CN103169713A - Anticancer application of sterols derivative - Google Patents

Anticancer application of sterols derivative Download PDF

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Publication number
CN103169713A
CN103169713A CN2011104420094A CN201110442009A CN103169713A CN 103169713 A CN103169713 A CN 103169713A CN 2011104420094 A CN2011104420094 A CN 2011104420094A CN 201110442009 A CN201110442009 A CN 201110442009A CN 103169713 A CN103169713 A CN 103169713A
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extract
methanol
ethyl acetate
petroleum ether
water
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CN103169713B (en
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段震文
郭树仁
李雪梅
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Beijing Peking University WBL Biotech Co Ltd
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Beijing Peking University WBL Biotech Co Ltd
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Priority to SG11201403618PA priority patent/SG11201403618PA/en
Priority to ES12862540.7T priority patent/ES2666459T3/en
Priority to MYPI2014001905A priority patent/MY172011A/en
Priority to US14/368,494 priority patent/US10889612B2/en
Priority to TW101149915A priority patent/TWI518094B/en
Priority to EP12862540.7A priority patent/EP2799444B1/en
Priority to CN201280062316.2A priority patent/CN104024270B/en
Priority to PCT/CN2012/087360 priority patent/WO2013097681A1/en
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Priority to HK14112046.3A priority patent/HK1198539A1/en
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Priority to US17/071,963 priority patent/US11634454B2/en
Priority to US17/071,958 priority patent/US20210024570A1/en
Priority to US17/818,302 priority patent/US11845774B2/en
Priority to US17/818,667 priority patent/US11845775B2/en
Priority to US17/820,553 priority patent/US20220402967A1/en
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Abstract

The invention belongs to the field of medicine and chemical industry, and relates to an anticancer application of a sterols derivative. The sterols derivative is a compound shown as the formula I, or a pharmaceutically acceptable salt thereof, wherein R1 is selected form -OH, =O, H and C1-C3 alkyl; R2 is selected form -OH, H and C1-C3 alkyl; R3 is selected form -OH, =O, H and C1-C3 alkyl; R4 is selected form -OH, H and C1-C3 alkyl; and any two, three or four of R1, R2, R3 and R4 are -OH simultaneously. The compound provided by the invention is capable of effectively inhibiting proliferation of cancer cells (tumor cells), and the inhibition effect is in concentration-effect relationships, thus the sterols derivative has the potential of a medicament for prevention and/or treatment and/or adjuvant treatment of cancers.

Description

A kind of anticancer purpose of sterols derivant
Technical field
The invention belongs to field of medicine and chemical technology, relate to a kind of anticancer purpose of sterols derivant.
Background technology
Monas cuspurpureus Went (Monascus-fermented rice) is take rice as raw material, a kind of aubergine rice-koji of making through monascus (Monascus) fermentation.Monas cuspurpureus Went claims red bent ancient times, is to be that main bent mother or distillers yeast are inoculated in the rice top fermentation and form with monascus, and its red complexion is red, thus have another name called red song, red rice, red rice, red wine dregs, therefore again because of main product in Fujian etc. ground. have another name called good fortune song, good fortune rice etc.
China utilizes the with a long history of Monascus anka Nakazawa et sato, just uses its yeast production from the Han dynasty.Monas cuspurpureus Went is the Chinese medicine that dietetic therapy is simply had both.Early it has been widely used in food color, wine brewing, fermentation, Chinese medicine aspect in ancient times.Principle of Correct Diet has Monas cuspurpureus Went " sweet in the mouth, flat, nontoxic ", " spleen invigorating, QI invigorating, warming middle-JIAO "; Compendium of Material Medica have " sweet, warm, nontoxic ", " control woman's blood pain and puerperal stagnant blood unclean, beat the good of beverage "; " Amplification on Materia Medica addendum " has records such as " invigorate blood circulation, help digestion, spleen invigorating warming the stomach, control red white dysentery, traumatic injury ".
The seventies in last century, Japan professor Endo isolates biological active substances Mo Nakelin K (monacolin K) first from red monascus (Monascus ruber) since, numerous Chinese scholars are constantly found biological active substances in the monascus metabolite, comprise some terpenoids of monacolin compounds, monascorubin, antihypertensive compositions GABA and antioxidant content dimerumic acid and separation recently etc.Along with modern biochemistry and pharmacological development, the effects such as the blood fat reducing of Monas cuspurpureus Went, blood pressure lowering, blood sugar lowering, obesity, anticancer, control senile dementia and osteoporosis are constantly excavated.Thereby increased new intension for traditional Monas cuspurpureus Went.
XUEZHIKANG JIAONANG is efficient, the safe domestic modern fat Chinese medicine of transferring that the mould fermentation of purpose-made monascus of the autonomous research in Beijing WBL Peking University Biotech Co., Ltd is made.The main effective ingredient of Xuezhikang is lovastatin, and lovastatin is laboratory anticancer positive reference substance commonly used.But, except lovastatin, also may have some unknown anticancer components in Xuezhikang.To find the new compound with antitumaous effect therefore still need.
Summary of the invention
The inventor is through deep research and performing creative labour, obtained a kind of sterols derivant, and the inventor is surprised to find, compound of the present invention is the propagation of anticancer (tumor cell) effectively, and conduct prevents and/or treats and/or the potentiality of the medicine of auxiliary for treating cancer thereby have.Following invention is provided thus:
One aspect of the present invention relates to the compound shown in formula I, or its pharmaceutically acceptable salt,
Figure BDA0000124636100000021
Wherein,
R 1Be selected from-OH ,=O (carbonyl), H and C 1-C 3Alkyl;
R 2Be selected from-OH, H and C 1-C 3Alkyl;
R 3Be selected from-OH ,=O, H and C 1-C 3Alkyl;
R 4Be selected from-OH, H and C 1-C 3Alkyl;
And R 1, R 2, R 3, and R 4In any 2,3 or 4 be-OH simultaneously.
