CN100528870C - Internal ester monomer compound and its application in preparing anti cancer medicine - Google Patents
Internal ester monomer compound and its application in preparing anti cancer medicine Download PDFInfo
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- CN100528870C CN100528870C CNB2006100854411A CN200610085441A CN100528870C CN 100528870 C CN100528870 C CN 100528870C CN B2006100854411 A CNB2006100854411 A CN B2006100854411A CN 200610085441 A CN200610085441 A CN 200610085441A CN 100528870 C CN100528870 C CN 100528870C
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- expoxyrolin
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Abstract
An anticancer annona lactone monomer 'expoxyrolin B' for preventing and treating liver cancer is prepared from the annona seeds through drying, breaking, immersing in petroether, recovering petroether to obtain red oily liquid, laying aside, filtering to obtain white deposit, chromatography, and eluting.
Description
One, technical field
The present invention relates to a kind of cancer therapy drug, specifically is a kind of sugar apple lactone monomeric compound and the application in preparation treatment cancer therapy drug thereof that raw material extracts with the Sirikaya seed.
Two, background technology
Cancer is the formidable enemy of harm humans health.The annual New Development cases of cancer of China has 1,600,000 people approximately, that dies from cancer every year has 1,300,000 people approximately, rise year by year because of the dead number of cancer in the whole nation, China is the zone occurred frequently of cancers such as liver cancer, cancer of the stomach, the esophageal carcinoma, mammary cancer, lung cancer, and cancer mortality is high.
Still there are not the most of cancer patientss of effective cured substance at present.Though chemotherapeutics has certain curative effect to cancer, toxic side effect is big, and Chinese patent medicine is generally lower to the curative effect of cancer, only is 3.5% as the former cancer kitchen range remission rate to lung, cancer of the stomach of ginseng lotus glue, and curative effect is all undesirable.
The inventor has studied bark, the branches and leaves of sweetsop (Annona squamosa Linn), the anticancer active substance and the chemical ingredients of seed, therefrom extract multiple anticancer monomeric compound (activeconstituents), show through anticancer experimental study, to human liver cancer cell, gastric carcinoma cells, human esophagus cancer cell and animal transplanting tumor (as S
180, H
22And Heps) remarkable vitro and vivo antitumor result of treatment are all arranged, and applied for obtaining 3 antineoplastic product invention patent certificates (patent No. is respectively: ZL02148474.0, ZL02148475.9, ZL03112707.X).On the basis of above-mentioned research, the inventor continues the anticancer active chemical of extraction separation, screening sweetsop (Annona squamosa Linn) seed, has found again that therefrom 4 kinds of internal ester monomer compositions have the especially significantly anticancer purpose (its antitumour activity several times are higher than the chemotherapeutic 5-fluor-uracil) of antitumour activity.
Three, summary of the invention
1, goal of the invention: the purpose of this invention is to provide a kind of antitumour activity height, the wide anticancer monomeric compound of anticancer spectrum, specifically is the application of a kind of sugar apple lactone monomeric compound (expoxyrol in B) aspect the preparation cancer therapy drug that raw material extracts with the Sirikaya seed.
2, technical scheme: the present invention from sweetsop (Annona squamosa Linn) seed extraction separation to a kind of cancer therapy drug sugar apple lactone monomeric compound (also not having this compound of bibliographical information that antitumour activity is arranged at present) through data consultation, it is characterized in that the white powder material, be soluble in organic solvents such as ethyl acetate, methyl alcohol, chloroform.It is accredited as expoxyrol in B, and molecular formula is C
36H
66O
3
A kind of cancer therapy drug sugar apple lactone monomeric compound, it is to extract the anticancer monomeric compound that obtains from Sirikaya seed.Its preparation method be Sirikaya seed air-dry after, be ground into meal, earlier with 3 times (room temperature) of 10 times of amount sherwood oil cold soakings extractions, each 2 days; Reclaim sherwood oil and get red oily liquids, room temperature is placed, and the bottom has a large amount of white precipitates to separate out, and filters out white precipitate, and white precipitate is through silica gel column chromatography repeatedly; Use sherwood oil, petroleum ether-ethyl acetate, ethyl acetate-methyl alcohol gradient elution obtains a kind of sugar apple lactone monomeric compound (expoxyrolin B).The anticancer pharmacological evaluation through the inside and outside, its growth to human liver cancer cell, mouse bearing liver cancer has the obvious suppression effect, and its antitumour activity several times are higher than the chemotherapeutic 5-fluor-uracil.
