CN101798306A - Uncaria alkaloid monomer as well as preparation method and application thereof - Google Patents
Uncaria alkaloid monomer as well as preparation method and application thereof Download PDFInfo
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- CN101798306A CN101798306A CN 201010128383 CN201010128383A CN101798306A CN 101798306 A CN101798306 A CN 101798306A CN 201010128383 CN201010128383 CN 201010128383 CN 201010128383 A CN201010128383 A CN 201010128383A CN 101798306 A CN101798306 A CN 101798306A
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Abstract
The invention relates to an uncaria alkaloid monomer as well as a preparation method and application thereof. The preparation method comprises the following steps of: pulverizing uncaria medicinal materials into a powder shape; adding 95 percent of alcohol according to the proportion of 5-8 times of the medicinal materials for hot refluxing extraction for 2-3 hours at the first time; adding 95 percent of alcohol according to the proportion of 2-5 times of the medicinal materials for hot refluxing extraction for 1-2 hours at the second time; combining and concentrating the extract liquid in the two steps to dryness, adding a proper amount of water for dissolving and adjusting a pH value to 1-2 by concentrated hydrochloric acid of 4M; standing for 12-16 hours and then suction filtering; adjusting a pH value of the filtrate to 9-11 by concentrated ammonia water or a sodium hydroxide aqueous solution; then extracting for 2-4 times by a middle polarity organic solvent, combining and concentrating the extract liquid to dryness and obtaining an uncaria total alkaloid extract; carrying out MCI-gel column chromatography and methanol-water gradient elution on uncaria total alkaloid, wherein the gradients are respectively 50 percent, 60 percent, 70 percent, 80 percent, 90 percent and 100 percent; collecting 80 percent and 90 percent of methanol-water elution parts and concentrating to dryness; and adding acetone for dissolving and then recrystallizing to obtain the uncaria alkaloid monomer. The uncaria alkaloid monomer can be used as a strong acetylcholinesterase inhibiting agent.
Description
Technical field
The present invention relates to the preparation and the purposes of alkaloid monomer.
Background technology
Alzheimer's disease (Alzheimer disease, promptly senile dementia is called for short AD) is a kind of chronic progressive external brain degenerative disease, is core symptom clinically with the cognitive decrease.Sickness rate and the age of AD are proportionate, and are the main types of senile dementia.In recent years, clinical study both at home and abroad shows that acetylcholinesterase depressant is the most effective medicine of treatment AD, in addition to the treatment of diseases such as glaucoma, myasthenia gravis, intestinal obstruction also have better action (Jin Youyu. pharmacology (the 5th edition), 2001; 54-55.).
Early stage neurochemistry studies show that AD patient's brain vagusstoff obviously lacks, and choline acetyl transfers enzyme activity reduces in the cerebral tissue, and vagusstoff is synthetic to be reduced, and causes the presynaptic cholinergic neuron obviously to degenerate.Acetylcholinesterase depressant combines with acetylcholinesterase, and enzyme is lost activity, the content of vagusstoff increase between nerve synapse in the endogenic vagusstoff bulk deposition, brain, thereby the effect of performance treatment AD.
Yncaria stem with hooks (Uncaria rhynchophylla (Miq.) Jacks.) is Rubiaceae (Rubiaceae) wild gambier (Uncaria) plant, main effective constituent is alkaloid, as uncarine (rhynchophylline), Isorhynchophylline (isorhynchophylline) etc.Yncaria stem with hooks is a traditional Chinese medical science medicine commonly used, has the flat liver of heat-clearing, dispelling wind and relieving convulsion, hypotensive effect (Yang Chengjin. Yunnan plant research, 1995,17:209-214.).But up to the present, do not see the report of yncaria stem with hooks alkaloid monomer composition geissoschizine methyl ether as yet about inhibiting activity of acetylcholinesterase.
Summary of the invention
The purpose of this invention is to provide yncaria stem with hooks alkaloid monomer monomer and preparation method and purposes.
The present invention is yncaria stem with hooks alkaloid monomer and preparation method and purposes, and the chemical structure of yncaria stem with hooks alkaloid monomer is:
The preparation method of yncaria stem with hooks alkaloid monomer the steps include: the yncaria stem with hooks pulverizing medicinal materials powdered.Adopt for the first time the ratio of 5～8 times of quality of medicinal materials to add 95% pure thermal backflow extraction 2～3h; Ratio according to 2～5 times of quality of medicinal materials adds 95% pure thermal backflow extraction 1～2h for the second time.Twice extracting solution merges and is concentrated into driedly, adds the suitable quantity of water dissolving, with concentrated hydrochloric acid adjust pH to 1～2 of 4M, leaves standstill suction filtration behind 12～16h.Filtrate is used the Semi-polarity organic solvent extraction 2～4 times then with strong aqua or aqueous sodium hydroxide solution adjust pH to 9～11, and the extraction liquid merging is concentrated into dried, obtains the yncaria stem with hooks total alkaloids extract; The yncaria stem with hooks total alkaloids is by MCI-gel column chromatography methanol-water gradient elution, and its gradient is respectively: 50%, 60%, 70%, 80%, 90%, 100%, collect 80% and 90% methanol-water wash-out part, be concentrated into dried, add acetone solution after, recrystallization obtains the yncaria stem with hooks alkaloid monomer.