In one embodiment of the invention, R 1For-OH or=O (carbonyl), R 2, R 3And R 4Be H.
The described compound of any one according to the present invention or its pharmaceutically acceptable salt, it is the compound shown in following formula II, or its pharmaceutically acceptable salt,
Figure BDA0000124636100000022
The chemistry of formula II compound is by name: 16,22-epoxy Ergota steroid-5, and 7-diene-3,20,23, the 25-tetrol (16,22-epoxy-ergosta-5,7-dien-3,20,23,25-tetraol).
The invention still further relates to hydrate or the solvate of above-mentioned formula I or formula II compound.
Another aspect of the present invention relates to the preparation method of formula I or formula II compound, comprises the steps:
1) get ethanol extract (the XUEZHIKANG JIAONANG content for example of Monas cuspurpureus Went and/or Monas cuspurpureus Went, it is dry powder), one or more organic solvents that are selected from dichloromethane, ethyl acetate, acetone, methanol, ethanol with 2-6 times of volume extract one or many as solvent supersonic, each 20-40 minute, merge extractive liquid,, desolventizing obtains extract;
Alternatively, described ethanol extract can following method make: 50%-100% ethanol or 50%-100% methanol with 2-6 times of volume extract one or many as solvent supersonic, and each 20-40 minute, merge extractive liquid,, desolventizing obtains ethanol extract.
Being not limited to theoretical restriction, is the ethanol extract of Monas cuspurpureus Went due to Xuezhikang itself, can be directly therefore raw material with Monas cuspurpureus Went, and extraction step and XUEZHIKANG JIAONANG content dry powder are basic identical, but the content of this compound in Monas cuspurpureus Went is relatively low.The concrete bacterial strain of described Monas cuspurpureus Went is not particularly limited, and comprises arbitrary strain or bacterial strain that belongs to Monas cuspurpureus Went.XUEZHIKANG JIAONANG (for example Beijing University's dimension letter is produced) can be bought by hospital or pharmacy and obtain.
2) with step 1) extract that obtains carries out silica gel column chromatography and separates, and carries out gradient elution with petroleum ether and ethyl acetate; The volume ratio of petroleum ether-ethyl acetate is followed successively by 75: 25,50: 50-25: 75,0: 100;
3) get step 2) in petroleum ether-ethyl acetate be 50: 50-25: 75 eluting part, separate through the C18 reversed-phase column chromatography, carry out gradient elution with methanol-water, the volume ratio of methanol-water is followed successively by 10: 90,50: 50-75: 25,100: 0;
4) get step 3) in methanol-water be 50: 50-75: 25 eluting is partly used half preparative high-performance liquid chromatographic purification, take acetonitrile-0.2% acetic acid aqueous solution (45: 55) as mobile phase, the C18 semi-preparative column is immobile phase, collects the chromatographic peak part of 9.2min; With
5) with step 4) product carry out lyophilization, obtain formula I or formula II compound.
The described preparation method of any one according to the present invention, it satisfies any one in following (1)-(9) or multinomial:
(1) step 1), described organic solvent is preferably dichloromethane;
(2) step 1), described supersound extraction is carried out 3 times;
(3) step 1), by the concentrating under reduced pressure desolventizing;
(4) step 2), the volume ratio of petroleum ether-ethyl acetate is followed successively by 75: 25,50: 50,25: 75,0: 100;
(5) step 3), get step 2) in petroleum ether-ethyl acetate be the eluting part of 50: 50 or 25: 75;
The inventor finds by test, and petroleum ether-ethyl acetate is 50: 50-25: 75 eluting part all contains compound of the present invention.
(6) step 3), the volume ratio of methanol-water is followed successively by 10: 90,50: 50,75: 25,100: 0;
(7) step 4), get step 3) in methanol-water be the eluting part of 50: 50 or 75: 25;
The inventor finds by test, and methanol-water is 50: 50-75: 25 eluting part all contains compound of the present invention.
(8) step 4), the chromatographic peak of the 9.2min that collects is partly merged; With
(9) step 5), cryodesiccated condition is: condenser temperature-40 are to-85 ℃, vacuum 0-100Pa; Be preferably condenser temperature-50 to-82.7 ℃, vacuum 2-13Pa; Condenser temperature-82.7 ℃ more preferably, vacuum 2Pa, or condenser temperature-50 ℃, vacuum 8.5Pa.
Of the present inventionly relate in one aspect to a kind of extract, it contains formula II compound of the present invention again.
The described extract of any one according to the present invention, it is the extract of XUEZHIKANG JIAONANG content dry powder or the extract of Monas cuspurpureus Went.
The described extract of any one according to the present invention, it is any one in following (1) to (3):
(1) above-mentioned step 1) to 2) in the petroleum ether-ethyl acetate that makes be 50: 50-25: 75 eluting part; Preferred petroleum ether-ethyl acetate is the eluting part of 50: 50 or 25: 75; Further preferred petroleum ether-ethyl acetate is the eluting part of 25: 75.
(2) above-mentioned step 1) to 3) in the methanol-water that makes be 50: 50-75: 25 eluting part; Particular methanol-water is the eluting part of 50: 50 or 75: 25; Further particular methanol-water is the eluting part of 75: 25; With
(3) above-mentioned step 1) to 4) in the chromatographic peak part of the 9.2min that makes.
Of the present inventionly relate in one aspect to a kind of compositions, it comprises the described extract of any one in the compound of formula I or formula II or the present invention again; Alternatively, also comprise pharmaceutically acceptable carrier or adjuvant.Particularly, described compositions is pharmaceutical composition.
Of the present invention relate in one aspect to again compound of the present invention or the described extract of any one of the present invention or compositions of the present invention preparation prevent and/or treat and/or the medicine of auxiliary for treating cancer in purposes; Particularly, described cancer is colon cancer, hepatocarcinoma, lymphatic cancer or melanoma.
