CN100387603C - Eremophil dilactone natural product with tumour cell growth inhibiting activity - Google Patents
Eremophil dilactone natural product with tumour cell growth inhibiting activity Download PDFInfo
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- CN100387603C CN100387603C CNB2006100517193A CN200610051719A CN100387603C CN 100387603 C CN100387603 C CN 100387603C CN B2006100517193 A CNB2006100517193 A CN B2006100517193A CN 200610051719 A CN200610051719 A CN 200610051719A CN 100387603 C CN100387603 C CN 100387603C
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- dilactone
- airy
- fragrant
- compound
- eremophil
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Abstract
The present invention relates to an eremophil di-lactone, a pharmaceutical salt thereof and solvate thereof. The present invention also relates to a preparation method of the eremophil di-lactone, a medical composition of the eremophil di-lactone, and the medicament purposes of the eremophil di-lactone. The compound of the present invention has the function of eliminating the activity of human body's oral epithelium cancer cells (KB) of a tumour cell strain and person's hepatoma carcinoma cell (BEL-7404), and is expected to be developed so as to have the purposes of antitumour medicines.
Description
Technical field
The invention belongs to Natural Medicine Chemistry and pharmacology technical field.Particularly, preparation and this natural product that the present invention relates to not fragrant dilactone natural product of Airy suppresses screening active ingredients to two kinds of human body tumour cell strain oral squamous carcinoma cells (KB) and human liver cancer cell (BEL-7404) growth of tumour cell.This natural product is found has certain inhibition tumor cell growth activity, can expect as the antitumor drug purposes.
Technical background
At present, because the problems such as environmental pollution that industrial development brings, the existent environment of people quality constantly descends, and the sickness rate of tumor disease and lethality rate also constantly rise.Yet the selectivity of at present clinical used cytotoxicity antitumor drug is not high, causes Normocellular pernicious killing and wounding limited the general usability of such medicine.Therefore, seek and find that the high cytotoxicity antitumor drug of new selectivity is worldwide research focus.We also are devoted to the research of this class medicine.
Black purple Farfugium kaemferi Ligularia atroviblacea (Franch.) Hand.-Mazz. is a composite family Farfugium kaemferi platymiscium, and Yunnan is among the people to be used for clearing heat and detoxicating and treatment flu, cough are used.The inventor is in extraction and chemical constitution study to composite family Farfugium kaemferi platymiscium and composite family Senecio, once found wherein to contain a large amount of eremophilane lactones, find that as contriver in recent years the eremophilane lactone in the Senecio wightii has tumour cell HL-60, A549 and KB strain all have certain cytotoxicity (Zhao Yu etc., Chinese Chemical Letters, 2002,13 the 4th phases of volume, 333-334 page or leaf).In addition, the inventor has reported that also several eremophilane lactones of chicken foot squaw weed also have certain cytotoxicity (Zhao Yu etc., ChineseChemical Letters, 2002 to human body nasopharyngeal carcinoma KB tumor cell line and A-549 human lung carcinoma cell line, 13 the 8th phases of volume, the 754-757 page or leaf; Zhao Yu etc., Chinese Chemical Letters,, 16 the 3rd phases of volume, 362-364 page or leaf in 2005).But, do not appear in the newspapers as yet for the chemical constitution study and the bioactivity research of black purple Farfugium kaemferi.We identify chemical separation and structure that it has carried out biological tracking, obtained the not fragrant dilactone formula of the Airy described in the present invention (1) compound with novel structure, and according to the whole world especially susceptibility of often swell the knurl spectrum of disease and the tumour cell of China, the finger border of having selected oral squamous carcinoma cell (KB) and the strain of human liver cancer cell (BEL-7404) human body tumour cell to estimate as cell in vitro cytotoxic activity pharmacology, the new compound that separation is obtained has carried out the cytotoxicity screening.The result demonstrates it the effect that suppresses above-mentioned human body tumour cell growth, finishes the present invention thus.
Summary of the invention
The object of the present invention is to provide a kind of not fragrant dilactone compound of the active Airy of human body tumour cell growth of inhibition that has.Particularly, the invention provides the not fragrant dilactone derivative of the Airy shown in the formula (1):
Another object of the present invention has provided formula (1) compound and has been used to suppress the active purposes of human body tumour cell growth; And the active in view of the above purposes that formula (1) compound is become control tumor disease medicine.
