thus formula I compound has antidepressant effect, and activity is stronger.
2. formula I compound is to the provide protection of the PC-12 cell of Kendall compound damage
(1) method:
Is that every milliliter of suspension contains 2 * 105 cells with the DMEM nutrient solution that contains 5% calf serum and 5% horse serum with the PC-12 cell dilution, be inoculated in then in advance in 96 orifice plates of handling with poly-lysine, and in 37 ℃, 5%CO
2Cultivated under the condition 2～3 days, and promptly can be used for experiment after waiting cell to cover with at the bottom of the hole.Nutrient solution is removed in suction, adds to contain relative medicine concentration and 10
-4Mol.L
-1The serum-free DMEM of Kendall compound, each hole adding 5mg/ml MTT10 μ l also shakes up gently after 48 hours, after 4 hours, every hole adds 10%SDS100 μ l and shakes up, and puts and spends the night in 37 ℃ of incubators (8～12 hours), treats that dark blue crystallization is all after the dissolving, shake up gently, absorbance (A) when measuring each hole at the 570nm wavelength on the microplate reader is used the ANOVA statistical study, the results are shown in Table four.
Table four. formula I compound is to the provide protection of the PC-12 cell of Kendall compound damage
| Medicine (μ M) | Absorbancy (A) | A value rising percentage (%) |
| Normal control damage contrast formula I compound 4.04 13.48 40.43 134.77 404.31 | ?0.77±0.12 ?0.24±0.04 ? ?0.74±0.14 **?0.48±0.08 ***?0.86±0.10 ***?0.77±0.11 ***?0.61±0.16 ** | ? ? ? 208.3 250.0 258.3 220.8 154.2 |
**P＜0.01，
***P＜0.001
(2) discuss
Can be seen that by data in the table 4 formula I compound A value rising percentage when concentration 4.04 μ M reaches 208.3%, A value rising percentage is big more, shows that the provide protection of the PC-12 cell that Kendall compound is damaged is strong more.Therefore, formula I compound of the present invention has very strong provide protection to the PC-12 cell of Kendall compound damage.
3. forced swimming experiment
(1) method
Press document (Arch Int Pharmacodn Ther, 1977,229 (2): 327) method is carried out, ip in mice put into open glass cylinder (high 19cm, diameter 12cm) in 30 minutes for medicine, depth of water 8cm in the cylinder, 22～23 ℃ of water temperatures, mouse was put in the water 6 minutes, resolve instrument with Vidio motion and observe accumulative total dead time and the reactivity in 4 minutes behind the mouse, statistical method is the same, the results are shown in Table five.
Table five. formula I compound is to the influence of mouse forced swimming behavior
| Medicine | Dead time (sec) |
| Physiological saline formula I compound (mg/kg) 0.31 1.25 5.00 | 184.94±19.15 ? 148.69±30.81 *149.94±34.87 *134.38±40.99 ** |
(2) discuss
Mouse forced swimming behavioral experiment is classical depression model, animal places water to struggle before this, attempt is escaped, enter desperate state at last and transfixion, antidepressive can obviously shorten the dead time, and table 5 finds out that formula I compound low dosage 0.31mg/kg of the present invention can make the dead time shorten, therefore, compound formula I antidepressant activity is stronger.
4.5HT
1AThe acceptor experiment
(1) method: the experimental technique according to table six is operated.
(2) begging for: 5HT
1AThe acceptor experiment shows compound formula I and 5HT
1AStronger combination rate is arranged.Its IC
5010
-1About 1mol.
Table six .5HT
1AThe acceptor experiment
| Test solution | Reaction system and volume (μ L) | Total binding | Non-specific combination |
| The mark aglucon | 20nMOL?H 3-OH-DPAT liquid | 20 | 20 |
| The non-marked aglucon | 1mMOL 5-TH sulfuric acid flesh liver liquid | -- | -- |
| The receptor membrane preparation | 1: 5 rat brain cortex suspension | 50 | 50 |
| Buffered soln | 50mMOL Tris-HCl pH6.4 damping fluid | 130 | 110 |
| Behind the above-mentioned solution mixing, reaction is 30 minutes in 25 ℃ water-bath | |||
Claims (4)
1. formula I compound
2. the pharmaceutical composition that contains formula I compound and pharmaceutical carrier.
3. the compound according to claim 1 is used for the treatment of and 5HT in preparation
1APurposes in the medicine of diseases related or symptom.
4. the purposes of claim 3 is wherein with 5HT
1ADiseases related or symptom are depression or anxiety.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB991202163A CN1169822C (en) | 1999-09-17 | 1999-09-17 | Quercetin derivative and its medicinal use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB991202163A CN1169822C (en) | 1999-09-17 | 1999-09-17 | Quercetin derivative and its medicinal use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1288896A CN1288896A (en) | 2001-03-28 |
| CN1169822C true CN1169822C (en) | 2004-10-06 |
Family
ID=5281438
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB991202163A Expired - Fee Related CN1169822C (en) | 1999-09-17 | 1999-09-17 | Quercetin derivative and its medicinal use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1169822C (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002076473A1 (en) * | 2001-03-26 | 2002-10-03 | Academy Of Military Medical Sciences Institute Of Pharmacology And Toxicology | Quercetin derivative and its medicinal use |
| CN101088502B (en) * | 2006-06-16 | 2012-11-21 | 中国科学院化学研究所 | Mixture solution containing conjugate of transferrin and quercetin and use thereof |
| CN101091706B (en) * | 2006-06-23 | 2011-05-04 | 和泓生物技术（上海）有限公司 | Excitant of dopamine transport protein and usage |
| CN104592331B (en) * | 2015-02-03 | 2017-03-29 | 天津科技大学 | A kind of quercetin derivative and its preparation technology and application |
| CN105412074A (en) * | 2015-12-24 | 2016-03-23 | 厦门大学 | Application of quercetin in preparation of medicine for preventing and treating diseases related to ApoE protein level |
-
1999
- 1999-09-17 CN CNB991202163A patent/CN1169822C/en not_active Expired - Fee Related
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| Publication number | Publication date |
|---|---|
| CN1288896A (en) | 2001-03-28 |
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