Usually pharmaceutical composition of the present invention contains formula I or formula II compound and/or its physiologically acceptable salt of 0.1-90 % by weight.Pharmaceutical composition can prepare according to methods known in the art.When being used for this purpose, if necessary, formula I or formula II compound and/or stereoisomer and one or more solids or liquid medicine excipient and/or adjuvant can be combined, make the suitable administration form or the dosage form that can be used as human.
Formula I of the present invention or formula II compound or contain its pharmaceutical composition can the unit dosage form administration, route of administration can be intestinal or non-intestinal, as oral, muscle, subcutaneous, nasal cavity, oral mucosa, skin, peritoneum or rectum etc.Form of administration such as tablet, capsule, drop pill, aerosol, pill, powder, solution, suspensoid, Emulsion, granule, liposome, transdermal agent, buccal tablet, suppository, lyophilized injectable powder etc.Can be ordinary preparation, slow releasing preparation, controlled release preparation and various particulate delivery system.For the unit form of administration is made tablet, can be widely used various carrier well known in the art.Example about carrier is, for example diluent and absorbent are as starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, carbamide, calcium carbonate, kaolin, microcrystalline Cellulose, aluminium silicate etc.; Wetting agent and binding agent are as water, glycerol, Polyethylene Glycol, ethanol, propanol, starch slurry, dextrin, syrup, Mel, glucose solution, mucialga of arabic gummy, gelatine size, sodium carboxymethyl cellulose, lac, methylcellulose, potassium phosphate, polyvinylpyrrolidone etc.; Disintegrating agent, such as dry starch, alginate, agar powder, laminaran, sodium bicarbonate and citric acid, calcium carbonate, polyoxyethylene, Sorbitol fatty acid ester, dodecyl sodium sulfate, methylcellulose, ethyl cellulose etc.; Disintegrate inhibitor, for example sucrose, glyceryl tristearate, cocoa butter, hydrogenation wet goods; Absorption enhancer, such as quaternary ammonium salt, sodium lauryl sulphate etc.; Lubricant, such as Pulvis Talci, silicon dioxide, corn starch, stearate, boric acid, liquid paraffin, Polyethylene Glycol etc.Tablet further can also be made coated tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablet and multilayer tablet.For pill is made in the administration unit, can be widely used various carrier well known in the art.Example about carrier is, for example diluent and absorbent are as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, Gelucire, Kaolin, Pulvis Talci etc.; Binding agent such as arabic gum, Tragacanth, gelatin, ethanol, Mel, liquid sugar, rice paste or batter etc.; Disintegrating agent is as agar powder, dry starch, alginate, dodecyl sodium sulfate, methylcellulose, ethyl cellulose etc.For suppository is made in the administration unit, can be widely used various carrier well known in the art.Example about carrier is, such as the ester of Polyethylene Glycol, lecithin, cocoa butter, higher alcohol, higher alcohol, gelatin, semi-synthetic glyceride etc.For capsule is made in the administration unit, effective ingredient formula I compound or its stereoisomer are mixed with above-mentioned various carriers, and the mixture that will obtain thus is placed in hard obviously capsule or soft capsule.Also effective ingredient formula I compound or its stereoisomer can be made microcapsule, be suspended in and form suspensoid in aqueous medium, in the hard capsule of also can packing into or make injection and use.For injection preparation is made in the administration unit, as solution, Emulsion, lyophilized injectable powder and suspensoid, can use this area all diluent commonly used, for example, the isooctadecanol of water, ethanol, Polyethylene Glycol, 1,3-PD, ethoxylation, the isooctadecanol of polyoxy, Polyoxyethylene Sorbitol Fatty Acid Esters etc.In addition, to ooze injection in order preparing etc., can to add appropriate sodium chloride, glucose or glycerol in injection preparation, in addition, can also add conventional cosolvent, buffer agent, pH adjusting agent etc.
In addition, as needs, also can add coloring agent, antiseptic, spice, correctives, sweeting agent or other material in pharmaceutical preparation.
Formula I of the present invention or formula II compound, or the dosage of its officinal salt depends on many factors, for example will prevent or treat character and the order of severity of disease, the sex of patient or animal, age, body weight and individual reaction, particular compound used, route of administration and administration number of times etc.Above-mentioned dosage can the single dose form or be divided into several, for example two, three or four dosage form administrations.
Term used herein " compositions " means to comprise the product of respectively specifying composition that comprises specified amount, and directly or indirectly from any product of the combination results of respectively specifying composition of specified amount.
The reactive compound amount of gained can change the actual dose level of each active component in pharmaceutical composition of the present invention, so that can effectively obtain required therapeutic response for concrete patient, compositions and administering mode.The dosage level fibrous root is selected according to activity, route of administration, the order of severity of the patient's condition for the treatment of and the patient's to be treated patient's condition and the medical history of particular compound.But the way of this area is, the dosage of compound is from lower than increasing gradually dosage, until obtain required effect for obtaining level that required therapeutic effect requires.
The compound of the present invention or the described extract of any one of the present invention or compositions of the present invention of relating in one aspect to again of the present invention is in the medicine of preparation inhibition tumor cell or the purposes in reagent; Particularly, described tumor cell is colon cancer cell, hepatoma carcinoma cell, lymphocytic cancer cell or melanoma cell.
A kind of method that relates in one aspect to again inhibition tumor cell of the present invention comprises the compound of the present invention that uses effective dose or the step of its pharmaceutically acceptable salt or the described extract of any one of the present invention or compositions of the present invention; Particularly, described tumor cell is colon cancer cell, hepatoma carcinoma cell, lymphocytic cancer cell or melanoma cell.
The evidence of embodiment 4, compound of the present invention is inhibition tumor cell effectively.
Of the present inventionly relate in one aspect to again a kind of preventing and/or treating and/or the method for auxiliary for treating cancer, comprise to the compound of the present invention of effective dose or the step of the described extract of any one of the present invention or compositions of the present invention; Particularly, described cancer is colon cancer, hepatocarcinoma, lymphatic cancer or melanoma.