The purposes of yncaria stem with hooks alkaloid monomer can be as strong acetylcholinesterase depressant.
The structure of yncaria stem with hooks alkaloid monomer composition geissoschizine methyl ether of the present invention is identified as follows:
Colourless rib shape crystallization (acetone), mp 190-192 ℃.It is orange red that Dragendorff reagent shows.ESI-MSm/z：367[M+H]
+。
1H-NMR(600MHz，CDCl
3)δppm：1.55(3H，d，J＝7.2Hz，H-18)，1.87(1H，ddd.J＝12.0，5.0，2.4Hz，H-14a)，2.33(1H，ddd.J＝12.0，12.0，2.4Hz，H-14b)，2.64(1H，m，H-5a)，2.72(1H，br?d，J＝15.0Hz，H-6a)2.97(1H，m，H-6b)，3.06(1H，m，H-5b)，3.15(1H，br?d，J＝12.0Hz，H-21a)，3.42(1H，d，J＝12.0Hz，H-21b)，3.49(1H，Br?d，J＝12.0Hz，H-3)，3.70(1H，d，J＝12.0Hz，H-15)，3.73(3H，s，-COOCH
3)，3.80(3H，s-OCH
3)，5.42(1H，q，J＝7.2Hz，H-19)，7.06(1H，dt，J＝7.8，1.2Hz，H-10)，7.10(1H，dt，J＝7.8，1.2Hz，H-11)，7.26(1H，dt，J＝7.8，1.2Hz，H-12)，7.35(1H，s，H-17)，7.46(1H，dt，J＝7.8，1.2Hz，H-9)，7.92(1H，s，-NH)。
13C-NMR (125MHz, CDCl
3) δ ppm:134.0 (C-2), 58.7 (C
3), 51.4 (C
5), 21.4 (C
6), 108.2 (C
7), 127.3 (C
8), 118.1 (C
9), 119.2 (C
10), 120.4 (C
11), 110.7 (C
12), 136.0 (C
13), 34.2 (C
14), 36.4 (C
15), 112.5 (C
16), 159.6 (C
17), 13.0 (C
18), 121.1 (C
19), 134.9 (C
20), 64.5 (C
21), 168.7 (COOCH
3), 51.4 (COOCH
3), 61.7 (C
17-OMe), above spectroscopic data and document (H.Takayama et al.Tetrahedron Letters, 1992,33 (45): 6831-6834) in full accord.So this yncaria stem with hooks alkaloid monomer composition is accredited as geissoschizine methyl ether.
The present invention adopts Ellman method (Ellman G.L..Biochemical Pharmacology, 1961 of improvement; 7:88-95), studied the anti-acetylcholinesterase activity of yncaria stem with hooks alkaloid monomer composition geissoschizine methyl ether, and studied influence to the ability of learning and memory of Scopolamine inductive dementia mice (Jiang Hongliu. Chinese Pharmacological circular, 2008; 24 (10): 1399-1400).The result shows that yncaria stem with hooks alkaloid monomer composition geissoschizine methyl ether is good natural acetylcholinesterase depressant; Can obviously improve the ability of learning and memory of dementia mice.With pharmaceutically acceptable carrier or other excipient combine, make interior injection or other formulation of oral administration administration according to ordinary method, can be used to develop anti-acetylcholinesterase activity medicine and treatment nerve degenerative diseases (alzheimer's disease etc.) clinically with type and non-oral administration.
Embodiment
The present invention is yncaria stem with hooks alkaloid monomer and preparation method and purposes, and the chemical structure of yncaria stem with hooks alkaloid monomer is:
The preparation method of yncaria stem with hooks alkaloid monomer the steps include: the yncaria stem with hooks pulverizing medicinal materials powdered.Adopt for the first time the ratio of 5～8 times of quality of medicinal materials to add 95% pure thermal backflow extraction 2～3h; Ratio according to 2～5 times of quality of medicinal materials adds 95% pure thermal backflow extraction 1～2h for the second time.Twice extracting solution merges and is concentrated into driedly, adds the suitable quantity of water dissolving, with concentrated hydrochloric acid adjust pH to 1～2 of 4M, leaves standstill suction filtration behind 12～16h.Filtrate is used the Semi-polarity organic solvent extraction 2～4 times then with strong aqua or aqueous sodium hydroxide solution adjust pH to 9～11, and the extraction liquid merging is concentrated into dried, obtains the yncaria stem with hooks total alkaloids extract; The yncaria stem with hooks total alkaloids is by MCI-gel column chromatography methanol-water gradient elution, and its gradient is respectively: 50%, 60%, 70%, 80%, 90%, 100%, collect 80% and 90% methanol-water wash-out part, be concentrated into dried, add acetone solution after, recrystallization obtains the yncaria stem with hooks alkaloid monomer.
