CN1081190C - Antineoplastic and insecticidal total annonacin and preparing process thereof - Google Patents
Antineoplastic and insecticidal total annonacin and preparing process thereof Download PDFInfo
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- CN1081190C CN1081190C CN98101363A CN98101363A CN1081190C CN 1081190 C CN1081190 C CN 1081190C CN 98101363 A CN98101363 A CN 98101363A CN 98101363 A CN98101363 A CN 98101363A CN 1081190 C CN1081190 C CN 1081190C
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- annonacin
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Abstract
The present invention relates to total annonacin for manufacturing antineoplastic drugs and insecticide, which is prepared by using annonaceae seeds as raw materials and extracting total effective components thereof. The present invention has the technology that hexane is used for degreasing, and alcohol is used for diacolation; chloroform is used for extraction, and 90% of hexane-alcohol is used for distribution processing; finished products can be obtained by silica-gel adsorption chromatography and elution of chloroform-methanol. Pharmacodynamic experiments prove that the present invention has strong inhibiting effects on liver cancer, colon cancer, ovarian cancer, etc. and also has the function of killing various pests. The products of the present invention have the advantages of rich raw materials, simple technology, high content of total effective components and low cost; therefore, the present invention is suitable for popularization.
Description
The present invention relates to the gross activity composition total annonacin (Annonaceous acetogenins or polyketides) that from annonaceae (Annonaceae) plant sweetsop (Annona squamosa) seed, extracts, be used to make antitumor drug and agricultural or domestic pesticide.
Sweetsop is a kind of medicinal plant that produce the South China Tropical subtropical zone, and its fruit is an edible fruits.Some platymisciums contain the natural compounds of the very strong long chain fatty acid gamma lactone of the tetrahydrofuran (THF) ring class of the antitumor and insecticidal activity of a class, i.e. kind litchi element in the annonaceae.Report first kind litchi element so far from nineteen eighty-two, found 260 of analogues.But still rest on the research of aspects such as the synthetic and biological activity of chemical structure, analogue so far.Owing to the plain homologous series compound of the contained kind litchi of every kind of plant is various in style, as found more than 40 homologue from sweetsop, the physico-chemical property of each homologue is very approximate, separate difficulty, and the content of individualized compound is relatively low, accumulate pure monomeric compound for activity research, evaluating drug effect and exploitation anti-cancer agent or sterilant, its difficulty is all bigger.Although scientist studies for many years through various countries, find that the different kind litchi element of structure surpasses 260 already, and measured them in external physiologically active and a few compounds activity in vivo wherein.In the molecular structure of kind litchi element a plurality of chiral carbon atoms are arranged, go out to expand the also non-easy thing in medicine source with chemical synthesis process.Therefore, no matter from plant, separate or, one section distance of growing is still arranged apart from practical stage with chemical synthesis process synthon kind litchi element.
The objective of the invention is from Sirikaya seed, to extract gross activity composition total annonacin, replace single effective constituent to make anti-cancer agent and agricultural or domestic pesticide with total effective constituent.Because this patent is a raw material with resource plant rich and easy to get, adopts better simply manufacturing process again, has reduced production cost, helps practical purpose.