A further object of the present invention has provided a kind of active pharmaceutical composition of human body tumour cell growth that is used to suppress.
Generally be rich in the eremophilane lactone in the Farfugium kaemferi platymiscium, its extracting method mostly is organic solvent and soaks extracting or refluxing extraction, and behind the recovery solvent, gained medicinal extract carries out liquid liquid and distributes and/or various chromatography method, gets in conjunction with the recrystallization technology purifying.
According to aforesaid method, extraction separation of the present invention obtains formula (1) compound, and structure chemical name is: Airy Mo Fen-3,7 (11), 8-triolefin-12,8 (14,6 α)-dilactone.
Particularly, the preparation method of Chinese style of the present invention (1) compound is as follows: by the underground part of black purple Farfugium kaemferi through pure water or the extraction of ketone water system, organic solvent column chromatography, preparation of lamina chromatography and recrystallization method purifying.Specifically comprise the following steps:
A. extract medicinal material through pulverizing with pure water or ketone water mixed solvent, concentrated extracting solution reclaims alcoholic solvent or ketone solvent;
B. the medicinal extract that step a is obtained carries out the solvent distribution through sherwood oil, vinyl acetic monomer, propyl carbinol; The ethyl acetate extract that obtains is carried out column chromatography, use the organic solvent wash-out, thin-layer chromatography detects, collect stream part of containing the not fragrant dilactone compound of Airy shown in the formula (1) respectively, again through preparation thin layer or dextrane gel Sephadex LH-20 column chromatography, gradient elution, thin-layer chromatography detects, contain stream part of the not fragrant dilactone compound of Airy shown in the formula (1) and reduce pressure respectively and volatilize solvent, select for use suitable organic solvent to carry out recrystallization, obtain pure product.
Among the preparation method among the present invention, alcohol can be methyl alcohol, ethanol, propyl alcohol, butanols, ethylene glycol or their mixture.Preferred alcohol.The alcohol water mixed solvent can be alcohol and water with arbitrary proportion blended solvent, the mixed solvent of preferred alcohol and water, the aqueous ethanolic solution of especially preferred 60-95%.Ketone can be acetone, methylethylketone, butanone or their mixture, the ketone water mixed solvent can be ketone and water with arbitrary proportion blended solvent, the mixed solvent of preferred acetone and water, especially preferred acetone content is greater than 60% ketone solution.Recrystallization solvent can be straight or branched ester class, ethers, alcohols, ketone or their mixture of 1 to 6 carbon among the step b.Preferred acetone and vinyl acetic monomer.The column chromatography used medium can be silica gel, diatomite, reverse phase silica gel, macroporous resin, aluminum oxide, dextrane gel (Sephadex) class among the step b.Preferred silica gel.Eluting solvent can be ether, ester, ketone, chloroform, methylene dichloride, alcohol or they the two or three's a mixture.The preferred sherwood oil and the mixed solvent of acetone sherwood oil and vinyl acetic monomer or the mixed solvent of chloroform and methyl alcohol carry out gradient elution.
Medicinal material among the present invention can be arbitrary position of black purple Farfugium kaemferi Ligularia atroviblacea (Franch.) Hand.-Mazz., promptly can be its root, stem, leaf, seed, skin, fruit, also can be their mixture.Preferred its underground part.
Formula (1) compound has important biological, external cytotoxic activity test to human oral cavity epithelial cancer cells strain (KB) and human liver cancer cell (BEL-7404) shows that the not fragrant dilactone compound of this Airy (specifically seeing embodiment) is inhibited to human body tumour cell growth, might develop into new control tumour medicine.
Formula of the present invention (1) compound or pharmaceutically acceptable salt thereof and solvate thereof can combine with auxiliary material or carrier pharmaceutically commonly used, have the active pharmaceutical composition that can be used for anti-curing oncoma of growth of tumour cell inhibition thereby prepare.Above-mentioned various kinds of drug composition can adopt drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment, can also adopt the known controlled release of modern pharmaceutical circle or slow release formulation or nanometer formulation.
