CN100368428C - 5 alpha, 8 alpha-epidioxy-24-dimethycholestane-6-alkene-three beta-alcohol and its heterosides and ester preparation process and use - Google Patents
5 alpha, 8 alpha-epidioxy-24-dimethycholestane-6-alkene-three beta-alcohol and its heterosides and ester preparation process and use Download PDFInfo
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Abstract
The present invention discloses 5 alpha, 8 alpha-epidioxy-24-dimethylcholest-6-ene-3 beta-alcohol, the glycosides and the esters thereof, a preparation method and the application thereof. The compounds are extracted and separated from ascidian and used as anticancer and antiviral medicines. The structural formula of the compounds is as below, wherein R can be one of a hydrogen atom, glucose, rhamnose, xylose, arabinose, an acetate radical, a nitrate radical and a sulfate radical. Medicines containing the compounds of the present invention have strong antineoplastic activity and antiviral activity in vivo or in vitro. Glucosyl, rhamnose radical, arabinose redical, xylose radical, sulfate radical, nitrate radical and acetate radical.
Description
Technical field
The present invention relates to a kind of 5 α that extraction separation obtains from Ascidian, 8 α-epidioxy-24-dimethyl courage steroid-6-alkene-3 β-alcohol and glycosides and ester, its preparation method and its are antiviral in preparation, the application in the cancer therapy drug.
Background technology
Ascidian (Tunicate) is a distinctive class and the very similar protochordate of vertebrates in the marine organisms, because of it occupies special status on taxonomy, becomes bionical biology, immunochemistry and physiological fabulous research material already.Since the eighties, the foreign scholar isolates multiple new compounds such as indoles, cyclic peptide, alkaloid, nitrogenous macrolide successively from Ascidian, and finds to have multiple physiologically actives such as antiviral, anticancer, and toxicity is lower.
Ascidian is quite abundant in china natural resources, mainly is distributed in marine sites such as the Bohai Sea, the Huanghai Sea, the East Sea, the South Sea, has recorded 66 kinds in China, and the advantage kind mainly contains Styela clava (Styela clava), Ciona (Cionaintestinalis) etc.But China also carries out to such an extent that be not very abundant to the research and development of Ascidian.
Summary of the invention
The objective of the invention is by system and sufficient research to Ascidian, therefrom extraction separation goes out can be used as 5 α antiviral, cancer therapy drug, 8 α-epidioxy-24-dimethyl courage steroid-6-alkene-3 β-alcohol and glycosides and ester.
Second purpose of the present invention provides that extraction separation obtains 5 α from Ascidian, the method for 8 α-epidioxy-24-dimethyl courage steroid-6-alkene-3 β-alcohol and glycosides and ester.
The 3rd purpose of the present invention provides 5 α, and 8 α-epidioxy-24-dimethyl courage steroid-6-alkene-3 β-alcohol and glycosides thereof and ester are antiviral in preparation, the application of cancer therapy drug.
Extraction separation has obtained 5 αs of structural formula as shown in the formula (1) in the inventor Ascidian, 8 α-epidioxy-24-dimethyl courage steroid-6-alkene-3 β-alcohol and glycosides and ester,
Wherein,
R is hydrogen, glucosyl, rhamanopyranosyl, xylosyl, Arabic glycosyl, acetate, nitrate radical or sulfate radical.
The present invention also provides the preparation method of above-mentioned formula (1) compound, comprises the steps:
(1) with fresh Ascidian with the aqueous solution of the aqueous solution of the alcohol of 10-95% or ketone with 1: the weight ratio refluxing extraction of 6-10 or soak infiltration and extract at least once, each time is 1-6 hour, and the extracting solution concentrating under reduced pressure is obtained spissated Ascidian extracting solution;
(2) extracting solution that step (1) is obtained, remove by filter impurity after, the Fatty Alcohol(C12-C14 and C12-C18) with C6-C7 alkane, halohydrocarbon, organic ether, organic ester and C3-C5 extracts successively, obtains extractive with organic solvent and water extract respectively;
(3) the ester extract that step (2) is obtained separates through silica gel column chromatography, obtains 5 α shown in the formula (1), 8 α-epidioxy-24-dimethyl courage steroid-6-alkene-3 β-alcohol.
