CN1141093C - Anticancer lichee lectone medicine and its prepn - Google Patents
Anticancer lichee lectone medicine and its prepn Download PDFInfo
- Publication number
- CN1141093C CN1141093C CNB011075945A CN01107594A CN1141093C CN 1141093 C CN1141093 C CN 1141093C CN B011075945 A CNB011075945 A CN B011075945A CN 01107594 A CN01107594 A CN 01107594A CN 1141093 C CN1141093 C CN 1141093C
- Authority
- CN
- China
- Prior art keywords
- anticancer
- arnold
- lectone
- lichee
- silica gel
- 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 - Lifetime
Links
- 239000003814 drug Substances 0.000 title claims abstract description 64
- 230000001093 anti-cancer Effects 0.000 title claims abstract description 35
- 150000002596 lactones Chemical class 0.000 claims abstract description 58
- 238000002360 preparation method Methods 0.000 claims abstract description 32
- 239000003208 petroleum Substances 0.000 claims abstract description 21
- 239000003960 organic solvent Substances 0.000 claims abstract description 16
- HWJHWSBFPPPIPD-UHFFFAOYSA-N ethoxyethane;propan-2-one Chemical compound CC(C)=O.CCOCC HWJHWSBFPPPIPD-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 9
- 229940079593 drug Drugs 0.000 claims abstract description 8
- 238000004519 manufacturing process Methods 0.000 claims abstract description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 34
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 25
- 238000000605 extraction Methods 0.000 claims description 23
- 239000000463 material Substances 0.000 claims description 22
- 239000000741 silica gel Substances 0.000 claims description 21
- 229910002027 silica gel Inorganic materials 0.000 claims description 21
- 229960001866 silicon dioxide Drugs 0.000 claims description 21
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 18
- 238000004809 thin layer chromatography Methods 0.000 claims description 16
- 239000002026 chloroform extract Substances 0.000 claims description 10
- 239000000839 emulsion Substances 0.000 claims description 9
- 238000011049 filling Methods 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 9
- 239000002904 solvent Substances 0.000 claims description 9
- 238000004587 chromatography analysis Methods 0.000 claims description 8
- 239000012141 concentrate Substances 0.000 claims description 8
- 239000007924 injection Substances 0.000 claims description 8
- 238000002347 injection Methods 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- WORJEOGGNQDSOE-UHFFFAOYSA-N chloroform;methanol Chemical compound OC.ClC(Cl)Cl WORJEOGGNQDSOE-UHFFFAOYSA-N 0.000 claims description 7
- 238000007689 inspection Methods 0.000 claims description 7
- 238000005238 degreasing Methods 0.000 claims description 6
- 239000000469 ethanolic extract Substances 0.000 claims description 5
- 239000000843 powder Substances 0.000 claims description 5
- 235000012424 soybean oil Nutrition 0.000 claims description 5
- 239000003549 soybean oil Substances 0.000 claims description 5
- 239000000126 substance Substances 0.000 claims description 5
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 229940067606 lecithin Drugs 0.000 claims description 4
- 235000010445 lecithin Nutrition 0.000 claims description 4
- 239000000787 lecithin Substances 0.000 claims description 4
- 238000007670 refining Methods 0.000 claims description 4
- 230000001186 cumulative effect Effects 0.000 claims description 3
- 230000001804 emulsifying effect Effects 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 230000001954 sterilising effect Effects 0.000 claims description 3
- 238000004659 sterilization and disinfection Methods 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 2
- 238000000638 solvent extraction Methods 0.000 claims 2
- 230000000694 effects Effects 0.000 abstract description 18
- 239000000203 mixture Substances 0.000 abstract description 11
- 241001081440 Annonaceae Species 0.000 abstract description 6
- 239000002994 raw material Substances 0.000 abstract description 5
- 235000013336 milk Nutrition 0.000 abstract description 4
- 239000008267 milk Substances 0.000 abstract description 4
- 210000004080 milk Anatomy 0.000 abstract description 4
- 238000003908 quality control method Methods 0.000 abstract description 4
- 239000002246 antineoplastic agent Substances 0.000 abstract description 3
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 3
- -1 and firstly Substances 0.000 abstract description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 22
- 206010028980 Neoplasm Diseases 0.000 description 18
- 238000000034 method Methods 0.000 description 14
- 210000004027 cell Anatomy 0.000 description 13
- 230000002401 inhibitory effect Effects 0.000 description 13
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 10
- 238000012360 testing method Methods 0.000 description 10
- CMSMOCZEIVJLDB-UHFFFAOYSA-N Cyclophosphamide Chemical compound ClCCN(CCCl)P1(=O)NCCCO1 CMSMOCZEIVJLDB-UHFFFAOYSA-N 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- 150000001875 compounds Chemical class 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
- 241000196324 Embryophyta Species 0.000 description 6
- 230000002496 gastric effect Effects 0.000 description 6
- 238000001802 infusion Methods 0.000 description 6
- 229960002949 fluorouracil Drugs 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- 210000002784 stomach Anatomy 0.000 description 5
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 5
- 241001529936 Murinae Species 0.000 description 4
- 229930012538 Paclitaxel Natural products 0.000 description 4
- 206010039491 Sarcoma Diseases 0.000 description 4
- 231100000215 acute (single dose) toxicity testing Toxicity 0.000 description 4