When being used for above-mentioned treat and/or prevent or during auxiliary treatment, a kind of the compounds of this invention that treats and/or prevents effective dose can be used with pure form, perhaps uses with the acceptable ester of pharmacy or prodrug forms (in the situation that having these forms).Perhaps, described compound can be accepted the pharmaceutical composition administration of excipient to contain this purpose compound and one or more medicines.Term " effective dose " refers to realize treating, prevent, alleviate and/or alleviating the dosage of disease of the present invention or disease in the experimenter.But the total consumption per day that it should be understood that the compounds of this invention and compositions must be examined the doctor by the master and maked decision in the medical judgment scope reliably.For any concrete patient, the concrete horizontal fibrous root for the treatment of effective dose is decided according to many factors, and described factor comprises the order of severity of the obstacle for the treatment of and this obstacle; The activity of the particular compound that adopts; The concrete compositions that adopts; Patient's age, body weight, general health situation, sex and diet; The administration time of the particular compound that adopts, route of administration and excretion rate; The treatment persistent period; The medicine that is used in combination with the particular compound that adopts or uses simultaneously; And the known similar factor of medical field.For example, the way of this area is, the dosage of compound is from lower than increasing gradually dosage, until obtain required effect for obtaining level that required therapeutic effect requires.In general, particularly people's dosage can be between the 0.001-1000mg/kg body weight/day, for example between the 0.01-100mg/kg body weight/day, for example between the 0.01-10mg/kg body weight/day for mammal for formula I compound of the present invention.
Can effectively prevent and/or treat various diseases of the present invention or disease according to compound of the present invention.
The invention still further relates to following aspect 1-11:
Any one in following (1)-(4) preparation prevent and/or treat and/or the medicine of auxiliary for treating cancer in purposes; Particularly, described cancer is colon cancer, hepatocarcinoma, lymphatic cancer or melanoma,
(1) compound shown in formula I or its pharmaceutically acceptable salt,
Figure BDA0000124636100000081
Wherein,
R 1Be selected from-OH ,=O, H and C 1-C 3Alkyl;
R 2Be selected from-OH, H and C 1-C 3Alkyl;
R 3Be selected from-OH ,=O, H and C 1-C 3Alkyl;
R 4Be selected from-OH, H and C 1-C 3Alkyl;
And R 1, R 2, R 3, and R 4In any 2,3 or 4 be-OH simultaneously;
(2) compound shown in formula II or its pharmaceutically acceptable salt,
Figure BDA0000124636100000091
(3) extract, it contains formula II compound; With
(4) compositions, it contains any one in above-mentioned (1)-(3).
2. any one in (1) described in the 1st aspect-(4) is preparing in vivo or the medicine of extracorporeal suppression tumor cell or the purposes in reagent; Particularly, described tumor cell is colon cancer cell, hepatoma carcinoma cell, lymphocytic cancer cell or melanoma cell.
3. according to the 1st or 2 described purposes in aspect, wherein, the extract in described (3) is the extract of Monas cuspurpureus Went extract and/or Monas cuspurpureus Went ethanol extract (for example XUEZHIKANG JIAONANG content).
4. according to the 3rd described purposes in aspect, wherein, the extract in described (3), it is following step 1) to 2) in the petroleum ether-ethyl acetate that makes be 50: 50-25: 75 eluting part; Or following step 1) to 3) in the methanol-water that makes be 50: 50-75: 25 eluting part; Or following step 1) to 4) in the chromatographic peak part of the 9.2min that makes:
1) get the ethanol extract (for example XUEZHIKANG JIAONANG content dry powder) of Monas cuspurpureus Went and/or Monas cuspurpureus Went, one or more organic solvents that are selected from dichloromethane, ethyl acetate, acetone, methanol, ethanol with 2-6 times of volume extract one or many as solvent supersonic, each 20-40 minute, merge extractive liquid,, desolventizing obtains extract;
2) with step 1) extract that obtains carries out silica gel column chromatography and separates, and carries out gradient elution with petroleum ether and ethyl acetate; The volume ratio of petroleum ether-ethyl acetate is followed successively by 75: 25,50: 50-25: 75,0: 100;
3) get step 2) in petroleum ether-ethyl acetate be 50: 50-25: 75 eluting part, separate through the C18 reversed-phase column chromatography, carry out gradient elution with methanol-water, the volume ratio of methanol-water is followed successively by 10: 90,50: 50-75: 25,100: 0; With
4) get step 3) in methanol-water be 50: 50-75: 25 eluting is partly used half preparative high-performance liquid chromatographic purification, take acetonitrile-0.2% acetic acid aqueous solution (45: 55) as mobile phase, the C18 semi-preparative column is immobile phase, collects the chromatographic peak part of 9.2min.
5. according to the 4th described purposes in aspect, it is characterized in that (1)-any one in (8) or multinomial:
(1) step 1), described organic solvent is dichloromethane;
(2) step 1), described supersound extraction is carried out 3 times;
(3) step 1), by the concentrating under reduced pressure desolventizing;
(4) step 2), the volume ratio of petroleum ether-ethyl acetate is followed successively by 75: 25,50: 50,25: 75,0: 100;
(5) step 3), get step 2) in petroleum ether-ethyl acetate be the eluting part of 50: 50 or 25: 75;
(6) step 3), the volume ratio of methanol-water is followed successively by 10: 90,50: 50,75: 25,100: 0;
(7) step 4), get step 3) in methanol-water be the eluting part of 50: 50 or 75: 25; With
(8) step 4), the chromatographic peak of the 9.2min that collects is partly merged.
6. according to the 1st or 2 described purposes in aspect, wherein, the compositions in described (4) also comprises pharmaceutically acceptable carrier or adjuvant.