According to the method described above, wherein the alcohol described in the step (1) is 1-4 carbon alcohol, and described ketone is acetone.
According to the method described above, wherein the C6-C7 alkane described in the step (2) is sherwood oil, hexanaphthene or hexane; Described halohydrocarbon is a methylene dichloride, trichloromethane or tetrachloromethane; Described organic ether is an ether; Described organic ester is ethyl acetate, butylacetate or pentyl acetate; Described C3-C5 Fatty Alcohol(C12-C14 and C12-C18) is a propyl carbinol.
According to the method described above, wherein in step (3), the ester extract that step (2) is obtained separates through silica gel column chromatography, uses earlier the sherwood oil wash-out, use sherwood oil again: ethyl acetate is 1: 10-1: the sherwood oil of 1 different ratios and ethyl acetate mixed solution gradient elution obtain formula (1) compound.
According to the method described above, 5 α that step (3) is obtained wherein, 8 α-epidioxy-24-dimethyl courage steroid-6-alkene-3 β-alcohol is further purified with silica gel.
The present invention also provides the application of above-mentioned formula (1) compound in anticancer, the antiviral of preparation.
The present inventor has carried out the deep research of system to Styela clava, and therefrom extraction separation has obtained structural formula as shown in the formula 5 α shown in (1) first, 8 α-epidioxy-24-dimethyl courage steroid-6-alkene-3 β-alcohol:
Wherein, R is hydrogen, glucosyl, rhamanopyranosyl, xylosyl, Arabic glycosyl, acetate, nitrate radical or sulfate radical.
According to second aspect of the present invention, the invention provides 5 αs of structural formula shown in following formula, the extraction preparation method of 8 α-epidioxy-24-dimethyl courage steroid-6-alkene-3 β-alcohol comprises the steps:
(1) with fresh Ascidian with concentration be the alcohol solution of 10-95% (weight) or the ketone aqueous solution with 1: the weight ratio refluxing extraction of 6-10 or soak infiltration and extract at least once, each extraction time is 1-6 hour, and the extracting solution concentrating under reduced pressure is obtained spissated Ascidian extracting solution;
(2) extracting solution that step (1) is obtained, remove by filter impurity after, extract with C6-C7 alkane, halohydrocarbon, organic ether, organic ester and C3-C5 Fatty Alcohol(C12-C14 and C12-C18) successively, obtain extractive with organic solvent and water extract respectively;
(3) the ester extract that step (2) is obtained separates through silica gel column chromatography, obtains 5 α shown in the formula (1), 8 α-epidioxy-24-dimethyl courage steroid-6-alkene-3 β-alcohol.
In the method for the present invention, the aqueous solution that at first with fresh Ascidian with concentration is the aqueous solution of alcohol of 10-95% or ketone is with 1: the weight ratio refluxing extraction of 6-10 or soak infiltration and extract.The backflow of this step or immersion infiltration are extracted and are carried out once at least, preferably extract with the alcohol of different concns or the aqueous solution gradation of ketone, for example, elder generation permeates extraction with 95% aqueous ethanolic solution immersion, permeates extraction with 80% aqueous ethanolic solution immersion then, permeates extraction with 60% aqueous ethanolic solution immersion again, after obtaining extracting solution, united extraction liquid then with its concentrating under reduced pressure, obtains its concentrated solution.Wherein, the pressure during concentrating under reduced pressure is 0.01～0.03Pa, and temperature is 25～50 ℃, and described alcohol is C1-C4 alcohol, for example methyl alcohol, ethanol, propyl alcohol and butanols; Described ketone is acetone.