The present invention relates to the application of a kind of cancer therapy drug sugar apple lactone monomeric compound (expoxyrolin B) in the preparation cancer therapy drug.
Adopt the MTT development process, get 2 * 10
4/ ml viable cell (human liver cancer cell SMMC-7721 or HepG2) is inoculated in 96 orifice plates, and every hole 90ul establishes four multiple holes.Treat to add respectively behind the cell attachment medicine 10ul of different concns, control wells adds 10ulPBS, puts 37 ℃, 5%CO
2Be cultured to the scheduled time under the condition, every hole adds the MTT50ul/ hole that concentration is 1mg/ml, continue to cultivate 4 hours, remove whole supernatants, add the DMS0100ul/ hole, microoscillator vibration 5min dissolves crystallization fully, joins instrument with enzyme, measure absorbance (OD) in 570nm wavelength place, nutrient solution is only contained in the zeroing hole.Cell viability dosing cell mean light absorbency value/control cells mean light absorbency value * 100%, inhibiting rate (%)=(1-dosing cell mean light absorbency value/control cells mean light absorbency value) * 100%.
The result shows that cancer therapy drug sugar apple lactone monomeric compound (expoxyrolin B) is very high to the inhibition activity of human liver cancer cell, and the active several times of its inhibition to human liver cancer cell are higher than chemotherapeutic 5-fluor-uracil (5-Fu).
3, beneficial effect: a kind of cancer therapy drug sugar apple lactone monomeric compound of the present invention, it is to extract the anticancer monomeric compound that obtains from Sirikaya seed.Anticancer experimental result shows that cancer therapy drug sugar apple lactone monomeric compound (expoxyrolin B) is to the king in the cancer---the inhibition activity of liver cancer is very high, and it is higher than chemotherapeutic 5-fluor-uracil (5-Fu) to suppressing active several times in the body of liver cancer.This provides very promising efficient preliminary election medicine for improving anticancer clinical efficacy.
Four, embodiment
Embodiment 1: a kind of cancer therapy drug sugar apple lactone monomeric compound (expoxyrolin B) extracting method
A kind of cancer therapy drug sugar apple lactone monomeric compound, it is to extract the anticancer monomeric compound that obtains from Sirikaya seed.Its preparation method be Sirikaya seed air-dry after, be ground into meal, earlier with 3 times (room temperature) of 10 times of amount sherwood oil cold soakings extractions, each 2 days; Reclaim sherwood oil and get red oily liquids, room temperature is placed, and the bottom has a large amount of white precipitates to separate out, and filters out white precipitate, and white precipitate is through silica gel column chromatography repeatedly; Use sherwood oil, petroleum ether-ethyl acetate, ethyl acetate-methyl alcohol gradient elution obtains a kind of sugar apple lactone monomeric compound (expoxyrolin B).