One kind in vivo or the method for extracorporeal suppression tumor cell, comprise the step of any one in (1) described in the 1st aspect of using effective dose-(4); Particularly, described tumor cell is colon cancer cell, hepatoma carcinoma cell, lymphocytic cancer cell or melanoma cell.
8. according to the 7th described method in aspect, wherein, the extract in described (3) is the extract of Monas cuspurpureus Went extract and/or Monas cuspurpureus Went ethanol extract (for example XUEZHIKANG JIAONANG content).
9. according to the 8th described method in aspect, wherein, the extract in described (3), it is following step 1) to 2) in the petroleum ether-ethyl acetate that makes be 50: 50-25: 75 eluting part; Or following step 1) to 3) in the methanol-water that makes be 50: 50-75: 25 eluting part; Or following step 1) to 4) in the chromatographic peak part of the 9.2min that makes:
1) get the ethanol extract (for example XUEZHIKANG JIAONANG content dry powder) of Monas cuspurpureus Went and/or Monas cuspurpureus Went, one or more organic solvents that are selected from dichloromethane, ethyl acetate, acetone, methanol, ethanol with 2-6 times of volume extract one or many as solvent supersonic, each 20-40 minute, merge extractive liquid,, desolventizing obtains extract;
2) with step 1) extract that obtains carries out silica gel column chromatography and separates, and carries out gradient elution with petroleum ether and ethyl acetate; The volume ratio of petroleum ether-ethyl acetate is followed successively by 75: 25,50: 50-25: 75,0: 100;
3) get step 2) in petroleum ether-ethyl acetate be 50: 50-25: 75 eluting part, separate through the C18 reversed-phase column chromatography, carry out gradient elution with methanol-water, the volume ratio of methanol-water is followed successively by 10: 90,50: 50-75: 25,100: 0; With
4) get step 3) in methanol-water be 50: 50-75: 25 eluting is partly used half preparative high-performance liquid chromatographic purification, take acetonitrile-0.2% acetic acid aqueous solution (45: 55) as mobile phase, the C18 semi-preparative column is immobile phase, collects the chromatographic peak part of 9.2min.
10. according to the 9th described method in aspect, it is characterized in that (1)-any one in (8) or multinomial:
(1) step 1), described organic solvent is dichloromethane;
(2) step 1), described supersound extraction is carried out 3 times;
(3) step 1), by the concentrating under reduced pressure desolventizing;
(4) step 2), the volume ratio of petroleum ether-ethyl acetate is followed successively by 75: 25,50: 50,25: 75,0: 100;
(5) step 3), get step 2) in petroleum ether-ethyl acetate be the eluting part of 50: 50 or 25: 75;
(6) step 3), the volume ratio of methanol-water is followed successively by 10: 90,50: 50,75: 25,100: 0;
(7) step 4), get step 3) in methanol-water be the eluting part of 50: 50 or 75: 25; With
(8) step 4), the chromatographic peak of the 9.2min that collects is partly merged.
11. according to the 7th described method in aspect, wherein, the compositions in described (4) also comprises pharmaceutically acceptable carrier or adjuvant.
In the present invention, term " C 1-C 3Alkyl " comprise methyl, ethyl, propyl group or isopropyl.
The beneficial effect of the invention
Compound of the present invention is the propagation of anticancer (tumor cell) effectively, and inhibitory action and be concentration-effect relation; Conduct prevents and/or treats and/or the potentiality of the medicine of auxiliary for treating cancer thereby have.
Description of drawings
Fig. 1: the inhibitory action curve of formula II compound to the HCT116 Growth of Cells.
Fig. 2: the inhibitory action curve of formula II compound to the H22 Growth of Cells.
Fig. 3: the inhibitory action curve of formula II compound to the HepG2 Growth of Cells.
Fig. 4: the inhibitory action curve of formula II compound to the S180 Growth of Cells.
Fig. 5: the inhibitory action curve of formula II compound to the YAC-1 Growth of Cells.
Fig. 6: the inhibitory action curve of formula II compound to the THP1 Growth of Cells.
Fig. 7: the inhibitory action curve of formula II compound to the U937 Growth of Cells.
Fig. 8: the inhibitory action curve of formula II compound to the B16-F10 Growth of Cells.
The specific embodiment
Below in conjunction with embodiment, embodiment of the present invention are described in detail.It will be understood to those of skill in the art that the following examples only are used for explanation the present invention, and should not be considered as limiting scope of the present invention.Unreceipted concrete technology or condition person in embodiment, according to the described technology of the document in this area or condition (such as works such as reference J. Pehanorm Brookers, " the molecular cloning experiment guide " that Huang Peitang etc. translate, the third edition, Science Press) or carry out according to product description.The unreceipted person of production firm of agents useful for same or instrument, being can be by the conventional products of commercial acquisition.
Embodiment 1: the preparation of formula II compound (1)
Operating procedure:
1) getting approximately 1kg of XUEZHIKANG JIAONANG (Beijing University dimension letter produce) content dry powder, is that solvent supersonic extracts 3 times with the dichloromethane of 2-6 times of volume, each 20-40 minute, and merge extractive liquid,, concentrating under reduced pressure also reclaims solvent, obtains dichloromethane extract 91g.
2) get dichloromethane extract 50g, upper silica gel column chromatography separates, and carries out gradient elution with petroleum ether and ethyl acetate.The volume ratio of petroleum ether-ethyl acetate is followed successively by 75: 25, and 50: 50,25: 75,0: 100.
3) getting petroleum ether-ethyl acetate is 25: 75 part 5.0g, separate through the C18 reversed-phase column chromatography, (10: 90-100: 0) gradient elution obtains 4 part (methanol-waters 10: 90 to methanol-water, 50: 50, 75: 25, 100: 0), wherein methanol-water (75: 25) eluting part 1.3g is with half preparative high-performance liquid chromatographic purification, take acetonitrile-0.2% acetic acid aqueous solution (45: 55) as mobile phase, flow velocity is 4mL/min, C18 half preparative hplc post (10 * 250mm, 5 μ m) be immobile phase, it is 270nm that the DAD detector detects wavelength, collect the chromatographic peak of 9.2min, repeatedly cumulative rear concentrated, lyophilization must this compound about 40mg.