Then, the concentrated extracting solution that obtains removed by filter impurity after, extract with C6-C7 alkane, halohydrocarbon, organic ether, organic ester and C3-C5 Fatty Alcohol(C12-C14 and C12-C18) successively, obtain the extract and the water extract of organic solvent respectively; Wherein, described C6-C7 alkane is sherwood oil, hexanaphthene, hexane; Described halohydrocarbon is a methylene dichloride, trichloromethane, tetrachloromethane; Described organic ether is an ether, and described organic ester is ethyl acetate, butylacetate, and pentyl acetate is preferably ethyl acetate; Described C3-C5 Fatty Alcohol(C12-C14 and C12-C18) is preferably propyl carbinol.
The ethyl acetate extract that obtains is separated through silica gel column chromatography, obtain 5 α shown in the formula (1), 8 α-epidioxy-24 1 dimethyl courage steroid, one 6 one alkene, one 3 β, one alcohol.
The present inventor is through discovering fully, and structural formula is as shown in the formula shown in (1)
5 α, 8 α, one epidioxy, one 24 one dimethyl courage steroids-6-alkene one 3 p one alcohol has good anticancer and antiviral activity, has therefore further developed it as application anticancer, antiviral.
Adopt assistant agent well known in the art, can be with 5 α of the present invention, 8 α, one epidioxy, one 24 one dimethyl courage steroids, one 6 one alkene-3 β-alcohol is prepared into various pharmaceutical dosage form, for example tablet, pill, capsule, electuary, sprays, oral liquid, suspension, externally-applied liniment, cutaneous permeable agent and injection.When being used for cancer therapy drug, the consumption of compound of the present invention is 10-30 milligram/kg body weight/sky; When being used for antiviral, the consumption of compound of the present invention is 10-25 milligram/kg body weight/sky.
Below the present invention is described in more detail with embodiment and experimental example.But it should be understood that the present invention is not restricted to these embodiment and experimental example.
Embodiment
Embodiment 1
5 α, the preparation of 8 α-epidioxy-24-dimethyl courage steroid-6-alkene-3 β-alcohol (SC1)
Getting fresh Ascidian double centner, is that 95%, 80% and 50% aqueous ethanolic solution respectively soaked 2,3 and 4 hours for 800 kilograms, 500 kilograms and 600 kilograms with concentration successively, and united extraction liquid at 0.02Pa and 40 ℃ of following concentrating under reduced pressure, obtains 10 kilograms of concentrated solutions with it.
After the concentrated solution that obtains removed by filter impurity, use 10 kilograms of sherwood oils, 10 kilograms of ethylene dichloride, 10 kilograms of ether, 300 kilograms of ethyl acetate and 10 kilograms of n-butanol extraction successively, obtain sherwood oil, ethylene dichloride, ether, ethyl acetate, propyl carbinol and water extract respectively.
Collecting ethyl acetate extract, use the sherwood oil wash-out earlier on silica gel (200～300 order) post, is 1: 1 sherwood oil, the mixed solution wash-out of ethyl acetate with volume ratio then.Collecting with volume ratio is the elutriant that obtains behind 1: 1 the mixed solution wash-out of sherwood oil, ethyl acetate, and concentrating under reduced pressure is placed, and obtains 100 and restrains the standard specimen compounds, and it is a white, needle-shaped crystals.Be soluble in non-polar solvents such as chloroform, ethyl acetate, ethanol.