Main contents of the present invention and main points:
One. chemistry and pharmacology part
Total annonacin extracts and enrichment: Sirikaya seed is broken for meal, under the room temperature, with hexane or sherwood oil soak degreasing, after flinging to solvent, continue with 95% ethanol (methyl alcohol, propyl alcohol, Virahol or acetone) diacolation, decompression and solvent recovery gets alcohol extract, in water with chloroform (methylene dichloride, ethylene dichloride, ether or ethyl acetate) allocation process, kind litchi is plain to be the chloroform extraction proposition, again with 90% ethanol (methyl alcohol, propyl alcohol or Virahol) hexane (or sherwood oil) allocation process chloroform gets and carries thing, at last with 90% ethanol extraction with the silica gel adsorption chromatography, chloroform (methylene dichloride, ethylene dichloride, ether or ethyl acetate)-methyl alcohol (98: 2～90: 10) wash-out, collect and wash out part (～70%) at first, can make total annonacin content be enriched to 90%, Fig. 1 is seen in its technical process.The quality controlling means of kind litchi element
1. colorimetric method for determining total annonacin content: this law is based on containing a α in the plain molecule of kind litchi, β-unsaturated gamma lactone ring, can be in ethanolic soln with 3,5-dinitrobenzoic acid (2%) and sodium hydroxide (5%) ethanol reagent show pink reaction, put in the visible spectrophotometer, 530nm measures optical density down, calculates content.Regression equation: y=0.4048x-1.097 * 10
-3Linearity range: 0.07～0.30mg γ=0.9999 (relation conefficient)
Total annonacin content in each extract of table 1 colorimetric method for determining
| The sample title | Total annonacin content *％ |
| The Annona squamosa seed chloroform is got and is carried thing 90% ethanol extraction total annonacin | 1.5％ 35％ 65％ 74％ 90％ |
*Data are for measuring mean value repeatedly
2. the content of main kind of litchi element of high effective liquid chromatography for measuring: adopt the alkyl linked silicagel column of C-18 (4.5mm * 25cm), methyl alcohol: water (8: 2) be moving phase, and flow velocity 1ml/ minute, detection wavelength 220nm measured the optical density of each composition, and the result is as follows:
| Compound | Content (%) | Regression equation γ value |
| 2 annonareticin kinds of litchi booth E 3 squamostatin E of cherimoya essence 1 squamocin OX-heart cherimoya essence kind litchi booth B1 4 squamostatin B 1 | 28～35 8～10 3～6 9～10 | y＝6.521×10 4+5.69×10 5x γ＝0.9999 y＝-8.22×10 3+5.19×10 5x γ＝0.9998 y＝-2.08×10 3+3.64×10 5x γ＝0.9996 y＝-1.49×10 4+5.75×10 4x γ＝0.9998 |
The high performance liquid chromatography separation graph is seen accompanying drawing 2.Two. the acute toxicity test of pharmacology part 1. total annonacins
Mouse medium lethal dose (LD
50) the pH-value determination pH result is as follows:
Abdominal injection ip * 1 LD
50=6.11 ± 0.10mg/kg
Intravenous injection iv * 1 LD
50=3.89 ± 0.10mg/kg
Oral po * 1 LD
50The LD of=82.98 ± 5.40mg/kg total annonacin
50Value is close with some antitumor drugs such as the vincristine(VCR) (VCR) of clinical application at present.Very obvious in sensitive dose district amount-effect (death) relation.Minimum in three kinds of route of administration with the oral toxicity reaction.The intraperitoneal injection post-absorption is very fast, and the high dosage death time concentrated in 2 hours, and low dosage concentrated in 8 hours, if animal can survive in 24～48 hours, just substantially can be not dead, and the medicine absorption in vivo is described, transform or discharge very fast.2. total annonacin extracorporeal anti-tumor function
External to human liver cancer cell Bel, human colon cancer cell HCT-8, Proliferation of Human Ovarian Cell A-2780, human oral cavity epithelial cancer cells KB and drug-resistant cell strain KBv-200 thereof, human cervical carcinoma cell HeLa S
3, the female fibroma cell of Chinese hamster fibroma of lung cell V-79 and mouse L-729, carried out the inhibition growth experiment.The result shows the liver cancer to the people, human colon carcinoma, and the human ovarian cancer tumor-suppression activity is the strongest; Oral cavity epithelial cancer and persister KBv-200 thereof are had equal drug effect, illustrate that total annonacin does not have the shortcoming of the easy generation multidrug resistance (MDR) of general cancer therapy drug existence.See Table 3,4,5 and 6.
