CN100432065C - Lactone monomer compound and its application in preparing anticancer medicine - Google Patents
Lactone monomer compound and its application in preparing anticancer medicine Download PDFInfo
- Publication number
- CN100432065C CN100432065C CNB2006100857814A CN200610085781A CN100432065C CN 100432065 C CN100432065 C CN 100432065C CN B2006100857814 A CNB2006100857814 A CN B2006100857814A CN 200610085781 A CN200610085781 A CN 200610085781A CN 100432065 C CN100432065 C CN 100432065C
- Authority
- CN
- China
- Prior art keywords
- anticancer
- monomeric compound
- drug
- cherimoya
- liver cancer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The present invention relates to an anticancer drug, namely a cherimoya lactone monomeric compound which is an anticancer monomeric compound extracted from cherimoya seeds. In a preparation method of the drug, cherimoya seeds are pulverized into coarse powder after being dried by air, and the coarse powder is extracted by ethanol through refluxing; extractum is suspended in proper amounts of water by normal-pressure concentration and is extracted by using petroleum ether sequentially, water-saturation ethyl acetate and water-saturation normal butyl alcohol. The cherimoya lactone monomeric compound is obtained from the part of ethyl acetate by the methods of repeated silica gel column chromatography, gel column chromatography, high-efficiency preparation of liquid phase chromatography, recrystallization, etc. Anticancer pharmacological experiments in/out vivo show that the drug has obvious inhibiting effects on the growth of human liver cancer cells and mice's transplanting liver cancer, and the anticancer activity of the drug is obviously higher than that of chemotherapy drugs of cisplatin and 5-fluorouracil.
Description
One, technical field
The present invention relates to a kind of cancer therapy drug, specifically is the application of a kind of sugar apple lactone monomeric compound in preparation treatment cancer therapy drug 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 therefrom invented 5 kinds of internal ester monomer compositions again and has had the especially significantly anticancer purpose (its antitumour activity is significantly higher than chemotherapeutic cis-platinum and 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 be the new purposes of a kind of sugar apple lactone monomeric compound (desacetyluvaricin) of raw material extraction with the Sirikaya seed, i.e. application in preparation treatment cancer therapy drug.
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 it is a white waxy solid, is soluble in organic solvents such as chloroform, ethyl acetate.It is accredited as desacetyluvaricin, and molecular formula is C
37H
66O
6, the following (R of chemical structural formula
1, R
2, R
3Be H, THF-THF is configured as threo/trans/threo/trans/erythro):
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, measure 95% alcohol reflux 3 times with 10 times, each 2h, normal pressure concentrates, and medicinal extract is suspended in the suitable quantity of water, uses sherwood oil (60～90 ℃), water-saturated n-butanol extraction successively, by methods such as silica gel column chromatography, gel column chromatography, high performance preparative liquid chromatography and recrystallization repeatedly, partly obtain a kind of sugar apple lactone monomeric compound (desacetyluvaricin) from ethyl acetate.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 is significantly higher than chemotherapeutic cis-platinum and 5-fluor-uracil.
The present invention relates to the application of a kind of cancer therapy drug sugar apple lactone monomeric compound (desacetyluvaricina) in the preparation cancer therapy drug.
Adopt the MTT development process, get 2 * 10
4/ ml viable cell (human liver cancer cell 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 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%.
The result shows that cancer therapy drug sugar apple lactone monomeric compound (desacetyluvaricin) is very high to the inhibition activity of human liver cancer cell, its to the inhibition activity of human liver cancer cell apparently higher than chemotherapeutic cis-platinum (PDD).