Formula of the present invention (1) compound or pharmaceutically acceptable salt thereof and solvate thereof can lose carbon vincaleucoblastine (Vinorebine with the antitumor drug that has now gone on the market such as platinum medicine cis-platinum (DDP), camptothecine irinotecan (Irinatecan, CPT-11), vinca alkaloids medicine, the NVB nvelbine), deoxidation born of the same parents former times class medicine gemcitabine (Gemcitabine, Gemzar, strong selecting), etoposide (Etoposide), taxol (Paclitaxel) wait and unite use, prepare and prevent and treat tumor disease class pharmaceutical composition.Such pharmaceutical composition can adopt drug forms such as injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment, can also adopt the known controlled release of modern pharmaceutical circle or slow release formulation or nanometer formulation.
Embodiment
In order to understand essence of the present invention better, at first use the process of formal specification formula (1) compound of embodiment below, embodiment has provided part physics and the chemistry and the Wave Spectrum data of this compound.Mandatory declaration, embodiments of the invention are to be used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Secondly respectively with the inhibiting The pharmacological results of the not fragrant dilactone compound of this Airy, its new purposes in the antitumor drug research field is described to two kinds of tumor cell line growths.Pharmacology embodiment has provided the activity data of this compound.Mandatory declaration, pharmacology embodiment of the present invention is used to illustrate the present invention rather than limitation of the present invention.Essence according to the present invention all belongs to the scope of protection of present invention to the simple modifications that the present invention carries out.
Embodiment 1: the preparation of formula (1) compound
Obtain 89.0 gram vinyl acetic monomer medicinal extract from the black purple Farfugium kaemferi of 5.0 kilograms of exsiccant.This medicinal extract restrains 100-200 order silica gel column chromatographies, chloroform-methanol (50: 0-0: 1) gradient elution with 800.Thin-layer chromatography detects and merges same stream part, the part medicinal extract that contains formula (1) compound is again through 16 gram silica gel H (60-90 ° of sherwood oil-vinyl acetic monomer 4: 1-2: 1) purifying, continue with Sephadex LH-20 column chromatography purification (methanol-eluted fractions), finally obtain formula (1) compound (19mg).Colourless needle, fusing point: 233-235 ℃; [α]
D 20:+29.0 ° of (chloroforms; C0.30); UV λ
Max(CHCl
3) nm:223; IR v
Max KBr(cm
-1): 1772,1756,1681; Electrospray ionization mass spectrum ESI-MS (m/z): 259[M+H]
+High resolution electrospray ionization mass spectrum HR-ESI-MS (m/z): 259.0936 (Calc.for[C
15H
16O
4+ H]
+259.0926);
13C and
1H NMR spectral data sees Table 1 and table 2.
Table 1. formula (1) compound
13C-NMR spectrum data *
* (in deuterochloroform, measure.Q represents primary carbon; T represents tertiary carbon; D represents secondary carbon; S represents quaternary carbon).
Table 2. formula (1) compound
1H-NMR spectrum data *
* in deuterochloroform, measure.
Pharmacology embodiment 1:Formula (1) compound is to the cytotoxic activity of KB cell
KB (oral epithelium cancer) cell contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 5 * 10
3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing mtt assay.Cell is through after 24 hours hatch, the dimethyl sulfoxide solution of the formula that will newly join (1) compound joins in each hole with concentration gradient respectively, make hole Chinese style (1) compound ultimate density be respectively 100 μ g/mL, 33.3 μ g/mL, 11.1 μ g/mL and 3.7 μ g/mL.After 72 hours, the phosphate buffered saline buffer that adds 10 μ LMTT (5mg/mL), continue 37 ℃ of cultivations after 4 hours again, removed unconverted MTT in centrifugal 5 minutes, add 200 μ L methyl-sulphoxides in every hole, with the MTT crystal Jia Za (formazan) of dissolving and reducing, formed formazan microplate reader colorimetric under the 570nm wavelength, cell survival rate is by the ratio calculation of sample with respect to reference substance.Its Chinese style (1) compound is to KB cell 503nhibiting concentration (IC
50) obtain by dose effect curve.
The IC of formula (1) compound
50For: 7.65 * 10
-5M; The positive control cis-platinum is to the IC of KB cell
50Be 5.67 * 10
-6M.Experiment conclusion: the KB cell is Cytotoxic effective tool and the evaluation index of test compounds to tumour cell.This experiment shows that the not fragrant dilactone compound of this Airy has stronger cytotoxicity to the KB cell, might develop into the new medicine with antitumor action.
