CN1112182C - Medical application of aquatic-sunflower lactone - Google Patents
Medical application of aquatic-sunflower lactone Download PDFInfo
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- CN1112182C CN1112182C CN 99108173 CN99108173A CN1112182C CN 1112182 C CN1112182 C CN 1112182C CN 99108173 CN99108173 CN 99108173 CN 99108173 A CN99108173 A CN 99108173A CN 1112182 C CN1112182 C CN 1112182C
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Abstract
The present invention relates to an application of aquatic-sunflower lactone in the field of medicine manufacture. The substance has an obvious killing function and an obvious growth inhibiting function for cancer cells and leukemia cells of the lung, the stomach, the intestines, the cervix, the rhinopharynx, the urinary bladder, etc.; recommended clinical dosage is 1 mg/kg; the substance has no damaging function on normal cells. The aquatic-sunflower lactone provided by the present invention has the advantages of wide and rich raw material source, cheap raw material, simple preparing technique and intensive medicinal function; the aquatic-sunflower lactone has very important operation significance for solving the cosmepolitical medicinal problem of cancers.
Description
The present invention system divides an application the applying date of original application: on January 4th, 1993, application number: 93100687.2 denominations of invention: anti-cancer medicine inula helianthus-aquatica lactone.
The present invention relates to the purposes of aquatic-sunflower lactone, relate in particular to the purposes in pharmaceutical field.
The object of the present invention is to provide a kind of curative effect height, cancer therapy drug safe in utilization.
Cancer therapy drug name provided by the invention is called Flos Inulae helianthus-aquaticae lactone (abbreviation compd A), and its chemical constitution is:
This medicine is a kind of white, needle-shaped crystals, and fusing point 187-189 ℃, molecular formula C17H22O5 molecular weight 306 is soluble in chloroform, is dissolved in ether, petroleum ether and the alcohol of heat slightly soluble when cold.Be dissolved in alkali liquor and add acid out and go out, Lei Mengde (Raymond) reagent is purple.Salt acid amide reacting positive.210nm has absorption maximum in ultraviolet.Infrared have ester and lactone and Ketocyclopentane absworption peak (1765,1735,1710,1670Cm
-1).HNMR reaches
13C NMR DEPT spectrum shows 17 carbon and 22 hydrogen atom signals, by three methyl (one is acyl group), four methylene (one of them is terminal thiazolinyl); five methines (wherein two combine with oxygen); and five quaternary carbons (a ketone carbon, two ester carbon, an olefinic carbon) are formed.Mass spectrum has provided 306 molecular weight, and pointing out this medicine is the half as much again terpene lactones
1, the position of acetyl group
After hydrolysis, the hydrolysate Aa that gets deacetylate checks not had the acetyl base peak and hydroxyl peak (3490-3380 is strong) occurred through 1R figure with chemical compound.The nuclear magnetic resonance, NMR figure of Aa and A is found that relatively σ 5.51Hd moves to σ 4.15ppm to High-Field, and appearance can be by the hydroxyl peak σ 4.71HBr of heavy water conversion.Through the test of uncoupling, when irradiation σ 5.51HD peak, simplifying appears in σ 3.05ppm peak.When irradiation 3.05 peaks, changing all appears in peaks such as σ 4.5,5.5,5.9,6.15, thereby determines that acetyl group is positioned at the C6 position, and the terminal thiazolinyl of σ 5.9,6.15 is positioned on the lactone ring C11 position.From C6 position hydrogen peak shape be the d peak as can be known the C5 position be that season is broken.
2, the position of ketone group
13C NMR spectrum has provided the ketone carbon peak of σ-218.2,1R (1735Cm
-1) prompting has Ketocyclopentane in the molecule, therefore ketone group should be on the A ring, unimodal and coupling relation and the complexity supposition ketone group that splits branch be on the C3 position from the no 2H of hydrogen spectrum, and may be positioned on C2 or the C4, tests from uncoupling and know that the chemical shift of A ring hydrogen is all between σ 1.25-σ 2.23.When shining the methyl peak of σ 1.17, change all appears simplifying in peaks such as σ 1.5,1.7,2.3.And during the σ 5.5 of irradiation C6 position, do not have change substantially with the superiors.Compare A and approximate thing (1. chemical journal 41 (3): 254,1983 again; 2.J, arg, chem 39 (14): 2013,1974; 3.J, arg, chem 46:1356,1981:4.C.A81:63800d, 1974) carbon spectrum find that the chemical shift of compd A C5 position by low field, is σ 56.06.Show C5 except that being subjected to C6 position hydroxyl influences, neighbouring also have the group that influence is bigger.And the chemical shift of C1 position is σ 46.66, and the chemical compound displacement of not having replacement to the C2 position is similar, therefore thinks that ketone group is positioned at the C4 position.