Embodiment 2: a kind of cancer therapy drug sugar apple lactone monomeric compound, it is characterized in that the white powder material, and be soluble in organic solvents such as ethyl acetate, methyl alcohol, chloroform.It is accredited as expoxyrolin B, and molecular formula is C
36H
66O
3, chemical structural formula is as follows:
Embodiment 3: a kind of sugar apple lactone monomeric compound (expoxyrolin B) is to the restraining effect of human liver cancer cell
1, cell cultures:
SMMC-7721 or HepG2 cell strain are inoculated in the culturing bottle, add RPMI-1640 nutrient solution (containing 10% calf serum, penicillin 100u/ml, Streptomycin sulphate 100ug/ml), in 37 ℃, 5%CO
2Cultivate in the incubator, cell is monolayer adherence growth, goes down to posterity once in per 3～5 days, with 0.25% trysinization 3min, blows and beats with nutrient solution and to inoculate after making cell suspension when going down to posterity.
2, drug treating
The cell of taking the logarithm vegetative period is by 2 * 10
5/ ml is inoculated in the Tissue Culture Flask, treat cell adherent fully (about 4 hours) after, change again and add the nutrient solution that contains medicine, be cultured to the scheduled time.The experiment medicine is a kind of sugar apple lactone monomeric compound (expoxyrolin B) of identifying through chemical structure; Control drug is 5-fluor-uracil (5-Fu).
2, experimental technique:
Adopt the MTT development process, get 2 * 10
4/ ml viable cell is inoculated in 96 orifice plates, and every hole 90ul establishes four multiple holes.Treat to add respectively behind the cell attachment medicine 10ul of different concns, control wells adds 10ulPBS, puts 37 ℃, 5%CO
2Be cultured to the scheduled time under the condition, every hole adds the MTT 50ul/ hole that concentration is 1mg/ml, continue to cultivate 4 hours, remove whole supernatants, add the DMSO100ul/ hole, microoscillator vibration 5min dissolves crystallization fully, joins instrument with enzyme, measure absorbance (OD) in 570nm wavelength place, nutrient solution is only contained in the zeroing hole.Cell viability dosing cell mean light absorbency value/control cells mean light absorbency value * 100%, inhibiting rate (%)=(1-dosing cell mean light absorbency value/control cells mean light absorbency value) * 100%.
3, experimental result
Result such as table 1, table 2 show, along with the rising of internal ester monomer compound (expoxyrolin B) concentration, the inhibiting rate of human liver cancer cell also raise, and the active several times of its inhibition to human liver cancer cell are higher than chemotherapeutic 5-fluor-uracil (5-Fu).
Table 1 expoxyrolin B is to the restraining effect (n=9) of SMMC-7721 liver cancer cell growth
* P＜0.05, * * P＜0.01 and control group comparison
Table 2 expoxyrol in B is to the restraining effect (n=9) of HepG2 liver cancer cell growth
* P＜0.05, * * P＜0.01 and control group comparison
Embodiment 4: a kind of sugar apple lactone monomeric compound (expoxyrolin B) is to the restraining effect of transplanted hepatoma
1, laboratory animal and knurl strain
Male and healthy Kunming mouse body weight, 18-22g, in mouse 6-8 in age week, from experimentation on animals center, this school, Kunming mouse goes down to posterity the strain of ascitic type mouse liver cancer Heps knurl all available from experimentation on animals center, institute of oncology, Jiangsu Province.Mouse is raised in the experimentation on animals room at Nanjing University of Traditional Chinese Medicine experimentation on animals center, and 21～25 ℃ of temperature, humidity are 45%～55%.
2, modeling (transplanted hepatoma Heps)
60 of Kunming kind male white mouses stay 10 negative control groups in proportion at random, and all the other 50 are carried out modeling.The ascites of 8 days mouse of aseptic extraction inoculation Heps knurl kind, with 10 times of physiological saline dilutions, the dyeing of 0.02% Yihong is added drop-wise on the cell counting count board behind the counting, transfers cell concn to 1 * 10
7/ ml, promptly respectively with the right armpit skin degerming of 50 mouse, every mouse inoculation 0.2mlHeps tumour cell suspension is in subcutaneous.Whole seeded process must be carried out with aseptic technique in aseptic cover, finishes inoculation in the 1h.
