CN102000047B - Cyclohexenone Compounds of Antrodia Antrodia for Inhibiting the Growth of Bone Cancer Tumor Cells - Google Patents
Cyclohexenone Compounds of Antrodia Antrodia for Inhibiting the Growth of Bone Cancer Tumor Cells Download PDFInfo
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- CN102000047B CN102000047B CN2009101710647A CN200910171064A CN102000047B CN 102000047 B CN102000047 B CN 102000047B CN 2009101710647 A CN2009101710647 A CN 2009101710647A CN 200910171064 A CN200910171064 A CN 200910171064A CN 102000047 B CN102000047 B CN 102000047B
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Abstract
本发明是关于一种化合物的新用途，本发明是由牛樟芝萃取物中分离纯化而得4-羟基-2，3-二甲氧基-6-甲基-5(3，7，11-三甲基-2，6，10-十二碳三烯)-2-环己烯酮(4-hydroxy-2，3-dimethoxy-6-methy-5(3，7，11-trimethyl-dodeca-2，6，10-trienyl)-cyclohex-2-enone)，该环己烯酮化合物可应用于抑制骨癌肿瘤细胞的生长，同时可应用于抑制骨癌肿瘤细胞生长的医药组合物中。The present invention relates to a new application of a compound, which is obtained by separating and purifying 4-hydroxy-2,3-dimethoxy-6-methyl-5(3,7,11-tri Methyl-2,6,10-dodecatriene)-2-cyclohexenone (4-hydroxy-2,3-dimethoxy-6-methy-5(3,7,11-trimethyl-dodeca-2 , 6,10-trienyl)-cyclohex-2-enone), the cyclohexenone compound can be applied to inhibit the growth of bone cancer tumor cells, and can be applied to a pharmaceutical composition for inhibiting the growth of bone cancer tumor cells.
Description
Technical field
The invention relates to a kind of new application of chemical compound, especially about a kind of purposes that suppresses the osteocarcinoma growth of tumour cell by the chemical compound of institute's separation and purification in Antrodia Camphorata (Antrodia cinnamomea) extract of utilizing.
Background technology
Osteosarcoma; Be commonly called as osteocarcinoma (Osteosarcoma), it is a kind of malignant tumor that is grown by skeletal system, and is modal a kind of in the bone tumor; Can invade contiguous tissue and organ; Also may be transferred to other organ at a distance, good sending out on one's body the child and teenager of age between ten years old to 20 years old, and male's occurrence probability is a little more than the women.The pathogenesis of osteocarcinoma is not bright so far; The age of quick growth is born in multiple in former position by it; Show it and follow osteoblastic active increase possibility relevant, and as if inherited genetic factors also play a role in osteocarcinoma, in addition also maybe be relevant with chronic inflammation, radiation or viral infection.
The osteocarcinoma regular incidence is terminal in long bone; Have 50% to be positioned at nearly knee approximately; Can cause pain, swelling, pathologisch Bruch even, and possibly occur dyskinesia, part occur lump or other nonspecific symptom as lose weight, inappetence, feveret or sore waist and aching in the waist and the back or the like; And its mortality rate is very high, so osteocarcinoma is the cancer of the complexion changed that makes us hearing.In the sixties mainly is to take amputation (amputation) treatment operation; Yet the survival rate after patient's amputation in 5 years is also quite low, along with chemotherapeutical rapid progress, cooperates the lifting of radiodiagnostics and surgical technic; The survival rate in 5 years of osteocarcinoma has improved between 70～80% at present; And can expect to reach secular survival (long-term survival), but still can't control fully, and when treatment merges the multiple chemotherapeutics that uses; Very strong bone marrow depression effect is all arranged; Therefore exploitation effectively and the little medicine of side effect be that its necessity is arranged for clinical practice, on the human osteocarcinoma of clinical treatment, both can having reduced drug use concentration and reduce side effect, and can reach preferable therapeutic effect.