3, mass spectrum, ultraviolet, infrared, it is as shown in the table for the nuclear-magnetism test data:
Table 1, ultra-violet absorption spectrum absworption peak and parsing tabulation
| Chemical compound | maximum λnm | minimum | The absorption band ownership | Remarks |
| Aquatic-sunflower lactone-A | 210 | The T-lactone | Dehydrated alcohol |
Table 2, infrared absorption spectroscopy absworption peak and parsing tabulation
| Absworption peak wave number Cm -1 | Absorption peak strength | Group and resonance-type | Remarks |
| 1765 1735 1710 1670 1460 1410 1280 1252 | Strong strong and weak weak strong | The two key T-lactone OAC of T-lactonic ring pentanone OAC | KBr |
Table 3 hydrolysate Aa infrared absorption spectroscopy absworption peak and parsing tabulation
| Absworption peak wave number Cm -1 | Absorption peak strength | Group and resonance-type | Remarks |
| 3540-3300 1765 1730 1625 1455 1400 1260 1240 | Qiang Qiangqiang is strong | OH T-lactonic ring pentanone | KBr |
The absworption peak of table 4, hydrolysate Aa ultra-violet absorption spectrum and parsing tabulation
| Chemical compound | maximum λnm | minimum | The absorption band ownership | Remarks |
| Aquatic-sunflower lactone-A | 212 | Gamma lactone | Dehydrated alcohol |
Table 5, hydrolysate Aa's
13C nuclear magnetic resonance, NMR resolution table (400MHz heavy hydrogen pyridine)
| The carbon number of chemical compound | Chemical shift σ ppm | The DEPT spectrum | Relevant hydrogen atom |
| 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 | 45.50 24.76 44.40 220 57.41 74.79 53.61 77.76 39.11 30.17 141.14 169.93 119.58 19.02 19.97 | CH CH CH CH C＝O C CH CH CH CH C C CH CH CH | 1-H 2-H 2 3-H 2 T T 6-H 7-H 8-H 9-H 2 10-H T 13-H 2 14-ME 15-ME |
The proton nmr spectra resolution table instrument of table 6, compd A: Bruker-400 solvent: chloroform
| Chemical shift σ ppm | Number of hydrogen atoms | Peak shape J=Hz | Remarks |
| 1.07 1.12 1.55 1.86 1.97 2.15 2.25 2.4 2.5 3.05 4.5 5.5 5.8 6.2 | 3H 3H 2H 1H 3H 2H 1H 1H 1H 1H 1H 1H 1H 1H | S d m m s m T dd t m m d dJ＝3Hz dJ＝3Hz | C 15-H 3 C 14-H 3 OAC C 7-H C 8-H C 8-H C 13-αH C 13-βH |
The mass spectrometric data of table 7, compd A and resolution table
| Mass-to-charge ratio (m/e) | 307 | 264 | 246 | 173 | 119 | 97 | 43 |
| Fragment ion | m +1 | m-OAC | |||||
| Remarks |
Table 8, hydrolysate Aa mass spectrometric data and resolution table
| Mass-to-charge ratio (m/e) | 264 | 248 | ||||
| Fragment ion | m + | m-H 2O | ||||
| Remarks |
Table 9, compd A
13C nuclear magnetic resonance, NMR resolution table (400MHz chloroform)
| The carbon number of chemical compound | Chemical shift σ ppm | The DEPT spectrum | Relevant hydrogen atom |
| 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 | 46.66 24.49 44.40 218.2 56.06 74.84 52.77 76.24 37.85 30.08 137.46 169.26 121.94 18.42 19.95 169.49 21.05 | CH CH 2 CH 2 C＝O C CH CH CH CH 2 CH C C＝O CH 2 CH 3 CH 3 C＝O CH 3 | 1-H 2-H 2 3-H 6-H 7-H 8-H 9-H 2 10-H 13α-H，13β-H 14-Me 15-Me 17-Me |
Table 10, hydrolysate Aa proton nmr spectra resolution table instrument: Bruker-400 solvent: heavy hydrogen pyridine
| Chemical shift σ ppm | Number of hydrogen atoms | Peak shape J=Hz | Remarks |
| 0.93 1.02 1.25 1.41 1.66 1.91 2.22 2.33 3.15 4.15 4.54 4.7 6.01 6.23 | 3H 3H 1H 1H 1H 1H 1H 3H 1H 1H 1H 1H 1H 1H | d s m q m m m m m a m Br αJ＝3Hz αJ＝3Hz | C 15-H 3 C 14-H 3 OAC C 7-H C 6-H C 8-H D 2O disappearance C 13-αH C 13-βH |
Embodiment: this chemical compound can extract with following method: Flos Inulae helianthus-aquaticae grass 1Kg (Inula helianthus Aquatica C ' Y ' Uu ex ling) is put in the apparatus,Soxhlet's, add petroleum ether (60-90 ℃) 2Kg, heat on the water-bath, reflux, extract,, there is crystallization to separate out when cold, filter,, promptly get the aquatic-sunflower lactone composition through methanol recrystallization repeatedly, again through silica gel column layer (sample: silica gel=1: 200, the chloroform eluting, the silica gel G thin layer chromatography is checked (developing solvent: chloroform, developer: Lei Mengde-Raymond reagent), merge same section, methanol crystallization can be got the aquatic-sunflower lactone that accounts for upper column quantity 90%, and the lactone yield can reach 3-5 ‰.