Embodiment 2: the preparation of formula II compound (2)
Operating procedure:
1) getting Monas cuspurpureus Went 5kg, is that solvent supersonic extracts 3 times with the dichloromethane of 2-6 times of volume, each 20-40 minute, and merge extractive liquid,, concentrating under reduced pressure also reclaims solvent, obtains dichloromethane extract 78g.
2) get dichloromethane extract 30g, upper silica gel column chromatography separates, and carries out gradient elution with petroleum ether and ethyl acetate.The volume ratio of petroleum ether-ethyl acetate is followed successively by 75: 25, and 50: 50,25: 75,0: 100.
3) getting petroleum ether-ethyl acetate is 25: 75 part 3.0g, separate through the C18 reversed-phase column chromatography, (10: 90-100: 0) gradient elution obtains 4 part (methanol-waters 10: 90 to methanol-water, 50: 50, 75: 25, 100: 0), wherein methanol-water (75: 25) eluting part 0.8g is with half preparative high-performance liquid chromatographic purification, take acetonitrile-0.2% acetic acid aqueous solution (45: 55) as mobile phase, flow velocity is 4mL/min, C18 half preparative hplc post (10 * 250mm, 5 μ m) be immobile phase, it is 270nm that the DAD detector detects wavelength, collect the chromatographic peak of 9.2min, repeatedly cumulative rear concentrated, lyophilization must this compound about 25mg.
Embodiment 3: the Structural Identification of compound
Specimen in use is the compound of embodiment 1 and 2 preparations.
1. the physicochemical data of compound
White powder, optical rotation: [α] 25 D-50.00 (c 0.118, CH 2Cl 2: MeOH=1: 1);
Three maximum absorption bands are arranged in UV spectrum, be respectively λ max(CH 2Cl 2: MeOH)=271.6nm, 282.2nm, 293.8nm.
FT-IR (KBr, cm -1) spectrum: 3392 (OH), 2969,2933 (saturated hydrocarbon), 1652,1647 (C=C), 1456,1378 (gem-dimethyls).
2. molecular formula determines
The m/z 483.3104[M+Na that HR-ESI-MS provides] +(calcd.483.3081, err2.3), the molecular weight that is inferred as this compound is 460.32. 1H-NMR and 13C-NMR shows, has 40 hydrogen signals and 28 carbon signals.Show 6 quaternary carbons are arranged, 10 CH, 6 CH from DEPT 2And 6 CH 3 13In C-NMR, 117.2ppm, 119.6ppm, there are 4 olefinic carbon signals at 139.1ppm and 140.6ppm place.With HSQC figure with 13C-NMR figure binding analysis, 70.5ppm, 72.4ppm, 74.5ppm, 80.4ppm, 6 carbon that 83.8ppm and 84.4ppm place's existence are connected with oxygen atom.The binding molecule amount and 1H、 13C-NMR and DEPT signal graph surpass 460.32 if this compound has 6 oxygen atom molecular weight, infer that thus this compound has 5 oxygen atoms and do not embody 4 hydrogen atoms of hydrogen spectrum signal.Thereby can judge that in above-mentioned 5 oxygen atoms, 4 oxygen atoms are attributed to 4 hydroxyls, other the 5th oxygen atom exists with the form of ether.According to above-mentioned analysis, can determine has 28 carbon atoms in this molecule, 44 hydrogen atoms and 5 oxygen atoms, and molecular formula is C 28H 44O 5
3. structural formula determines
Analyze this compound carbon spectrum ( 13C-NMR and DEPT), 28 carbon atoms are arranged, wherein 6 carbon are methyl.Based on 271.6nm in ultra-violet absorption spectrum, 3 absorption maximum and the ergosterol class at 282.2nm and 293.8nm place are substantially identical, infer that tentatively this compound has the skeleton of ergosterol.Can calculate its degree of unsaturation from molecular formula is 7.Thereby can infer: this compound also has a unsaturated place and can only be a ring herein except 6 unsaturated places of 2 two keys and 4 rings of sterol skeleton, can judge that thus this ring is the epoxide ring that forms by centered by the 5th oxygen atom.HSQC schemes to combine with HMBC coherent signal figure analysis, and 6 carbon that are connected with oxygen atom are attributed to respectively 4 carbon (70.5 that 4 hydroxyls are connected, 72.4,74.5,80.4ppm) and 2 carbon that are connected with surplus next oxygen atom (83.8,84.4ppm).Deep HMBC map analysis can infer that the 5th member ring systems is by C-16 (83.8ppm), C-17 (66.9ppm), C-20 (80.4ppm), 5 rings that C-22 (84.4ppm) and oxygen atom form.This not only satisfies degree of unsaturation, but also satisfies the carbon number that is connected with oxygen atom.Further analyze molecular weight and the molecular formula that mass spectrometry system provides, confirmed above-mentioned analysis.The above analysis can infer that this noval chemical compound is: 16,22-epoxy Ergota steroid-5,7-diene-3,20,23,25-tetrol
Namely (16,22-epoxy-ergosta-5,7-dien-3,20,23,25-tetraol).Structural formula is shown in following formula II.
Figure BDA0000124636100000151
4. the NMR data of formula II compound
As shown in following table 1.
Table 1: NMR data (600MHz, the CDCl of formula II compound 3, J in Hz)
Figure BDA0000124636100000161
Figure BDA0000124636100000171
Annotate: there is not coherent signal in "-" expression.
Embodiment 4: the inhibition of cancer cell experiment of noval chemical compound (formula II compound)
1 experiment material
1.1 cell strain
HCT116 and H22 are purchased from Korean cell line bank, Seoul, Korea;
S180, HepG-2, YAC-1, Thp1, U937 and B16-F10 are purchased from typical case's culture collection committee of Chinese Academy of Sciences cell bank.