Table 3. total annonacin is to the killing activity (ED of five kinds of human cancer cell strains
50Median effective dose)
*5-Fu: positive control drug 5 FU 5 fluorouracil medicine
| The cell strain kind | Total annonacin ED 50(μg/ml) | Positive control drug 5-Fu ED 50(μg/ml) |
| Proliferation of Human Ovarian Cell A-2780 human colon cancer cell HCT-8 human liver cancer cell Bel human oral cavity epithelial cancer cell KB human oral cavity epithelial cancer mdr cell KBv-200 | 0.0093 0.0063 0.0062 1.502 1.423 | 0.636 0.456 0.404 0.673 0.585 |
Table 4. total annonacin is to the restraining effect (data are inhibiting rate % in the table) of four kinds of human cancer cell incubation growth
| Cell strain | Total annonacin dosage (μ g/ml) | Positive control drug 5-Fu (μ g/ml) * |
| 0.10 0.01 0.001 0.0001 | 3.20 0.80 0.20 0.05 | |
| Human colon cancer cell HCT-8 Proliferation of Human Ovarian Cell A-2780 human oral cavity epithelial cancer cells KB human oral cavity epithelial cancer mdr cell KBv-200 | 78.5 73.9 18.3 7.8 56.0 52.8 24.3 0.8 34.9 34.3 31.5 2.2 44.8 44.6 38.6 7.0 | 82.6 74.4 42.0 5.7 82.4 60.3 25.2 5.7 72.6 59.4 26.9 9.6 64.7 59.0 39.9 16.4 |
Table 5. total annonacin is to the restraining effect (data are inhibiting rate % in the table) of human liver cancer cell Bel incubation growth
| Sequence number | Total annonacin dosage (μ g/ml) | Positive control drug 5-Fu (μ g/ml) * |
| 0.10 0.03 0.01 0.003 0.001 0.0003 0.0001 | 1.0 0.50 0.25 0.125 0.0625 | |
| 1 2 | 77.4 73.4 70.1 42.9 24.5 0.0 0.0 76.0 72.3 67.2 48.5 27.6 12.0 3.1 | 63.0 56.9 40.3 24.1 14.1 62.0 57.8 40.7 23.6 16.4 |
The restraining effect * of three kinds of cancer cells incubation growth of table 6. total annonacin (data are inhibiting rate % in the table)
| Cell strain | Total annonacin dosage (μ g/ml) | Positive control drug ADM (μ g/ml) * |
| 500 50.0 5.0 0.5 | 1.0 0.10 0.01 | |
| The female fibroma cell of human cervical carcinoma cell HeLa S3 Chinese hamster fibroma of lung cell V-79 mouse L-729 | 90.0 92.0 -7.0 -23 97.5 95.5 30.0 - 93.5 91.5 4.0 - | 45.5 10.5 -0.5 76.0 57.5 29.5 52.5 25.5 14.5 |
*ADM: the restraining effect to the animal transplanting tumor growth in the positive control drug Zorubicin 3. total annonacin bodies carries out pressing down in the body knurl growth test with 6 kinds of animal transplanting tumor cell strains such as rat liver cancer H-22, murine melanoma B-16, murine sarcoma S-180, mouse carcinoma of uterine cervix U-14, mouse ehrlich carcinoma solid tumor ESC and mouse Louis (Lewis) lung cancer.Total annonacin is established three dosage groups, and other establishes control group (giving the same solvent of sample dissolution) and endoxan (CTX) positive controls, and each organized the continuous oral administration 10～11 days.The result shows that total annonacin has stronger activity to rat liver cancer H-22, is melanoma B-16 and cervical cancer U-14 secondly.Show that total annonacin has certain toxicity target tissue and organ.
Table 7. total annonacin oral administration is to the tumor-inhibiting action of mouse bearing liver cancer H-22
| Group | Number of animals beginning/end | Dosage (mg/kg * 10 day) | The knurl weight (x ±, SD, g) | Inhibiting rate (%) | The p value |
| Control group positive control endoxan group CTX total annonacin+CTX organizes total annonacin: dosage group high dose group in the low dose group | 10/10 10/10 10/8 10/10 10/10 10/8 | 20.0ip 2.5+10ip 3.0 5.0 8.0 | 1.66±0.54 0.54±0.15 0.76±0.25 0.69±0.46 0.78±0.30 0.55±0.19 | 67.5 54 2 58.4 53.0 66.9 | ＜0.001 ＜0.001 ＜0.001 ＜0.001 |
Table 8. total annonacin oral administration is to the tumor-inhibiting action of murine melanoma B-16