EI-MS molecular weight: 444
1HNMR(CDCI3)δ：6.26(1H，d，J＝8.4Hz；H6)，6.52(1H，d，J＝8.4Hz，H7)；3.96(1H，m，H3)；0.801(3H，d，H28)；0.823(3H，d，H29)；0.852(3H，d，H21)；0.874(6H，s，H26，H27)；1.000(3H，s，H19)；1.089(3H，s，H18)。
13CNMR(CDCI3)δ(C1～C29)：28.2(t)，34.6(t)，66.4(d)，39.4(t)，82.1(s)，130.7(d)，135.4(d)，79.4(s)，51.0(d)，44.7(s)，20.8(t)，36.9(t)，36.9(s)，56.1(d)，23.4(t)，30.1(t)，51.5(d)，19.6(q)，12.8(q)，27.4(d)，18.5(q)，23.8(t)，35.9(t)，44.2(s)，35.2(d)，22.5(q)，22.7(q)，18.1(q)，18.1(q)。
EI-MS(m/z)：444(M
+)，412(M-O
2)，397(M-O
2-CH
3)，382(M-O
2-CH
3-CH
3)，364(M-O
2-CH
3-CH
3-H
2O)，252(M-O
2-CH
3-CH
3-H
2O-C
8H
16)。
The cracking rule is as follows:
Embodiment 2
5 α, pharmacodynamics activity experiment example 1 anti-tumor activity of 8 α-epidioxy-24-dimethyl courage steroid-6-alkene-3 β-alcohol (SC1)
One, the anti-tumor activity of The compounds of this invention (SC1)
1. to the antitumor activity of mouse H22 liver cancer cell tumor-bearing mice
Method: conventional pharmacological experimental method (seeing " pharmacological experimental methodology ", Xu Shuyun chief editor, People's Health Publisher, 1994, the 1432 pages) the results are shown in Table 1.
Table 1SC1 is to the antitumor activity of mouse H22 liver cancer cell tumor-bearing mice
| Medicine name | Drug dose (mg/Kg/d) | Average tumour inhibiting rate |
| SC1 SC1 SC1 ring phosphinylidyne ammonia | 22.6 45.2 90.4 100 (abdominal injections) | 45.94±1.23 55.60±0.87 62.71±0.98 82.72±0.68 |
The large, medium and small dosage of conclusion: SC1 has the obvious suppression effect to rat liver cancer, and inhibiting rate is all greater than 40%, and is dose-effect relationship.
2.SC1 antitumor action to Mice Bearing Lewis Lung Cancer
Method: conventional pharmacological experimental method (seeing " pharmacological experimental methodology ", Xu Shuyun chief editor, People's Health Publisher, 1994, the 1432 pages)
Conclusion: when SC1 concentration is 20～40mg/Kg/d, to the antitumor activity of Mice Bearing Lewis Lung Cancer about 36-45%.
3.SC1 antitumor action to mouse S180 sarcoma:
Method: conventional pharmacological experimental method (seeing " pharmacological experimental methodology ", Xu Shuyun chief editor, People's Health Publisher, 1994, the 1429 pages)
Conclusion: when SC1 concentration is 20～40mg/kg/d, to the antitumor activity of S180 sarcoma about 36-45%.
4.SC1 external anti-tumor activity to 7 strain human cancer cell strains such as Hela cell, KB cell, HCT-8 cell, KETR3 human renal carcinoma cell, A549 human lung adenocarcinoma, Ht29
Method: conventional pharmacological experimental method (seeing " pharmacological experimental methodology ", Xu Shuyun chief editor, People's Health Publisher, 1994, the 1440-1445 pages or leaves)
The result: external mtt assay detects the cytotoxic activity of SC1 to 7 strain human cancer cell strains such as Hela cell, KB cell, HCT-8 cell, KETR3 human renal carcinoma cell, A549 human lung adenocarcinoma, Ht29, IC
50Be 0.05-0.2 μ g/ml.
Two, the antiviral activity of The compounds of this invention (SC1)
1, SC1 anti-hepatitis B virus activity
(1), SC1 is to the inhibition activity of 2215 cell expressing HBsAg
Method: conventional pharmacological experimental method (seeing " modern medicine experimental methodology ", Wang Qian chief editor, People's Health Publisher, 1997, the 196 pages), result: see Table 2
Table 2:SC1 is to the inhibition activity of 2215 cell expressing HBsAg
| μg/ml | HBsAg (inhibiting rate %) | ||
| 3 days | 6 days | 9 days | |
| 0.30 | 984.3(80.3) | N | N |
| 0.15 | 1230.6(75.3) | N | N |
| Contrast | 4991.0 | 4991.5 | 3888.5 |
Conclusion: 0.15-0.30 μ g/ml SC1 has the obvious suppression effect to 2215 cell expressing HbsAg.