1.2 medicine
The noval chemical compound (formula II compound) of embodiment 1 or 2 preparations.
1.3 reagent
MTT is for being purchased from Amresco company; RPMI1640 and two anti-Sigma company that is purchased from; Hyclone (FBS) is purchased from U.S. Gibco company; Other reagent is domestic analytical pure.
2 experimental techniques
The take the logarithm cancerous cell of trophophase is with 2 * 10 4Individual/hole is inoculated in 96 well culture plates, adds medicine to medicine final concentration to be: 500,250,125,62.5,31.25,15.625 and 7.8125 μ g/mL, and in 37 ℃, 5%CO 2Cultivate in cell culture incubator and add MTT 10 μ L/ holes after 72h, hatch 4h in 37 ℃ of lucifuges, remove culture fluid, add 150 μ L DMSO or acidify isopropyl alcohol, after vibration 5min, measure the OD value in the 570nm wavelength.Repeat 3 times, establish blank.Various cell strain used mediums are all identical, are the RPMI1640 culture medium that contains 10% hyclone and 1% pair anti-(penicillin and streptomycin).
Computing formula:
Cell survival rate=(experimental group OD value/matched group OD value) * 100%.
Experimental procedure also can be with reference to Yang Xiuwei etc., " the anti tumor activity in vitro screening of Chemical Constituents of Alkaloids in Seeds of Strychnos nux-vomica L ", contemporary Chinese Chinese medicine, 2006,8 (9): 11-13.
3 experimental results
3.1 external anticancer (colon cancer) activity of formula II compound
Result as shown in Figure 1.The result demonstration, formula II compound has inhibitory action to the growth of human colon cancer cell strain HCT116, and is concentration-effect relation.As seen, this compound has the potentiality of the colon cancer of preventing and treating.
3.2 external anticancer (hepatocarcinoma) activity of formula II compound
3.2.1 as shown in Figure 2, formula II compound has inhibitory action to the growth of murine hepatocarcinoma cell strain H22, and is concentration-effect relation.Its IC 50Value is about 50 μ g/mL, and showing has good inhibitory action to murine hepatocarcinoma cell propagation.
3.2.2 as shown in Figure 3, formula II compound has inhibitory action to the growth of HepG2 cell lines, and is concentration-effect relation.Its IC 50Value is about 200 μ g/mL, and showing has inhibitory action preferably to human hepatoma cell proliferation.
3.2.3 as shown in Figure 4, formula II compound has inhibitory action to the growth of mice sarcoma cell strain S180, and is concentration-effect relation.
As seen, this compound has the potentiality of the hepatocarcinoma of preventing and treating.
3.3 external anticancer (lymphoma) activity of formula II compound
3.3.1 as shown in Figure 5, formula II compound has inhibitory action to the growth of mouse lymphoma cell YAC-1, and is concentration-effect relation.Its IC 50Value is about 62.5 μ g/mL, and showing has good inhibitory action to mouse lymphoma cell propagation.
3.3.2 as shown in Figure 6, formula II compound has inhibitory action to the growth of people's monokaryon lymphoma cell THP1, and is concentration-effect relation.Its IC 50Value is about 250 μ g/mL, and showing has inhibitory action preferably to people's monokaryon lymphoma cell propagation.Fig. 6
3.3.3 as shown in Figure 7, formula II compound has inhibitory action to the growth of the people oncocyte U937 of tissue lymph, and is concentration-effect relation.Its IC 50Value is about 50 μ g/mL, and showing has good inhibitory action to people tissue lymph tumor cell proliferation.
As seen, this compound has the potentiality of control lymphatic cancer (lymphoma).
3.4 external anticancer (melanoma) activity of formula II compound
Result as shown in Figure 8.The result demonstration, formula II compound has inhibitory action to the growth of B16 mouse melanoma cell line-F10, and is concentration-effect relation.Its IC 50Value is about 62.5 μ g/mL, and showing has good inhibitory action to mouse melanin tumor cell propagation.As seen, this compound has the melanomatous potentiality of control.
To sum up, formula II compound has effective inhibitory action to kinds of tumor cells, has to prevent and/or treat and/or the potentiality of the medicine of auxiliary for treating cancer.
Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.According to disclosed all instructions, can carry out various modifications and replacement to those details, these change all within protection scope of the present invention.Four corner of the present invention is provided by claims and any equivalent thereof.

Claims (11)

  1. Any one in following (1)-(4) preparation prevent and/or treat and/or the medicine of auxiliary for treating cancer in purposes; Particularly, described cancer is colon cancer, hepatocarcinoma, lymphatic cancer or melanoma,
    (1) compound shown in formula I or its pharmaceutically acceptable salt,
    Figure FDA0000124636090000011
    Wherein,
    R 1Be selected from-OH ,=O, H and C 1-C 3Alkyl;
    R 2Be selected from-OH, H and C 1-C 3Alkyl;
    R 3Be selected from-OH ,=O, H and Cx-C 3Alkyl;
    R 4Be selected from-OH, H and C 1-C 3Alkyl;
    And R 1, R 2, R 3, and R 4In any 2,3 or 4 be-OH simultaneously;
    (2) compound shown in formula II or its pharmaceutically acceptable salt,
    Figure FDA0000124636090000012
    (3) extract, it contains formula II compound; With
    (4) compositions, it contains any one in above-mentioned (1)-(3).
  2. 2. any one in (1) described in claim 1-(4) is preparing in vivo or the medicine of extracorporeal suppression tumor cell or the purposes in reagent; Particularly, described tumor cell is colon cancer cell, hepatoma carcinoma cell, lymphocytic cancer cell or melanoma cell.
  3. 3. purposes according to claim 1 and 2, wherein, the extract in described (3) is the extract of Monas cuspurpureus Went extract and/or Monas cuspurpureus Went ethanol extract (for example XUEZHIKANG JIAONANG content).