| Group | Number of animals beginning/end | Dosage (mg/kg * 10 day) | The knurl weight (x ± SD, g) | Inhibiting rate (%) | The p value |
| Control group positive control endoxan group CTX total annonacin: dosage group high dose group in the low dose group | 10/10 10/9 10/9 10/10 10/9 | 20ip 2.0 4.0 6.0 | 3.13±0.31 1.96±0.71 2.47±0.51 2.24±0.40 1.11±0.25 | 37.4 21.1 28.4 64.5 | ＜0.001 ＜0.01 ＜0.001 ＜0.001 |
Table 9. total annonacin oral administration is to the antitumor activity of murine sarcoma S-180
| Group | Number of animals beginning/end | Dosage (mg/kg * 11 day) | The knurl weight (x ± SD, g) | Inhibiting rate (%) | The p value |
| Control group positive control endoxan group CTX total annonacin: dosage group high dose group in the low dose group | 10/10 10/10 10/10 10/10 10/10 | 20ip 29 36 45 | 3.54±0.50 1.26±0.28 2.10±0.60 2.02±0.48 2.55±0.85 | 64.7 40 7 42.9 28.0 | ＜0.001 ＜0.01 ＜0.01 ＜0.05 |
Table 10. total annonacin oral administration is to the tumor-inhibiting action of mouse transplantability cervical cancer U-14
| Group | Number of animals beginning/end | Dosage (mg/kg * 10 day) | The knurl weight (x ± SD, g) | Inhibiting rate (%) | The p-value |
| Control group positive control endoxan group CTX total annonacin+CTX organizes total annonacin: dosage group high dose group in the low dose group | 10/10 10/10 10/10 10/10 10/10 10/10 | 20ip 2.5+10ip 3.0 5.0 8.0 | 2.23±0.44 0.36±0.09 0.68±0.15 1.97±0.47 1.42±0.44 1.73±0.42 | 83.9 69.5 11.5 36.3 22.4 | ＜0.001 ＜0.001 ＜0.001 ＜0.01 |
The total acetogenins oral administration of table 11. is to the antitumor activity of mouse ehrlich carcinoma solid tumor ESC
| Group | Number of animals beginning/end | Dosage (mg/kg * 11 day) | The knurl weight (x ± SD, g) | Inhibiting rate (%) | The p value |
| Control group positive control endoxan CTX organizes total annonacin: dosage group high dose group in the low dose group | 10 10 10 10 10 | 20ip 29 36 45 | 3.26±0.45 1.22±0.30 2.13±0.61 2.18±0.54 2.58±0.74 | 62.6 34.7 33.1 20.9 | ＜0.001 ＜0.01 ＜0.01 |
Table 12. total annonacin oral administration is to the tumor-inhibiting action of Mice Bearing Lewis Lung Cancer
| Group | Number of animals beginning/end | Dosage (mg/kg * 10 day) | The knurl weight (x ± SD, g) | Inhibiting rate (%) | The p value |
| Control group positive control endoxan CTX group total annonacin+CTX organizes total annonacin: dosage group high dose group in the low dose group | 10/10 10/9 10/9 10/10 10/10 10/9 | 20ip 2+10ip 2.0 4.0 6.0 | 3.20±0.57 1.73±0.35 1.83±0.44 2.81±0.78 2.48±0.37 2.41±0.41 | 45.9 42.8 12.2 22.5 24.7 | ＜0.001 ＜0.001 ＜0.01 ＜0.01 |
Table 13. total annonacin desinsection kills the activity test of mite biological activity
| Subjects (insect title) | Testing method | Concentration ppm | Mortality ratio % |
| Lipahis erysimi (Kaltenbach) (radish aphid) aphid: Myzus persicae (Sulzer) (black peach aphid worm) Brevicoryne brassicae (Linnaeus) (Lay aphid) | Medicine embrane method | 10 | 70 |
| The pot experiment spray method | 40 | 80 | |
| Tetranychid: Tetranychus cinnabarinus (Boisduval) T.viennensis (Zacher) | Leaf dipping method | 50 25 | 100 95 |
| Mythimna separata Mythimna separata (Walker) | Spray method is handled worm and feed | 100 | 80～90 |
| Cabbage caterpillar Pieris rapae (Linnaeus) | 100 | 80～90 | |
| Small cabbage moth Plutella xylostella (Linnaeus) | 100 | 90 |
4. mutagenesis (Ames experiment) and micronucleus only appear in special toxicological experiment total annonacin to be counted and is slight positive reaction in the higher time side of dosage, show this medicine to cause mutagenesis lighter, different with most antitumour drugs.