Antrodia Camphorata (Antrodia cinnamomea); Among the peoplely in Taiwan be called wild rice, Antrodia camphorata or red Camphor tree in Camphor tree mushroom, Camphor tree wild rice, the Camphor tree again; Be the exclusive medicinal mushrooms of this province, it belongs to the perennial mushroom fungus class of Aphyllophorales (Aphyllophorales), Polyporaceae (Polyporaceae).Because Antrodia camphorata only parasitizes on the dried hollow heartwood interior wall tissue of Taiwan distinctive child care class Cinnamomum kanahirai hay ebon at occurring in nature; Add artificial felling trees unlawfully; Make and to parasitize the wild Antrodia Camphorata quantity that wherein can grow more shape is rare; And since under naturalness the growth phase of Antrodia camphorata sporophore when slowly, so wild Antrodia camphorata quantity is rare and cost an arm and a leg.
The sporophore of Antrodia Camphorata is perennial, and stockless is suberin to wooden, and the intensive Lignum cinnamomi camphorae fragrance of its tool, and changeableization of form have tabular, mitriform, horse-hof shape or tower shape.Nascent is platypelloid type and is cerise that its periphery can present radiation warp shape afterwards, and to expansion growth all around, color also changes light red brown or khaki into, and many pores are arranged, and it is the abundantest position of medical value of Antrodia Camphorata.
Folk custom medically in Taiwan; Antrodia Camphorata has that the circulation of qi promoting of dispeling the wind, blood stasis dispelling are invigorated blood circulation, the effect of warming middle-JIAO removing food stagnancy, removing toxic substances and promoting subsidence of swelling and sedation-analgesia, and is regarded as first-class antidote, all alimentary toxicosis; Diarrhoea; Vomiting, pesticide intoxication all has Detoxication, all has the auxiliary treatment effect to improving liver, stomach malfunction and blood circulation disease in addition.Antrodia Camphorata is as the gill fungus mushrooms of general edible medicinal; Composition with many complicacies; In the known physiologically active ingredient; Comprise: triterpenoid compound (triterpenoids), polysaccharide body (polysaccharides; Like callose), adenosine (adenosine), vitamin (like vitamin B, niacin), protein (containing immunoglobulin), sudismase (superoxide dismutase; SOD), trace element (as: calcium, phosphorus, germanium), nucleic acid, steroid and blood pressure stabilization material (like antodia acid) etc., these a little physiologically active ingredients are considered to have antitumor, increase multiple efficacies such as immunocompetence, antiallergic, disease-resistant bacterium, resisting hypertension, blood sugar lowering and cholesterol reducing, and help the treatment of hepatoprotective and liver related disease.
The composition Study of relevant Antrodia camphorata; Focus on macromolecular polysaccharide body (polysaccharides) and micromolecular triterpenes (triterpenoids) and steroid (steroids) mostly; Wherein, Antrodia camphorata contains macromolecular polysaccharide body, forms with different monosaccharide to be present in its sporophore and the mycelium, but after spectrum analysis, all contains the callose (β-D-glucans) of tool physiologically active; Triterpenoid compound is the general name that is combined into hexagon or pentagon native compound by 30 carbons, and the bitterness of Antrodia Camphorata institute tool is promptly mainly from this composition of triterpenes, and it also is to be studied maximum compositions.The triterpenoid compound that obtains from sporophore has antrocin, 4,7-dimethoxy-5-methyl isophthalic acid, 3-benzo dioxy ring (4,7-dimethoxy-5-methy-1; 3-benzodioxole) with 2,2 ', 5,5 '-tetramethoxy-3; 4,3 ', 4 '-two-methylene-dioxy-6,6 '-dimethyl diphenyl (2; 2 ', 5,5 '-teramethoxy-3,4; 3 ', 4 '-bi-methylenedioxy-6,6 '-dimethylbiphenyl) (Chiang et al., 1995); With lumistane (ergostane) is new triterpenoid compound antcinA, antcin B, antcin C, antcin E, antcin F, methyl antcinate G and the methyl antcinateH (Cherng et al., 1995,1996) of skeleton.It is that the chemical compound of skeleton comprises Zhankuic acid A, B and C zhankuic acid D and zhankuic acid E (Chen and Yang, 1995 that sporophore contains with the lumistane in addition; Yang 1996), be noval chemical compound 15 α-acetyl-dehydrogenation sulfurenic acid (15 α-acetyl-dehydrosulphurenic acid), the dehydrogenation eburicoic acid (dehydroeburicoic acid) of skeleton and the sulfurenic acid (dehydrasulphurenic acid) that anhydrates with lanostane (lanostane).