Pharmacodynamic study proves, in vitro tests: cancerous cell such as people's lung, stomach, intestinal, cervix uteri, nasopharynx, bladder and leukaemia are all had tangible lethal effect and growth inhibited effect, and ID30 is 0.1mg/kg, and ID50 is 1mg/kg, and ID90 is 4mg/kg.Recommending clinical consumption is 1mg/kg, and normal cell is not had obvious damaging action.In vivo test: to mouse interior tumor, as ehrlich carcinoma, S180, U14, the acid anhydride cancer, kinds of tumors such as cancer of pancreas are all effective in cure, to ehrlich ascites carcinoma curative effect P＜0.01, solid tumor curative effect P＜0.05.Administrations such as abdominal cavity, filling stomach, intramuscular injection are all effective, and effective dose iP is 30mg/kg, and im is 30mg/kg, and Po is 200mg/kg.
Safety research: toxicologic study proves, mice LD5ip is 270mg/kg, po is 1400mg/kg, acute chronic toxicity and the long term toxicity test of rat and Canis familiaris L. are not seen hemogram, the heart, liver, renal function and bone marrow, the toxic reaction of brain etc. can cause blood pressure drops for the quick intravenous injection of Canis familiaris L., but available metaradrine and wide yellow alkali is prevented and treated effectively, wherein three Canis familiaris L.s respectively repeat three tests, each one month at interval, 10 times of at every turn testing dosage (in a day) intelligent's dosage, off-test is for the third time put to death, core, liver, spleen, kidney, organs and tissues paraffin wax cut sections for microscopic examination such as lung, no abnormality seen changes, and result of study proves that Flos Inulae helianthus-aquaticae lactone provided by the invention is the PTS of international initiative, have and have good stability, have cancer suppressing action, and toxicity is little, can try out in clinical.It is a kind of cancer therapy drug with fine DEVELOPMENT PROSPECT.
Claims (3)
1, the application of aquatic-sunflower lactone in the medicine of preparation treatment cancer.
2, the application of aquatic-sunflower lactone in the medicine of preparation treatment lung, stomach, intestinal, cervix uteri, nasopharynx, bladder cancer.
3, the application of aquatic-sunflower lactone in the leukemic medicine of preparation treatment.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 99108173 CN1112182C (en) | 1999-06-11 | 1999-06-11 | Medical application of aquatic-sunflower lactone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 99108173 CN1112182C (en) | 1999-06-11 | 1999-06-11 | Medical application of aquatic-sunflower lactone |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN93100687A Division CN1056142C (en) | 1993-01-04 | 1993-01-04 | Anti-cancer medicine inula helianthus-aquatica lactone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1255333A CN1255333A (en) | 2000-06-07 |
| CN1112182C true CN1112182C (en) | 2003-06-25 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 99108173 Expired - Fee Related CN1112182C (en) | 1999-06-11 | 1999-06-11 | Medical application of aquatic-sunflower lactone |
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Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102000066B (en) * | 2010-09-26 | 2012-07-25 | 中国科学院昆明植物研究所 | Inula helianthus-aquatica extract, anti-tumor medicament using same as active ingredient, preparation method and application thereof |
| CN110016041B (en) * | 2019-05-13 | 2020-08-04 | 山西大学 | Stemona alkaloid analogue and preparation method and application thereof |
| CN110563679B (en) * | 2019-08-21 | 2021-07-13 | 中山大学 | Sesquiterpene lactone compound, preparation method thereof and application of sesquiterpene lactone compound in preparation of medicine for preventing and treating nasopharyngeal carcinoma |
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| CN1255333A (en) | 2000-06-07 |
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