Be divided into 5 groups after the inoculation at random, 10 every group, be respectively tumor model control group, 15 μ g/kg, 30 μ g/kg and 60 μ g/kg test group, 5-fu positive controls, other adds negative control group, totally 6 groups.Behind the inoculation oncocyte 24h, test group abdominal injection expoxyrolin B, dosage is respectively 15 μ g/kg, 30 μ g/kg and 60 μ g/kg test group, negative control group and tumor model control group equal-volume injectable drug solvent, the 5-FU control group is solvent with physiological saline, dosage is 10mg/kg, each treated animal all by 0.2ml at abdominal injection, successive administration 8d.Next day after the last administration, carry out following observation:
1. completely peel off the knurl piece, and the calculating tumor control rate of weighing, tumor control rate=(control group tumor weight-treatment group tumor weight)/control group tumor weight * 100%;
2. histological examination: tumor tissues is fixed with 4% formaldehyde solution, paraffin embedding, section, light microscopy checking is used in HE dyeing back, and cuts the above-mentioned rat tumor tissue of respectively organizing, pre-fix and after the back fixes through 4% glutaraldehyde and 1% perosmic anhydride, alcohol and acetone dewater step by step, and the section of 0.5 μ m thickness is done in the Resins, epoxy embedding, uranyl acetate and lead citrate dyeing, transmission electron microscope observing.
3, experimental result:
Sugar apple lactone monomeric compound (expoxyrolinB) is to the growth-inhibiting effect of mice transplanted tumor Heps: the expoxyrolin B of various dose all can significantly suppress the growth (P＜0.01) of mouse tumor.The dosage of sugar apple lactone monomeric compound (expoxyrolin B) is minimum, and its antitumour activity is more than hundred times of chemotherapeutic 5-fluor-uracil (5-FU), sees Table 3.
Table 3 expoxyrolin B is to mouse bearing liver cancer Heps exercising result
The Ultrastructural transmission electron microscope observing result of tumor tissue cell: electron microscopic observation is one of important means that detects the apoptosis form, and the especially Ultrastructural observation of transmission electron microscope pair cell is for identifying that apoptosis provides the most direct and objective evidence.The tumour cell of sugar apple lactone monomeric compound medication group mouse, as seen comparatively typical apoptotic morphologic change under the Electronic Speculum, dwindle the tenuigenin increase in density as cell space, pyknosis, the interior chromatin of nucleus concentrates and is gathered into piece, limit collection phenomenon is arranged, and can see the apoptotic body of similar round, nuclear fragmentation, plastosome cavity sample change etc.; 5-Fu chemotherapy control group then mainly shows as necrocytosis, and apoptosis is rare.
Claims (1)
1. the application of sugar apple lactone monomeric compound expoxyrolin B in preparation treatment liver-cancer medicine.
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| CN100528870C true CN100528870C (en) | 2009-08-19 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102153529B (en) * | 2011-02-28 | 2012-07-18 | 南京中医药大学 | Single-tetrahydrofuran-type annonaceous acetogenin compounds with antitumor activity and application thereof |
| CN102070573B (en) * | 2011-02-28 | 2012-06-20 | 南京中医药大学 | Mono-tetrahydrofuran type sugar apple lactone compound with anti-tumor activity and application thereof |
| CN106543159B (en) * | 2016-11-10 | 2019-02-05 | 南京中医药大学 | Epoxy type Annonaceousacetogenicompounds compounds with anti-tumor activity and the preparation method and application thereof |
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| Structural elucidation of two new acetogenins,Epoxyrollins Aand B, by tandem mass spectrometry.. Olivier Laprevote, et al.Tetrahedron Letters,Vol.31 No.16. 1990 |
| Structural elucidation of two new acetogenins,Epoxyrollins Aand B, by tandem mass spectrometry.. Olivier Laprevote, et al.Tetrahedron Letters,Vol.31 No.16. 1990 * |
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