Though can learn that by many experiments at present the Antrodia Camphorata extract has aforementioned effect; And its ingredient is also analyzed successively; But which kind of effective ingredient in the extract can be facilitated the inhibition cancer effect of Antrodia Camphorata actually; Do not deliver concrete relevant effective ingredient, remain further experiment research to be differentiated, so if can find out the contained real composition that effectively suppresses tumor growth in this extract; To help Antrodia Camphorata and press down the research that cancer is shut down mutually changes, and Antrodia Camphorata is applied to cancer, and for example the treatment and the prevention of osteocarcinoma there are greatest help.
Summary of the invention
For be that what composition has the effect that presses down cancer in the clear Antrodia Camphorata extract actually, the present invention provides the chemical compound of following structural (1) by separation and purification in the Antrodia Camphorata extract;
Wherein, X is oxygen (O) or sulfur (S), and Y is oxygen or sulfur; R
1Be hydrogen base (H), methyl (CH
3) or (CH
2) m-CH
3, R
2Be hydrogen base, methyl or (CH
2) m-CH
3, R
3Be hydrogen base, methyl or (CH
2) m-CH
3, m=1～12; N=1～12.
In the chemical compound suc as formula (1) structural formula, the preferably is the chemical compound of formula as follows (2):
The chemical compound of formula (2), its chemistry 4-hydroxyl-2 by name, 3-dimethoxy-6-methyl-5 (3,7; 11-trimethyl-2,6,10-12 carbon triolefins)-2-cyclonene (4-hydroxy-2; 3-dimethoxy-6-methy-5 (3,7,11-trimethyl-dodeca-2; 6,10-trienyl)-cyclohex-2-enone), molecular formula is C
24H
38O
4, outward appearance is the pale yellow powder shape, molecular weight is 390.
The chemical compound of Chinese style of the present invention (1), formula (2) is that separation and purification is from Antrodia Camphorata water extract or organic solvent extraction thing; Organic solvent can comprise alcohols (for example methanol, ethanol or propanol), esters (for example ethyl acetate), alkanes (for example hexane) or alkyl halide (for example chloromethanes, ethyl chloride); But not as limit; Wherein the preferably is an alcohols, and better person is an ethanol.
Through aforesaid compound, the present invention is applied to suppress on the growth of tumour cell, enables further to use the medicine that is included in the treatment cancer and forms in part, gain treatment for cancer effect.The scope that the present invention must use this chemical compound comprises the growth inhibited for the osteocarcinoma tumor cell, makes the ramp that suppresses said tumor cell, and then suppresses the hypertrophy of tumor, and delays the deterioration of tumor.Wherein, preferable chemical compound is the 4-hydroxyl-2 of formula (2), 3-dimethoxy-6-methyl-5 (3,7,11-trimethyl-2,6,10-12 carbon triolefins)-2-cyclonene.
On the other hand, also can the chemical compound of formula (1) and/or formula (2) be used among the present invention in the composition of the medical composition that suppresses the osteocarcinoma growth of tumour cell.Aforementioned medical composition still can comprise pharmaceutically acceptable carrier except that the chemical compound of formula that comprises effective dose (1) and/or formula (2).Carrier can be excipient (like water), filler (like sucrose or starch), adhesive (like cellulose derivative), diluent, disintegrating agent, absorption enhancer or sweeting agent, but does not only limit to this.Medical composition of the present invention can be manufactured according to the method for preparing of general convention pharmacy; Formula (1) and/or formula (2) effective ingredient dosage are mixed with more than one carrier mutually; Prepare required dosage form; This dosage form can comprise lozenge, powder, granule, capsule or other liquid preparation, but not as limit.