  4. 4. purposes according to claim 3, wherein, the extract in described (3), it is following step 1) to 2) in the petroleum ether-ethyl acetate that makes be 50: 50-25: 75 eluting part; Or following step 1) to 3) in the methanol-water that makes be 50: 50-75: 25 eluting part; Or following step 1) to 4) in the chromatographic peak part of the 9.2min that makes:
    1) get the ethanol extract (for example XUEZHIKANG JIAONANG content dry powder) of Monas cuspurpureus Went and/or Monas cuspurpureus Went, one or more organic solvents that are selected from dichloromethane, ethyl acetate, acetone, methanol, ethanol with 2-6 times of volume extract one or many as solvent supersonic, each 20-40 minute, merge extractive liquid,, desolventizing obtains extract;
    2) with step 1) extract that obtains carries out silica gel column chromatography and separates, and carries out gradient elution with petroleum ether and ethyl acetate; The volume ratio of petroleum ether-ethyl acetate is followed successively by 75: 25,50: 50-25: 75,0: 100;
    3) get step 2) in petroleum ether-ethyl acetate be 50: 50-25: 75 eluting part, separate through the C18 reversed-phase column chromatography, carry out gradient elution with methanol-water, the volume ratio of methanol-water is followed successively by 10: 90,50: 50-75: 25,100: 0; With
    4) get step 3) in methanol-water be 50: 50-75: 25 eluting is partly used half preparative high-performance liquid chromatographic purification, take acetonitrile-0.2% acetic acid aqueous solution (45: 55) as mobile phase, the C18 semi-preparative column is immobile phase, collects the chromatographic peak part of 9.2min.
  5. 5. purposes according to claim 4 is characterized in that (1)-any one in (8) or multinomial:
    (1) step 1), described organic solvent is dichloromethane;
    (2) step 1), described supersound extraction is carried out 3 times;
    (3) step 1), by the concentrating under reduced pressure desolventizing;
    (4) step 2), the volume ratio of petroleum ether-ethyl acetate is followed successively by 75: 25,50: 50,25: 75,0: 100;
    (5) step 3), get step 2) in petroleum ether-ethyl acetate be the eluting part of 50: 50 or 25: 75;
    (6) step 3), the volume ratio of methanol-water is followed successively by 10: 90,50: 50,75: 25,100: 0;
    (7) step 4), get step 3) in methanol-water be the eluting part of 50: 50 or 75: 25; With
    (8) step 4), the chromatographic peak of the 9.2min that collects is partly merged.
  6. 6. purposes according to claim 1 and 2, wherein, the compositions in described (4) also comprises pharmaceutically acceptable carrier or adjuvant.
  7. One kind in vivo or the method for extracorporeal suppression tumor cell, comprise the step of any one in (1) described in the claim 1 of using effective dose-(4); Particularly, described tumor cell is colon cancer cell, hepatoma carcinoma cell, lymphocytic cancer cell or melanoma cell.
  8. 8. method according to claim 7, wherein, the extract in described (3) is the extract of Monas cuspurpureus Went extract and/or Monas cuspurpureus Went ethanol extract (for example XUEZHIKANG JIAONANG content).
  9. 9. method according to claim 8, wherein, the extract in described (3), it is following step 1) to 2) in the petroleum ether-ethyl acetate that makes be 50: 50-25: 75 eluting part; Or following step 1) to 3) in the methanol-water that makes be 50: 50-75: 25 eluting part; Or following step 1) to 4) in the chromatographic peak part of the 9.2min that makes:
    1) get the ethanol extract (for example XUEZHIKANG JIAONANG content dry powder) of Monas cuspurpureus Went and/or Monas cuspurpureus Went, one or more organic solvents that are selected from dichloromethane, ethyl acetate, acetone, methanol, ethanol with 2-6 times of volume extract one or many as solvent supersonic, each 20-40 minute, merge extractive liquid,, desolventizing obtains extract;
    2) with step 1) extract that obtains carries out silica gel column chromatography and separates, and carries out gradient elution with petroleum ether and ethyl acetate; The volume ratio of petroleum ether-ethyl acetate is followed successively by 75: 25,50: 50-25: 75,0: 100;
    3) get step 2) in petroleum ether-ethyl acetate be 50: 50-25: 75 eluting part, separate through the C18 reversed-phase column chromatography, carry out gradient elution with methanol-water, the volume ratio of methanol-water is followed successively by 10: 90,50: 50-75: 25,100: 0; With
    4) get step 3) in methanol-water be 50: 50-75: 25 eluting is partly used half preparative high-performance liquid chromatographic purification, take acetonitrile-0.2% acetic acid aqueous solution (45: 55) as mobile phase, the C18 semi-preparative column is immobile phase, collects the chromatographic peak part of 9.2min.
  10. 10. method according to claim 9 is characterized in that (1)-any one in (8) or multinomial:
    (1) step 1), described organic solvent is dichloromethane;
    (2) step 1), described supersound extraction is carried out 3 times;
    (3) step 1), by the concentrating under reduced pressure desolventizing;
    (4) step 2), the volume ratio of petroleum ether-ethyl acetate is followed successively by 75: 25,50: 50,25: 75,0: 100;
    (5) step 3), get step 2) in petroleum ether-ethyl acetate be the eluting part of 50: 50 or 25: 75;
    (6) step 3), the volume ratio of methanol-water is followed successively by 10: 90,50: 50,75: 25,100: 0;
    (7) step 4), get step 3) in methanol-water be the eluting part of 50: 50 or 75: 25; With
    (8) step 4), the chromatographic peak of the 9.2min that collects is partly merged.
  11. 11. method according to claim 7, wherein, the compositions in described (4) also comprises pharmaceutically acceptable carrier or adjuvant.
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CN1982327A (en) * 2005-12-13 2007-06-20 北京师范大学 Phytosterin compound and its use

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