CN104224785A - Application of 5-hydroxyl noracroycine in preparation of antitumour drug - Google Patents
Application of 5-hydroxyl noracroycine in preparation of antitumour drug Download PDFInfo
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- CN104224785A CN104224785A CN201410445648.XA CN201410445648A CN104224785A CN 104224785 A CN104224785 A CN 104224785A CN 201410445648 A CN201410445648 A CN 201410445648A CN 104224785 A CN104224785 A CN 104224785A
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- noracroycine
- alkali
- fructus citri
- citri grandis
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Abstract
The invention discloses application of 5-hydroxyl noracroycine in preparation of an antitumour drug. Anti-tumour effect of 5-hydroxyl noracroycine is observed through in vitro tumour cell in vitro inhibition test, and results show that 5-hydroxyl noracroycine has certain inhibiting effect on lung cancer and colon cancer and has obvious antitumour activity and toxic and side effects of 5-hydroxyl noracroycine are small. 5-hydroxyl noracroycine and medically acceptable auxiliary materials are prepared into the anti-tumour drug, and dosage forms of the anti-tumour drug can be one of an injection, a capsule, a tablet, a granule, a pill, a mixture and an oral liquid.
Description
Technical field
The invention belongs to field of medicaments, relate to 5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkali and preparing the application in antitumor drug.
Background technology
5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkali is acridine alkaloid, CAS accession number 27067-70-5, molecular formula C
19h
17nO
4, molecular weight is 323.35, molecular structural formula:
Pharmacological research shows, and 5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkali has active anticancer, and inhibition tumor cell grows; Antiviral effect, has the inhibit activities of 100% when 1000Mratio/TPA concentration, for antitumor promoter to Epstein-Bars virus; Antimalarial active.During external 10 μ g/mL concentration, be 88% to Yue Er plasmodium (Plasmodium yuelii) suppression ratio.
The little Fructus Citri tangerinae in mountain is rutaceae, and taste is micro-pungent, bitter, and property is put down.Have circulation of qi promoting to eliminate the phlegm, effect of dissipating blood stasis for subsidence of swelling, removing food stagnancy.Cure cold cough, abdominal pain due to retention of food, treating swelling and pain by traumatic injury, hernia pain due to disorder of QI.
By literature search, the domestic 5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkali that there is not yet is for the preparation of antitumor drug.
Summary of the invention
For meeting clinical needs, expand medicine variety, better Therapeutic cancer, application 5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkali prepares antitumor drug.
Technical scheme of the present invention is as follows:
The nor-mountain of 5-hydroxyl of the present invention Fructus Citri grandis Citrus chachiensis Hort. alkali, its preparation method comprises the following steps:
(1) get the little Radix Citri tangerinae in mountain to pulverize, be that 5:1.5-2 adds entrainer by solid-liquid volume ratio, under pressure 22-35MPa, temperature 35-48 DEG C condition, pass into liquid CO
2extraction 90-180min, resolves under pressure 7-9MPa, temperature 30-35 DEG C condition, collects extract;
(2) extract obtained in step (1) is added kieselguhr and stir decolouring, filter and obtain destaining solution;
(3) destaining solution obtained in step (2) being concentrated into relative density is 1.12, and upper neutral alumina column is eluting with petroleum ether-ethyl acetate, obtains 5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkali crude product;
(4) crude product is refined through preparative high performance liquid chromatography and is obtained highly purified 5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkali.
In described step (1), entrainer is methanol or alcoholic solution.
In described step (2), kieselguhr addition is the 3-4.5% of medical material amount
In described step (3), the volume ratio of petroleum ether-ethyl acetate is 3:14.
In described step (4), preparative high performance liquid chromatography mobile phase is methanol-acetonitrile-water, and volume ratio is 19:38:45.
5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkali is preparing the application in antitumor drug.
By tumor cell in vitro body outer suppressioning test, observe the antitumor action of 5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkali, result shows that 5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkali all has certain inhibitory action to A549 pulmonary carcinoma and HT29 colon cancer, have remarkable active anticancer, and its toxic and side effects is little.
Beneficial effect of the present invention obtains checking by following experiment:
Experimental technique:
1, tested extract: 5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkaline extraction thing
(1) character: crystallization, bitter in the mouth.
(2) specification: containing 5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkali >=90%.
(3) solvent: ethanol or methanol.
(4) condition of storage: 4 DEG C, sealing is preserved.
2, cell strain: lung cancer cell types, colon cancer cell line HT29.
3, dosage and method
5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkali group: 10mg/kg/ days, gastric infusion, every once a day, totally five days.
Negative control group: 10mg/kg/ days, normal saline intramuscular administration, every once a day, totally five days.
Positive controls: 30mg/kg/ days, 5-fluorouracil intramuscular administration, every once a day, totally five days.
2h after gavage, detects plasma drug level with HPLC.
4, the foundation of Implanted model and administration
(1) subcutaneous implantation: merged by above-mentioned cell culture to 90% respectively, collecting cell, gets 2 × 10
6cell suspension, is injected to subcutaneous tissue under mice rib, draws materials in 15 days after operation, weighs tumor weight.Separately get same model, observe 30 days, calculate medicine to the impact of animal pattern survival rate.