Below will cooperate the graphic embodiment of the present invention that further specifies; Following cited embodiment is in order to illustrate the present invention; Be not in order to limiting scope of the present invention, anyly have the knack of this art, do not breaking away from the spirit and scope of the present invention; When can doing a little change and retouching, so protection scope of the present invention is as the criterion when looking the accompanying Claim person of defining.
The specific embodiment
Through extraction Antrodia Camphorata water extract or organic solvent extraction thing later, can be further through in addition separation and purification of high performance liquid chroma-tography, again each separatory (fraction) is carried out the test of cancer resistant effect afterwards.At last, then the separatory to the tool cancer resistant effect carries out component analysis, and the composition that possibly produce cancer resistant effect is further done the inhibition measure of merit of osteocarcinoma tumor cell more respectively.Find promptly that finally the chemical compound suc as formula (1)/formula (2) is to have the effect that suppresses the osteocarcinoma growth of tumour cell among the present invention.
Be convenient explanation the present invention, below will be with the 4-hydroxyl-2 of formula (2), 3-dimethoxy-6-methyl-5 (3,7,11-trimethyl-2,6,10-12 carbon triolefins)-2-cyclonene chemical compound describes.In addition, for confirming 4-hydroxyl-2,3-dimethoxy-6-methyl-5 (3; 7,11-trimethyl-2,6; 10-12 carbon triolefins)-2-cyclonene chemical compound is to the inhibition effect of growth of tumour cell, is with the MTT analytic process among the present invention, according to American National ICR (National Cancer Institute; NCI) antitumor drug screening pattern is carried out the test of cell survival rate to the osteocarcinoma tumor cell.Confirm 4-hydroxyl-2,3-dimethoxy-6-methyl-5 (3 by those tests; 7,11-trimethyl-2,6; 10-12 carbon triolefins)-the 2-cyclonene can reduce its survival rate for osteocarcinoma tumor cell: MG-63, relatively under and can to reduce growth half suppression ratio desired concn simultaneously (be IC
50Value), therefore must pass through 4-hydroxyl-2,3-dimethoxy-6-methyl-5 (3,7,11-trimethyl-2,6,10-12 carbon triolefins)-2-cyclonene is applied on the growth inhibited of osteocarcinoma tumor cell, and further capable of using in the treatment of osteocarcinoma.Now aforementioned embodiments is elaborated as follows:
Embodiment 1:
4-hydroxyl-2, the separation of 3-dimethoxy-6-methyl-5 (3,7,11-trimethyl-2,6,10-12 carbon triolefins)-2-cyclonene
With Antrodia Camphorata mycelium, sporophore or the mixture of the two about 100 grams; Insert in the triangular pyramidal bottle; The water and the alcohols (70%～100% alcohol solution) that add proper proportion; Under 20～25 ℃, stir extraction more than at least 1 hour,, collect extract afterwards with filter paper and 0.45 μ m membrane filtration.
Antrodia Camphorata extract with aforementioned collection; Utilize high-effect chromatograph of liquid (High PerformanceLiquid chromatography); Chromatographic column (column) with RP18 is analyzed; And with methanol (A) and 0.1%～0.5% aqueous acetic acid (B) (its solution proportion is: 0～10 minute, the B ratio was 95%～20% as mobile phase (mobile phase); 10～20 minutes, the B ratio was 20%～10%; 20～35 minutes, the B ratio was 10%～90%; 35～40 minutes, the B ratio was 10%～95%), eluting under the speed of per minute 1ml is simultaneously with the long detector analysis of ultraviolet-visible light all-wave.