5. general pharmacology is learned this medicine of experiment at 0.03～0.1mg/kg, and respiratory rate, amplitude, the rhythm of the heart, heart rate and electrocardiogram(ECG to dog under the iv dosage all do not have influence; General activity to mouse does not have counting difference, only when 0.34mg/kg iv, mouse is had lighter excitation.
Advantage of the present invention and effect are to extract gross activity composition kind litchi element from Sirikaya seed, replace single active ingredient to make antitumor drug and agricultural or domestic pesticide with total effective constituent, characteristics that not only can each single active ingredient of centralized displaying, but also can improve the gross activity component content.Meanwhile,, adopt better simply manufacturing process again, reduced production cost, help practical application owing to being raw material as a means of plant rich and easy to get.
Description of drawings: Fig. 1: total annonacin process flow sheet Fig. 2: the high performance liquid chromatography separation graph wherein: (1) .----cherimoya essence (2) .----OX-heart cherimoya essence
(3) .----kind of litchi booth of .----kind of litchi booth E (4) B
1Instrument: Waters high performance liquid chromatograph
486 UV-detector;
Detect wavelength 220nm
Claims (3)
1. antitumour drug total annonacin, its feature at this medicine mainly by containing cherimoya essence, OX-heart cherimoya essence, kind litchi booth E and kind litchi booth B
1Deng total annonacin and the pharmaceutical carrier formed.
2. sterilant total annonacin, its feature at this sterilant mainly by containing cherimoya essence, OX-heart cherimoya essence, kind litchi booth E and kind litchi booth B
1Deng total annonacin and the insecticide carrier formed.
3. the preparation method of total annonacin is characterized in that Sirikaya seed is used the hexane degreasing earlier, uses alcohol percolation, chloroform extraction and hexane-90% ethanol allocation process then, get 90% ethanol part, at last again through silica gel column chromatography, the chloroform-methanol wash-out, can obtain total annonacin, content reaches 90%.
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| CN98101363A CN1081190C (en) | 1998-04-10 | 1998-04-10 | Antineoplastic and insecticidal total annonacin and preparing process thereof |
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| CN1081190C true CN1081190C (en) | 2002-03-20 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020156329A1 (en) * | 2019-01-31 | 2020-08-06 | 中国医学科学院药用植物研究所 | Pharmaceutical composition for selective killing or efficient killing at nm level of drug-resistant tumors and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101485700B (en) * | 2009-03-03 | 2011-08-31 | 南京中医药大学 | Refined cherimoya total inner ester with anti-tumor activity and preparation method thereof |
| CN109793732B (en) * | 2019-01-31 | 2021-08-03 | 中国医学科学院药用植物研究所 | Annona squamosa seed extract for treating choriocarcinoma, and preparation method and application thereof |
| CN109620822A (en) * | 2019-01-31 | 2019-04-16 | 中国医学科学院药用植物研究所 | It is a kind of for treating the sugar apple seed extract and its preparation method and application of people's malignant glioma or melanoma |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1165821A (en) * | 1997-04-09 | 1997-11-26 | 中国科学院上海有机化学研究所 | Annona lactone analogue and its use |
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1998
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1165821A (en) * | 1997-04-09 | 1997-11-26 | 中国科学院上海有机化学研究所 | Annona lactone analogue and its use |
Non-Patent Citations (3)
| Title |
|---|
| CHEM.PHARM.BULL42(6),1163-1174(1994) 1994.1.1 Mahendra Sahai efal"Amohaceeus Acetogenins from the Secds of Annona squamo * |
| CHEM.PHARM.BULL42(6),1163-1174(1994) 1994.1.1 Mahendra Sahai efal"Amohaceeus Acetogenins from the Secds of Annona squamo;IBID 1175-1184 1994.1.1;NATURAL PRODUCT REPORT13(4),275-306(1996) 1996.1.1 Lu Zeng et al "Recerct Advances in Amonacebus Acelogenins" * |
| IBID 1175-1184 1994.1.1;NATURAL PRODUCT REPORT13(4),275-306(1996) 1996.1.1 Lu Zeng et al "Recerct Advances in Amonacebus Acelogenins" * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020156329A1 (en) * | 2019-01-31 | 2020-08-06 | 中国医学科学院药用植物研究所 | Pharmaceutical composition for selective killing or efficient killing at nm level of drug-resistant tumors and use thereof |
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| CN1224016A (en) | 1999-07-28 |
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