Pharmacology embodiment 2:Formula (1) compound is to the cytotoxic activity of BEL-7404 cell
BEL-7404 (people's liver cancer) cell contains 10% foetal calf serum, the Streptomycin sulphate of 100U/mL penicillin and 100U/mL with RPMI 1640 culture medium culturing in the substratum.Cell is with every hole 5 * 10
3Concentration join in 96 orifice plates, contain 5%CO at 37 ℃
2Cultivated 24 hours in the incubator of damp atmosphere.
The mensuration of cell survival rate is with improveing MIT method, concrete grammar such as pharmacology embodiment 1.Its Chinese style (1) compound is to BEL-7404 cell 503nhibiting concentration (IC
50) obtain by dose effect curve.
The IC of formula (1) compound
50For: 1.44 * 10
-4M; And the positive control cis-platinum is to the IC of BEL-7404 cell
50Be 1.50 * 10
-5M.
Experiment conclusion: this experiment shows that the not fragrant dilactone compound of this Airy has stronger cytotoxicity to the BEL-7404 cell, might develop into the new medicine with anti-liver cancer and related neoplasms effect.
Claims (5)
1. the not fragrant dilactone analog derivative of Airy is characterized in that: have the Airy Mo Fen-3,7 (11) of structure shown in the formula (1), 8-triolefin-12,8 (14,6 α)-dilactone.
Formula (1)
2. the not fragrant dilactone derivative of Airy according to claim 1 is used in the medicine of preparation inhibition oral squamous carcinoma cell KB, human liver cancer cell BEL-7404 growth activity.
3. the not fragrant dilactone derivative of Airy according to claim 1 is prevented and treated application in human oral cavity epithelial cancer, the liver cancer tumor disease medicine in preparation.
4. pharmaceutical composition that is used to prevent and treat tumor disease, it contains the described Airy of the claim 1 as activeconstituents not fragrant dilactone platform thing or its pharmacologically acceptable salt and the pharmaceutically acceptable auxiliaries for the treatment of significant quantity.
5. pharmaceutical composition according to claim 4 is characterized in that: the dosage form of described medicine comprises injection, tablet, capsule, aerosol, suppository, film, pill, externally-applied liniment, ointment, controlled release or sustained release dosage or nanometer formulation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100517193A CN100387603C (en) | 2006-05-30 | 2006-05-30 | Eremophil dilactone natural product with tumour cell growth inhibiting activity |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100517193A CN100387603C (en) | 2006-05-30 | 2006-05-30 | Eremophil dilactone natural product with tumour cell growth inhibiting activity |
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| Publication Number | Publication Date |
|---|---|
| CN1850826A CN1850826A (en) | 2006-10-25 |
| CN100387603C true CN100387603C (en) | 2008-05-14 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006100517193A Expired - Fee Related CN100387603C (en) | 2006-05-30 | 2006-05-30 | Eremophil dilactone natural product with tumour cell growth inhibiting activity |
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| Country | Link |
|---|---|
| CN (1) | CN100387603C (en) |
-
2006
- 2006-05-30 CN CNB2006100517193A patent/CN100387603C/en not_active Expired - Fee Related
Non-Patent Citations (6)
| Title |
|---|
| Pharmaceutical Bulletin,Vol.53 No.10. 2005 * |
| Sesquiterpenes, nortriterpenes and other constituents fromLigularia tongolensis. Han, Yi Feng, Pan, Jing, Gao, Kun, Jia, Zhong Jian.Chemical & Pharmaceutical Bulletin,Vol.53 No.10. 2005 |
| Sesquiterpenes, nortriterpenes and other constituents fromLigularia tongolensis. Han, Yi Feng, Pan, Jing, Gao, Kun, Jia, Zhong Jian.Chemical & Pharmaceutical Bulletin,Vol.53 No.10. 2005 * |
| Sesquiterpenes, nortriterpenes and other constituents fromLigularia tongolensis. Han, Yi Feng, Pan, Jing, Gao, Kun, Jia, Zhong Jian.Chemical & * |
| Two new eremophilenolides from Ligularia tongolensis. Han, Yi Feng, Fei, Dong Qing, Gao, Kun, Jia, Zhong Jian.Chinese Chemical Letters,Vol.16 No.8. 2005 |
| Two new eremophilenolides from Ligularia tongolensis. Han, Yi Feng, Fei, Dong Qing, Gao, Kun, Jia, Zhong Jian.Chinese Chemical Letters,Vol.16 No.8. 2005 * |
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|---|---|
| CN1850826A (en) | 2006-10-25 |
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