With 25 minutes to 30 minutes eluents collect concentrate get final product the solid product of pale yellow powder shape, this is a 4-hydroxyl-2,3-dimethoxy-6-methyl-5 (3,7,11-trimethyl-2,6,10-12 carbon triolefins)-2-cyclonene.Through analyzing, its molecular formula is C
24H
38O
4, molecular weight 390, fusing point (m.p.) are 48 ℃～52 ℃.Nuclear magnetic resonance, NMR (NMR) assay value is then as follows:
1H-NMR (CDCl
3) δ (ppm): 1.51,1.67,1.71,1.75,1.94,2.03,2.07,2.22,2.25,3.68,4.05,5.07 and 5.14.
13C-NMR (CDCl
3) δ (ppm): 12.31,16.1,16.12,17.67,25.67,26.44,26.74,27.00,39.71,39.81,4.027,43.34,59.22,60.59,120.97,123.84,124.30,131.32,135.35,135.92,138.05,160.45 and 197.12.
Embodiment 2:
The active testing of external anti-osteocarcinoma tumor cell
By in the further test implementation example 1 the discovery chemical compound to the inhibition effect of tumor cell, present embodiment will be according to American National ICR (National Cancer Institute, NCI) antitumor drug screening pattern; At first get isolating 4-hydroxyl-2 among the embodiment 1,3-dimethoxy-6-methyl-5 (3,7; 11-trimethyl-2,6,10-12 carbon triolefins)-2-cyclonene chemical compound; Add in the human osteocarcinoma tumor cell MG-63 culture fluid, carry out the test of tumor cell viability.Wherein, The test of cell survival property can be adopted the MTT analytic process of convention and analyzed; And osteocarcinoma tumor cell MG-63 is osteoblast appearance fibroblast strain (osteoblast-1ike fibroblast cell line); This cell strain is from the isolated cancerous cell of human osteosarcoma (osteosarcoma), and its kenel is closely similar with characteristic and osteoblast.
The MTT analytic process is a kind of common analytical method that is used for analysis of cells hypertrophy (cell proliferation), survival rate (percent of viable cells) and cytotoxicity (cytotoxicity).Wherein, (3-[4 for MTT; 5-dimethylthiazol-2-yl] 2; 5-diphenyltetrazolium bromide) is yellow stain; It can be absorbed and be reduced into water insoluble and be hepatic first
(formazan) by the succinic acid tetrazolium reductase (succinate tetrazoliumreductase) in the Mitochondria by living cells, therefore whether forms through formazan, can judge and calculate the survival rate of cell.
At first with human osteocarcinoma cell MG-63 in the DMEM that contains 10% hyclone (fetal bovine serum) (Dulbecco ' s modified Eagle ' s medium) culture medium; It still comprises the penicillin (Penicillin) of 100IU/ml; And the streptomycin (Streptomycin) of 100mg/ml, and in 5%CO
2, cultivated 24 hours in 37 ℃ of environment.Cell after the hypertrophy is cleaned once with phosphate buffer (PBS), and handle cell with trypsin-EDTA of 1 times, subsequently in 1, under the 200rpm centrifugal 5 minutes, with cell precipitation and abandon supernatant.Add the new culture fluid of 10ml afterwards, slight wobble suspends cell once more, cell is placed in the 96 hole microtest plates again.During test, respectively at the Antrodia Camphorata ethanolic extract that adds 30,10,3,1,0.3,0.1 and 0.03 μ g/ml in each hole as matched group (without total extract of purifies and separates); And the 4-hydroxyl-2 that in each hole, adds 30,10,3,1,0.3,0.1 and 0.03 μ g/ml, 3-dimethoxy-6-methyl-5 (3,7,11-trimethyl-2,6,10-12 carbon triolefins)-2-cyclonene is as test group, in 37 ℃, 5%CO
2Under cultivated 48 hours.At the MTT that the environment of lucifuge under in each hole in add 2.5mg/ml, react lysis buffer (lysis buffer) cessation reaction that 4 hour after again in each hole in add 100 μ ls thereafter.Under 570nm extinction wavelength, measure its light absorption value with the enzyme immunoassay appearance at last, use the survival rate of calculating cell, and to extrapolate its half suppression ratio desired concn of growing (be IC
50Value), its result is shown in table one.