The preparation method of above-described yncaria stem with hooks alkaloid monomer, used alcohol is methyl alcohol, or ethanol.The Semi-polarity organic solvent is meant chloroform, perhaps methylene dichloride, perhaps ether, perhaps ethyl acetate.
The purposes of yncaria stem with hooks alkaloid monomer, its medicinal use are acetylcholinesterase depressant.Acetylcholinesterase depressant is meant and is used for senile dementia, perhaps intestinal obstruction, perhaps myasthenia gravis, perhaps glaucomatous medicine.The purposes of yncaria stem with hooks alkaloid monomer, with the carrier that pharmaceutically can accept, or other excipient combines, and make the interior of oral administration administration according to ordinary method and use the type formulation, or the injection of non-oral administration, or other formulation.
The present invention is further described below in conjunction with specific examples, but do not limit the present invention.
Embodiment 1: the preparation of yncaria stem with hooks alkaloid monomer composition geissoschizine methyl ether
Take by weighing Gambir Plant 10kg, add 95% ethanol 60L thermal backflow and extract 2h, suction filtration is done; Add 95% ethanol 40L thermal backflow again and extract 2h, suction filtration again.Twice extracting solution merges and is concentrated into driedly, adds the 7L dissolved in distilled water, with the concentrated hydrochloric acid adjust pH to 2 of 4M, leaves standstill suction filtration behind the 15h.Filtrate is used 2M aqueous sodium hydroxide solution adjust pH to 10.Each 7L chloroform extraction that adds, coextraction 3 times, the extraction liquid merging is concentrated into dried, obtains yncaria stem with hooks total alkaloids 14.8g.Then the yncaria stem with hooks total alkaloids that makes is passed through MCI-gel column chromatography methanol-water gradient elution (50%, 60%, 70%, 80%, 90%, 100%), collect 80% and 90% methanol-water wash-out part, be concentrated into dried, add acetone solution after, recrystallization obtains yncaria stem with hooks alkaloid monomer composition geissoschizine methyl ether 1.5g.
Embodiment 2: the Ellman method of improvement is measured the anti-acetylcholinesterase activity of yncaria stem with hooks alkaloid monomer composition geissoschizinemethyl ether
Utilize the Ellman method of improvement to measure the inhibiting rate of alkaloid geissoschizine methyl ether to acetylcholinesterase, Physostigmine is as positive control drug.Concrete experimentation is as follows:
Use 96 hole enzyme plates to come the inhibition activity of working sample to enzyme, every hole adds the phosphoric acid buffer (pH=8.0) of 140 μ L0.1M in the sample sets, the sample that adds 20 μ L then, add 160 μ L phosphoric acid buffers in the blank well and do not add any sample, add the Physostigmine of 20 μ L 0.1mg/mL and the phosphoric acid buffer of 140 μ L in the positive control control group, the phosphoric acid buffer of the sample of 20 μ L and 155 μ L in the sample copy bottom outlet, other Kong Zhongjun except at the bottom of the sample copy adds the acetylcholinesterase of 15 μ L, mixing is cultivated 2min down at 4 ℃, every then hole adds the DTNB (5 of 10 μ L 0.01mM, 5-dithio two (2-nitrobenzoic acids)) and the ATCI (acetylthiocholine iodide) of 10 μ L0.075mM, mixing is cultivated 20min down at 37 ℃, measures each hole OD value immediately under 405nm.Every group of experiment triplicate.And with the inhibiting rate of following formula calculation sample to acetylcholinesterase.
Can calculate the half-inhibition concentration value (IC of sample according to dose-effect relationship and return law of the straight line to acetylcholinesterase
50).The result shows that yncaria stem with hooks alkaloid monomer composition geissoschizine methyl ether has obvious inhibiting activity to acetylcholinesterase.Its half-inhibition concentration value (IC
50) be 10 μ M, experimental data sees Table 1.