(2), SC1 duplicates duck serum HBV-DNA (DHBV-DNA) and suppresses active
Method: use 32P mark DHBV-DNA probe and carry out DHBV-DNA dot hybridization in the duck serum, spot density is in the 0.D490nm colorimetric, and the significance of difference and inhibiting rate are analyzed in t check in groups.Analysis software is pharmcologic calculation system-version 4.1 versions.
Conclusion: (oral when the SC1 consumption is 10～20mg/Kg/ time, every day 2 times), administration group 3 days (P＜0.01) after the 5th, 10 day (P＜0.05) and drug withdrawal after the medication can reach about 65-80% control group acycloguanosine (inhibiting rate 70-88%) and physiological saline to the dot hybridization inhibiting rate of duck serum HBV-dna replication dna.
(3), the oral liver histopathology detected result of SC1 to inoculation duck HBV
With respect to table 2, the duck of inoculation duck HBV-DNA is 90.4 μ g/Kg/ time at the SC1 consumption, and the test of serum dot hybridization shows that the inhibiting rate to duck HBV-DNA is about 80%; The hepatic tissue pathology section shows that inflammatory reaction is light, and its inflammatory reaction is proportionate like the content with serum HBV-DNA, and virus levels descends more rapidly, and inflammatory disorders is lighter.
Three, the immunopharmacological activity of SC1 of the present invention
(1), SC1 is to the influence to the Turnover of Mouse Peritoneal Macrophages phagocytic function
Method: conventional pharmacological experimental method (seeing " pharmacological experimental methodology ", Xu Shuyun chief editor, People's Health Publisher, 1994, the 1233 pages).
The results are shown in Table 3.
Table 3SC1 is to the influence of Turnover of Mouse Peritoneal Macrophages phagocytic function
| Group | Mouse quantity | OD.(490nm) |
| Control group CTX CTX+SC120mg/ml CTX+SC145mg/ml CTX+SC190mg/ml | 8 8 8 8 8 | 0.155±0.063 0.070±0.015 0.417±0.184** 0.348±0.145** 0.168±0.120* |
Annotate: * P＜0.05, * * P＜0.01; CTX=endoxan 0.2ml/dx3
The large, medium and small various dose group of conclusion: SC1 has in various degree enhancement to the immunosuppression that is caused by endoxan, and is certain dose-effect relationship.
(2), SC1 is to the influence of mice spleen lymphocytes proliferation
Method: conventional pharmacological experimental method (seeing " pharmacological experimental methodology ", Xu Shuyun chief editor, People's Health Publisher, 1994, the 1233 pages)
The results are shown in Table 4.
Table 4SC1 is to the influence of mice spleen lymphocytes proliferation
| Group | Mouse quantity | OD.(490nm) |
| Control group CTX CTX+SC1 20mg/ml CTX+SC1 45mg/ml CTX+SC1 90mg/ml | 8 8 8 8 8 | 0.058±0.019 0.026±0.015 0.020±0.010 0.085±0.015* 0.104±0.025** |
Annotate: * P＜0.05, * * P＜0.01; CTX=endoxan 0.2ml/dx3
Conclusion: the SC1 of various dose suppresses to have in various degree rising effect to the mice spleen lymphocytes proliferation that caused by endoxan, and is certain dose-effect relationship.
Four, the toxicity test of SC1 of the present invention
Method: conventional pharmacological experimental method (seeing " pharmacological experimental methodology ", Xu Shuyun chief editor, People's Health Publisher, 1994, the 201 pages)
Conclusion: 200～1000mg/Kg/d adopts the maximum volume method, and dosage be equivalent to be grown up 20～30 times of consumption are irritated stomaches, carry out the mouse toxicity tolerance and measure trial test, observe for 2 weeks, do not see that toxic reaction occurs.
Brief summary
Pharmacodynamic experiment shows that The compounds of this invention SC1 has excellent anticancer and antiviral activity, and toxicity is very low.