(2) Implanted Lung metastases model in lung: get 2 × 10
6pallium cell injection, in mice spleen peplos, gets lung in 15 days after operation, measures tumor and weighs and Lung metastases number.
(3) administering mode: Implanted cell administration simultaneously.
5, result
Result such as table 1, table 2 and table 3 show, the effect that the Fructus Citri grandis Citrus chachiensis Hort. alkali group medication of 5-hydroxyl nor-mountain all has Tumor suppression growth in various degree and shifts, and can extend the life cycle of experiment mice.
Table 1 5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkali to the inhibitory action of Implanted (n=20,
± S)
Table 2 5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkali is on the impact (n=20, %) of neoplasm metastasis incidence rate
Table 3 5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkali is on the impact (n=20, %) of experiment mice survival rate
As can be seen from table 1, table 2 and table 3, the effect of the growth of 5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkali group medication Tumor suppression, transfer and positive controls are substantially suitable, and effectively can delay the existence life-span of experiment mice, its successful is better than matched group.
When the present invention is for the preparation of antitumor drug, nor-for 5-hydroxyl mountain Fructus Citri grandis Citrus chachiensis Hort. alkali is made anti-tumor drug together with medically acceptable adjuvant, and the dosage form of medicine is the one in injection, capsule, tablet, granule, pill, mixture, oral liquid.
When the present invention is for the preparation of antitumor drug, in its formula of oral, add intestinal absorption enhancers, comprise one or more in Medium chain fatty hydrochlorate, cholate, CDC, Chitosan-phospholipid complex.
Further illustrate the present invention below in conjunction with detailed description of the invention, but the scope of protection of present invention is not limited to following embodiments.
Detailed description of the invention
Embodiment 1
The preparation of 5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkali
Get the little Radix Citri tangerinae coarse powder in 500g mountain, be placed in extraction kettle, be that 5:2 adds methanol as entrainer by solid-liquid volume ratio, at pressure 22MPa, under temperature 38 DEG C of conditions, pass into liquid CO 2, CO2 flow is 4.5ml/g crude drug/min, extraction 120min, at pressure 7MPa, resolve under temperature 32 DEG C of conditions, collect extract, add 15g kieselguhr and stir decolouring, filtration obtains destaining solution, being concentrated into relative density is 1.12, (post pressure is 6bar to upper neutral alumina column, post blade diameter length ratio is 1:8), eluting with petroleum ether-ethyl acetate 3:14, obtain 5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkali crude product, with volume ratio 19:38:45 methanol-acetonitrile-water for mobile phase, crude product mobile phase dissolves, and injects preparative high performance liquid chromatography instrument, coutroi velocity is 20ml/min, collects target flow point, continuous production, lyophilization obtains highly purified 5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkali, detects, purity 94.9% through HPLC.
Embodiment 2
Tablet: 5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkali 40g, starch 135g, CDC 25g, granulate, tabletting makes 1000.Instructions of taking: be grown up one time 1,2 times on the one.
Embodiment 3
Capsule: 5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkali 40g, starch 135g, chitosan 25g, mixing, makes 1000.Instructions of taking: be grown up one time 1,2 times on the one.
Claims (3)
1. the 5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkali that structural formula is as follows is preparing the application in antitumor drug.
2. the nor-mountain of 5-hydroxyl as claimed in claim 1 Fructus Citri grandis Citrus chachiensis Hort. alkali is preparing the application in antitumor drug, it is characterized in that, the application of 5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkali in lung-cancer medicament.
3. the nor-mountain of 5-hydroxyl as claimed in claim 1 Fructus Citri grandis Citrus chachiensis Hort. alkali is preparing the application in antitumor drug, it is characterized in that, the application of 5-hydroxyl nor-mountain Fructus Citri grandis Citrus chachiensis Hort. alkali in colon cancer drug.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201410445648.XA CN104224785A (en) | 2014-09-04 | 2014-09-04 | Application of 5-hydroxyl noracroycine in preparation of antitumour drug |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016174674A1 (en) * | 2015-04-27 | 2016-11-03 | The Medical Research, Infrastructure and Health Services Fund of the Tel Aviv Medical Center | Egr1 targeting molecules for the treatment of inflammatory and hyperproliferative conditions |
-
2014
- 2014-09-04 CN CN201410445648.XA patent/CN104224785A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016174674A1 (en) * | 2015-04-27 | 2016-11-03 | The Medical Research, Infrastructure and Health Services Fund of the Tel Aviv Medical Center | Egr1 targeting molecules for the treatment of inflammatory and hyperproliferative conditions |
| CN108135863A (en) * | 2015-04-27 | 2018-06-08 | 特拉维夫医疗中心医学研究基础设施和保健服务基金会 | For treating the EGR1 targeted moleculars of inflammatory and the excess proliferative patient's condition |
| CN108135863B (en) * | 2015-04-27 | 2021-07-27 | 特拉维夫医疗中心医学研究基础设施和保健服务基金会 | EGR1 targeting molecules for the treatment of inflammatory and hyperproliferative conditions |
| AU2016255725B2 (en) * | 2015-04-27 | 2021-09-23 | The Medical Research, Infrastructure and Health Services Fund of the Tel Aviv Medical Center | EGR1 targeting molecules for the treatment of inflammatory and hyperproliferative conditions |
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Application publication date: 20141224 |
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| WD01 | Invention patent application deemed withdrawn after publication |