Table one: external test result to osteocarcinoma tumor cell survival rate
By knowing in the table one, through 4-hydroxyl-2, the effect of 3-dimethoxy-6-methyl-5 (3,7,11-trimethyl-2,6,10-12 carbon triolefins)-2-cyclonene, it is for the IC of the human osteocarcinoma tumor cell of MG-63
50Value is 2.09 μ g/ml, compared to the measured IC of matched group Antrodia Camphorata extraction mixture
50Value (result does not show) is low many, so the 4-hydroxyl-2 in the susceptible of proof Antrodia Camphorata extract, and 3-dimethoxy-6-methyl-5 (3,7,11-trimethyl-2,6,10-12 carbon triolefins)-2-cyclonene can be used in the inhibition of osteocarcinoma growth of tumour cell really.
In sum, the 4-hydroxyl-2 of separated from Antrodia camphorate of the present invention, 3-dimethoxy-6-methyl-5 (3,7,11-trimethyl-2,6,10-12 carbon triolefins)-2-cyclonene chemical compound can effectively suppress the growth of osteocarcinoma tumor cell.On the other hand; Because of the Cinnamomum kanahirai hay pimelie kelone compound is the material of natural extraction; When so it is applied to suppress osteocarcinoma; Can't cause other side effect such as patient's discomfort or toxigenicity, complication etc., and its also can with chemotherapeutic agents and usefulness, to reduce the chemotherapeutics using dosage and to reduce the side effect that those chemotherapeutic agents are caused; In addition, also can be with its medical composition that is prepared into treatment osteocarcinoma, wherein, this medical composition still can comprise pharmaceutically acceptable carrier except that the Cinnamomum kanahirai hay pimelie kelone compound that comprises effective dose.Carrier can be excipient (like water), filler (like sucrose or starch), adhesive (like cellulose derivative), diluent, disintegrating agent, absorption enhancer or sweeting agent, but does not only limit to this.Medical composition of the present invention can be manufactured according to the method for preparing of general convention pharmacy; The Cinnamomum kanahirai hay pimelie kelone compound of effective ingredient dosage is mixed with more than one carrier mutually; Prepare required dosage form; This dosage form can comprise lozenge, powder, granule, capsule or other liquid preparation, but not as limit.Use the purpose that reaches treatment osteocarcinoma tumor disease.
Claims (2)
1. compound 4-hydroxy base-2,3-dimethoxy-6-methyl-5 (3,7,11-trimethyl-2,6,10-12 carbon triolefins)-2-cyclonene suppress the application of the medicine of osteocarcinoma growth of tumour cell in preparation.
2. application according to claim 1, wherein, said osteocarcinoma tumor cell is a MG-63 cell line.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101710647A CN102000047B (en) | 2009-09-02 | 2009-09-02 | Cyclohexenone Compounds of Antrodia Antrodia for Inhibiting the Growth of Bone Cancer Tumor Cells |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2009101710647A CN102000047B (en) | 2009-09-02 | 2009-09-02 | Cyclohexenone Compounds of Antrodia Antrodia for Inhibiting the Growth of Bone Cancer Tumor Cells |
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| Publication Number | Publication Date |
|---|---|
| CN102000047A CN102000047A (en) | 2011-04-06 |
| CN102000047B true CN102000047B (en) | 2012-08-08 |
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| CN103948577A (en) * | 2012-11-14 | 2014-07-30 | 国鼎生物科技股份有限公司 | Use of compounds for the preparation of a composition for treating, alleviating or managing pain associated with bone cancer |
| TWI586359B (en) * | 2015-08-27 | 2017-06-11 | 喬本生醫股份有限公司 | Use of extract composition of fruiting body of antrodia cinnamomea |
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| US20110009495A1 (en) * | 2009-07-09 | 2011-01-13 | Golden Biotechnology Corporation | Inhibition of the Survival of Bone Cancer by Cyclohexenone Compounds from Antrodia Camphorata |
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