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, cancer therapy drug sugar apple lactone monomeric compound (desacetyluvaricin) is to the king in the cancer---and the inhibition activity of liver cancer is very high, and its inside and outside to liver cancer suppresses activity and is significantly higher than chemotherapeutic cis-platinum (PDD) and 5-fluor-uracil (5-Fu).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 of a kind of cancer therapy drug sugar apple lactone monomeric compound (desacetyluvaricin) extracting method, 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, measure 95% alcohol reflux 3 times with 10 times, each 2h, normal pressure concentrates, and medicinal extract is suspended in the suitable quantity of water, uses sherwood oil (60～90 ℃), water-saturated n-butanol extraction successively, by methods such as silica gel column chromatography, gel column chromatography, high performance preparative liquid chromatography and recrystallization repeatedly, partly obtain a kind of sugar apple lactone monomeric compound (desacetyluvaricin) from ethyl acetate.
Embodiment 2: sugar apple lactone monomeric compound is a white waxy solid, is soluble in organic solvents such as chloroform, ethyl acetate.It is accredited as desacetyluvaricin, and molecular formula is C
37H
66O
6, the following (R of chemical structural formula
1, R
2, R
3Be H, THF-THF rel configuration is threo/trans/threo/trans/erythro):
Embodiment 3: a kind of sugar apple lactone monomeric compound (desacetyluvaricin) is to the restraining effect of human liver cancer cell
1, cell cultures:
The HepG2 cell strain is inoculated in the culturing bottle, adds 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 (desacetyluvaricin) 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
The result along with the rising of internal ester monomer compound (desacetyluvaricin) concentration, also raises to the inhibiting rate of human liver cancer cell as shown in Table 12, its to the inhibition activity of human liver cancer cell apparently higher than chemotherapeutic cis-platinum (PDD).
Table 1desacetyluvaricin 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 (desacetyluvaricin) 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 desacetyluvaricin, 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 (desacetyluvaricin) is to the growth-inhibiting effect of mice transplanted tumor Heps: the desacetyluvaricin of various dose all can significantly suppress the growth (P＜0.01) of mouse tumor.The dosage of sugar apple lactone monomeric compound (desacetyluvaricin) is minimum, and its antitumour activity is more than hundred times of chemotherapeutic 5-fluor-uracil (5-FU), sees Table 3.
Table 3desacetyluvaricin is to mouse bearing liver cancer Heps exercising result
The Ultrastructural transmission electron microscope observing result of tumor tissue cell: the tumour cell of internal ester monomer 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 following formula sugar apple lactone monomeric compound in preparation treatment liver-cancer medicine,
R wherein
1, R
2, R
3Be H, tetrahydrofuran (THF)-tetrahydrofuran (THF) is configured as Soviet Union's formula/trans/Soviet Union's formula/trans/erythro form.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100857814A CN100432065C (en) | 2006-06-30 | 2006-06-30 | Lactone monomer compound and its application in preparing anticancer medicine |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2006100857814A CN100432065C (en) | 2006-06-30 | 2006-06-30 | Lactone monomer compound and its application in preparing anticancer medicine |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1869031A CN1869031A (en) | 2006-11-29 |
| CN100432065C true CN100432065C (en) | 2008-11-12 |
Family
ID=37442827
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2006100857814A Expired - Fee Related CN100432065C (en) | 2006-06-30 | 2006-06-30 | Lactone monomer compound and its application in preparing anticancer medicine |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN100432065C (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| 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 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1319424A (en) * | 2001-02-28 | 2001-10-31 | 南京中医药大学 | Anticancer medicine of Annona squamose extractum and preparation method thereof |
-
2006
- 2006-06-30 CN CNB2006100857814A patent/CN100432065C/en not_active Expired - Fee Related