Claims (21)
1. 5 α shown in the formula (1), 8 α-epidioxy-24-dimethyl courage steroid-6-alkene-3 β-alcohol or its glycosides or its ester,
Wherein
R is hydrogen, glucosyl, rhamanopyranosyl, xylosyl, Arabic glycosyl, acetate, nitrate radical or sulfate radical.
2. according to described 5 α of claim 1,8 α-epidioxy-24-dimethyl courage steroid-6-alkene-3 β-alcohol or its glycosides or its ester, wherein R is a hydrogen.
3. according to described 5 α of claim 1,8 α-epidioxy-24-dimethyl courage steroid-6-alkene-3 β-alcohol or its glycosides or its ester, wherein R is glucosyl, rhamanopyranosyl, xylosyl or Arabic glycosyl.
4. according to described 5 α of claim 1,8 α-epidioxy-24-dimethyl courage steroid-6-alkene-3 β-alcohol or its glycosides or its ester, wherein R is acetate, nitrate radical or sulfate radical.
5. a method for preparing the described formula of claim 1 (1) compound comprises the steps:
(1) with fresh Ascidian with the alcohol solution of 10-95% or the ketone aqueous solution with 1: the weight ratio refluxing extraction of 6-10 or soak infiltration and extract at least once, each time is 1-6 hour, and the extracting solution concentrating under reduced pressure is obtained spissated Ascidian extracting solution;
(2) extracting solution that step (1) is obtained, remove by filter impurity after, the Fatty Alcohol(C12-C14 and C12-C18) with C6-C7 alkane, halohydrocarbon, organic ether, organic ester and C3-C5 extracts successively, obtains extractive with organic solvent and water extract respectively;
(3) the ester extract that step (2) is obtained obtains 5 α shown in the formula (1), 8 α-epidioxy-24-dimethyl courage steroid-6-alkene-3 β-alcohol through the silica gel column chromatography separation.
6. method as claimed in claim 5, wherein the alcohol described in the step (1) is 1-4 carbon alcohol.
7. method as claimed in claim 5, wherein the alcohol described in the step (1) is ethanol.
8. method as claimed in claim 5, wherein the ketone described in the step (1) is acetone.
9. method as claimed in claim 5, wherein the alkane of the C6-C7 described in the step (2) is sherwood oil, hexanaphthene or hexane.
10. method as claimed in claim 5, wherein the halohydrocarbon described in the step (2) is methylene dichloride, trichloromethane or tetrachloromethane.
11. method as claimed in claim 5, wherein the organic ether described in the step (2) is an ether.
12. method as claimed in claim 5, wherein the organic ester described in the step (2) is ethyl acetate, butylacetate or pentyl acetate.
13. as each described method of claim 5-12, wherein the organic ester described in the step (2) is an ethyl acetate.
14. as each described method of claim 5-12, wherein the C3-C5 Fatty Alcohol(C12-C14 and C12-C18) described in the step (2) is a propyl carbinol.
15. method as claimed in claim 5, wherein, with 5 α that step (3) obtains, 8 α-epidioxy-24-dimethyl courage steroid-6-alkene-3 β-alcohol is further purified with silica gel.
16. method as claimed in claim 5, wherein in step (3), the ester extract that step (2) is obtained separates through silica gel column chromatography, earlier with the sherwood oil wash-out, use sherwood oil again: ethyl acetate is 1: 10-1: the sherwood oil of 1 different ratios and ethyl acetate mixed solution gradient elution obtain formula (1) compound.
17. the application of the described formula of claim 1 (1) compound in the preparation cancer therapy drug.
18. the application of the described formula of claim 1 (1) compound in the preparation antiviral.
19. a medicine contains 5 α, 8 α-epidioxy-24-dimethyl courage steroid-6-alkene-3 β-alcohol.
20. medicine as claimed in claim 19 is characterized in that also containing assistant agent.
21., it is characterized in that described medicine is tablet, pill, capsule, electuary, sprays, oral liquid, suspension, externally-applied liniment, cutaneous permeable agent or injection as claim 19 or 20 described medicines.
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