The Ellman method test result of table 1 improvement
Embodiment 3:Morris water maze laboratory
50 of healthy Male Kunming strain mice are divided into 5 groups: normal control group, model control group, yncaria stem with hooks alkaloid monomer composition geissoschizine methyl ether high dose group (1mg/kg), yncaria stem with hooks alkaloid monomer composition geissoschizine methyl ether low dose group (0.5mg/kg) and E2020 control group (0.1mg/kg) at random.Except that the physiological saline of normal control group and model control group abdominal injection equivalent, each organizes fixedly period intraperitoneal injection 1 time, 5d continuously of mouse every day.Carry out the orientation navigation training of water maze behind the administration 2d.Except that the physiological saline of normal control group abdominal injection equivalent, all the other respectively organize all 90min abdominal injection Scopolamine 2mg/kg before training of mouse.24h carries out the space exploration test after the last administration, the time of the inherent platform quadrant swimming of test 2min.The result shows that yncaria stem with hooks alkaloid monomer composition geissoschizinemethyl ether can obviously improve the ability of learning and memory of dementia mice, and experimental data sees Table 2.
Table 2 Morris water maze laboratory test result
*: compare P＜0.01 with two control groups
Claims (8)
1. yncaria stem with hooks alkaloid monomer, its chemical structure is:
2. the preparation method of yncaria stem with hooks alkaloid monomer the steps include: the yncaria stem with hooks pulverizing medicinal materials powdered.Adopt for the first time the ratio of 5～8 times of quality of medicinal materials to add 95% pure thermal backflow extraction 2～3h; Ratio according to 2～5 times of quality of medicinal materials adds 95% pure thermal backflow extraction 1～2h for the second time.Twice extracting solution merges and is concentrated into driedly, adds the suitable quantity of water dissolving, with concentrated hydrochloric acid adjust pH to 1～2 of 4M, leaves standstill suction filtration behind 12～16h.Filtrate is used the Semi-polarity organic solvent extraction 2～4 times then with strong aqua or aqueous sodium hydroxide solution adjust pH to 9～11, and the extraction liquid merging is concentrated into dried, obtains the yncaria stem with hooks total alkaloids extract; The yncaria stem with hooks total alkaloids is by MCl-gel column chromatography methanol-water gradient elution, and its gradient is respectively: 50%, 60%, 70%, 80%, 90%, 100%, collect 80% and 90% methanol-water wash-out part, be concentrated into dried, add acetone solution after, recrystallization obtains the yncaria stem with hooks alkaloid monomer.
3. the preparation method of yncaria stem with hooks alkaloid monomer according to claim 2 is characterized in that: alcohol is methyl alcohol, or ethanol.
4. the preparation method of yncaria stem with hooks alkaloid monomer according to claim 2 is characterized in that the Semi-polarity organic solvent is meant chloroform, perhaps methylene dichloride, perhaps ether, perhaps ethyl acetate.
5. the purposes of yncaria stem with hooks alkaloid monomer can be as strong acetylcholinesterase depressant.
6. the purposes of yncaria stem with hooks alkaloid monomer according to claim 5, its medicinal use are acetylcholinesterase depressant.
7. the purposes of yncaria stem with hooks alkaloid monomer according to claim 5 is characterized in that acetylcholinesterase depressant is meant and is used for senile dementia, perhaps intestinal obstruction, perhaps myasthenia gravis, perhaps glaucomatous medicine.
8. the purposes of yncaria stem with hooks alkaloid monomer according to claim 5, the carrier that it is characterized in that and pharmaceutically can accept, or other excipient combines, and makes the interior type formulation of using of oral administration administration according to ordinary method, or the injection of non-oral administration, or other formulation.
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|---|---|---|---|
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102093359A (en) * | 2011-02-18 | 2011-06-15 | 中国人民解放军第三军医大学第二附属医院 | Process for extracting rhynchophylline monomers from uncaria rhynchophylla |
| CN113975322A (en) * | 2020-07-27 | 2022-01-28 | 北京大学 | Uncaria rhynchophylla total alkaloids and extraction and purification method and application thereof |
| CN116854690A (en) * | 2023-06-28 | 2023-10-10 | 河南中医药大学 | Indole uncaria alkaloid substance extraction method and application thereof |
-
2010
- 2010-03-16 CN CN2010101283832A patent/CN101798306B/en not_active Expired - Fee Related
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102093359A (en) * | 2011-02-18 | 2011-06-15 | 中国人民解放军第三军医大学第二附属医院 | Process for extracting rhynchophylline monomers from uncaria rhynchophylla |
| CN102093359B (en) * | 2011-02-18 | 2012-07-04 | 中国人民解放军第三军医大学第二附属医院 | Process for extracting rhynchophylline monomers from uncaria rhynchophylla |
| CN113975322A (en) * | 2020-07-27 | 2022-01-28 | 北京大学 | Uncaria rhynchophylla total alkaloids and extraction and purification method and application thereof |
| CN113975322B (en) * | 2020-07-27 | 2022-08-30 | 北京大学 | Uncaria rhynchophylla total alkaloids and extraction and purification method and application thereof |
| CN116854690A (en) * | 2023-06-28 | 2023-10-10 | 河南中医药大学 | Indole uncaria alkaloid substance extraction method and application thereof |
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