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1319424A (en) * | 2001-02-28 | 2001-10-31 | 南京中医药大学 | Anticancer medicine of Annona squamose extractum and preparation method thereof |
Non-Patent Citations (8)
| Title |
|---|
| Determination of structure-activity relationshipsof Annonaceous acetogenins by inhibition of oxygen uptakeinrat liver mitochondria. J. L. Landolt, et al.Chemico-Biological Interactions,Vol.98. 1995 * |
| Determination of structure-activity relationshipsofAnnonaceous acetogenins by inhibition of oxygen uptakeinrat liver mitochondria.. J. L. Landolt, et al.Chemico-Biological Interactions,,Vol.98 . 1995 |
| Tryptamine Derived Amides and Acetogenins from the Seedsof Rollinia mucosa. Chavez, Daniel, et al.Journal of Natural Products,Vol.62 No.8. 1999 * |
| Tryptamine Derived Amides and Acetogenins from the Seedsof Rollinia mucosa.. Chavez, Daniel, et al.Journal of Natural Products,,Vol.62 No.8. 1999 |
| Tumor cell growth inhibition by several Annonaceousacetogenins in an in vitro disk diffusion assay. Nicholas H. Oberlies, Et al..Cancer Letters,Vol.96. 1995 * |
| Tumor cell growth inhibition by severalAnnonaceousacetogenins in an in vitro disk diffusion assay.. Nicholas H. Oberlies, Et al..Cancer Letters,,Vol.96 . 1995 |
| 番茄枝内酯类化合物对肝细胞耗氧呼吸的抑制作用及其构效关系. 徐志防等.药学学报，第37卷第10期. 2002 * |
| 番茄枝内酯类化合物对肝细胞耗氧呼吸的抑制作用及其构效关系。. 徐志防等.药学学报，第37卷第10期. 2002 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1869031A (en) | 2006-11-29 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101805390B (en) | Tripterine derivate and use thereof | |
| CN102125552A (en) | Use of piperlongumine derivatives in preparation of medicines for treating cancers and medicinal compositions thereof | |
| CN109970538A (en) | The Dimeric sesquiterpene compound in a kind of marine fungi source and preparation method thereof and application in preparing anti-inflammatory drugs | |
| CN100528870C (en) | Internal ester monomer compound and its application in preparing anti cancer medicine | |
| CN102178688B (en) | Preparation method of ivy saponins ingredient and application of the ingredient to resisting tumors | |
| CN100432065C (en) | Lactone monomer compound and its application in preparing anticancer medicine | |
| CN101880306B (en) | Stauntonia brachyanthera Hand-Mazz saponins components as well as preparation method and application thereof | |
| CN101229223B (en) | Applications of fructus psoraleae extractive on preparing antitumor medicines | |
| CN101336917B (en) | Use of annonaceous acetogenins in preparing medicine for treating lung cancer or breast cancer | |
| CN102267891A (en) | Novel triterpenoid compound and preparation method thereof | |
| CN101406499A (en) | Cherimoya inner ester extract as well as extraction method and use thereof in preparing anti-cancer medicine | |
| CN101289453B (en) | Ellagic acid compounds preparation method | |
| CN1869035A (en) | Lactone monomer compound and its application in preparing medicine for treating cancer | |
| CN1861588A (en) | Internal ester monomer compound and application in preparing anti cancer medicine | |
| CN101336918B (en) | Use of annonaceous acetogenins in preparing medicine for treating lung cancer or breast cancer | |
| CN1861587A (en) | Internal ester monomer compound and application in preparing anti cancer medicine | |
| CN100436443C (en) | Compound (2S)-5, 7.2', 6'-tetrahydroxy-6,8-diiso pentenyl-dihydro flavone extracting process and its use | |
| CN102531906B (en) | Application of natural compound P21 in inhibition of reproductive growth of tumor cell | |
| CN102008463A (en) | Application of annona squamosa Linn lactone compound to preparation of medicaments for treating breast cancer | |
| CN101342202A (en) | Application of sugar apple lactone compound V in preparing cancer-treating and anti-cancer medicine | |
| CN106177035B (en) | Preparation method and application of effective rosa chinensis flower extract with blood sugar reducing and anticancer functions | |
| CN108997473A (en) | A kind of non-sea cucumber alkane type selenka and the preparation method and application thereof | |
| CN104211592A (en) | Extracting method and application of corn linoleic acid | |
| CN101401806A (en) | Uses of sugar apple lactone monomeric compound in preparing medicament for treating lung cancer, mammary cancer or liver cancer | |
| CN105111168A (en) | Natural antineoplastic compound and preparation method and use thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20081112 Termination date: 20110630 |