- 238000011047 acute toxicity test Methods 0.000 description 4
- 230000000259 anti-tumor effect Effects 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
- 239000007928 intraperitoneal injection Substances 0.000 description 4
- 229960001592 paclitaxel Drugs 0.000 description 4
- 239000013641 positive control Substances 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- DAEFUOXKPZLQMM-UHFFFAOYSA-N squamocin A Natural products O1C(C(O)CCCC(O)CCCCCC)CCC1C1OC(C(O)CCCCCCCCCCCCC=2C(OC(C)C=2)=O)CC1 DAEFUOXKPZLQMM-UHFFFAOYSA-N 0.000 description 4
- 208000015914 Non-Hodgkin lymphomas Diseases 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 235000008504 concentrate Nutrition 0.000 description 3
- 206010012818 diffuse large B-cell lymphoma Diseases 0.000 description 3
- 238000004945 emulsification Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 201000007270 liver cancer Diseases 0.000 description 3
- 208000014018 liver neoplasm Diseases 0.000 description 3
- 239000002574 poison Substances 0.000 description 3
- 231100000614 poison Toxicity 0.000 description 3
- 201000006845 reticulosarcoma Diseases 0.000 description 3
- 208000029922 reticulum cell sarcoma Diseases 0.000 description 3
- 244000028821 Annona squamosa Species 0.000 description 2
- 235000005274 Annona squamosa Nutrition 0.000 description 2
- 206010006187 Breast cancer Diseases 0.000 description 2
- 208000026310 Breast neoplasm Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- 208000002454 Nasopharyngeal Carcinoma Diseases 0.000 description 2
- 206010061306 Nasopharyngeal cancer Diseases 0.000 description 2
- DAEFUOXKPZLQMM-AUDZWCKFSA-N Squamocin Chemical compound O1[C@@H]([C@@H](O)CCC[C@@H](O)CCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCCCCC=2C(O[C@@H](C)C=2)=O)CC1 DAEFUOXKPZLQMM-AUDZWCKFSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 230000006907 apoptotic process Effects 0.000 description 2
- 201000008275 breast carcinoma Diseases 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 229960004397 cyclophosphamide Drugs 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 235000013399 edible fruits Nutrition 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000002045 lasting effect Effects 0.000 description 2
- 230000036457 multidrug resistance Effects 0.000 description 2
- 201000011216 nasopharynx carcinoma Diseases 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 239000002547 new drug Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- MBABCNBNDNGODA-WPZDJQSSSA-N rolliniastatin 1 Natural products O1[C@@H]([C@@H](O)CCCCCCCCCC)CC[C@H]1[C@H]1O[C@@H]([C@H](O)CCCCCCCCCC[C@@H](O)CC=2C(O[C@@H](C)C=2)=O)CC1 MBABCNBNDNGODA-WPZDJQSSSA-N 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- MBABCNBNDNGODA-UHFFFAOYSA-N trilobacin Chemical compound O1C(C(O)CCCCCCCCCC)CCC1C1OC(C(O)CCCCCCCCCCC(O)CC=2C(OC(C)C=2)=O)CC1 MBABCNBNDNGODA-UHFFFAOYSA-N 0.000 description 2
- QGZCUOLOTMJILH-UHFFFAOYSA-N 2h-tetrazol-2-ium;bromide Chemical compound [Br-].C1=N[NH+]=NN1 QGZCUOLOTMJILH-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000010507 Adenocarcinoma of Lung Diseases 0.000 description 1
- 241000722951 Annona Species 0.000 description 1
- 235000007755 Annona Nutrition 0.000 description 1
- 235000011518 Annona purpurea Nutrition 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 102000004316 Oxidoreductases Human genes 0.000 description 1
- 108090000854 Oxidoreductases Proteins 0.000 description 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 1
- JQOYPOSGHDJFLI-AVNCTIOFSA-N Uvaricin Chemical compound O1[C@@H]([C@@H](OC(C)=O)CCCCCCCCCC)CC[C@@H]1[C@@H]1O[C@@H]([C@H](O)CCCCCCCCCCCCC=2C(O[C@@H](C)C=2)=O)CC1 JQOYPOSGHDJFLI-AVNCTIOFSA-N 0.000 description 1
- JQOYPOSGHDJFLI-UHFFFAOYSA-N Uvaricin Natural products O1C(C(OC(C)=O)CCCCCCCCCC)CCC1C1OC(C(O)CCCCCCCCCCCCC=2C(OC(C)C=2)=O)CC1 JQOYPOSGHDJFLI-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 238000005377 adsorption chromatography Methods 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000003542 behavioural effect Effects 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000011203 carbon fibre reinforced carbon Chemical group 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000002481 ethanol extraction Methods 0.000 description 1
- GCFHZZWXZLABBL-UHFFFAOYSA-N ethanol;hexane Chemical compound CCO.CCCCCC GCFHZZWXZLABBL-UHFFFAOYSA-N 0.000 description 1
- 238000010812 external standard method Methods 0.000 description 1
- 125000000457 gamma-lactone group Chemical group 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000010813 internal standard method Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 238000004811 liquid chromatography Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 210000003470 mitochondria Anatomy 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 230000035806 respiratory chain Effects 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
Images
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to an anticancer annonaceae lactone effective part drug and a preparation method thereof. Annonaceae seeds are used as raw materials, and firstly, organic solvents are used for extracting and preparing annonaceae total lactone which is eluted and refined by petroleum ether-acetone after silica gel column chromatography is carried out to prepare anticancer drugs of which the mass percentage of the total content of Arnonin-1 and Arnonin-2 is from 50% to 70%; fat milk is used as a preparation form. Because of the enrichment of high-activity annonaceae lactone components, the anticancer drug of the present invention has the advantages of strong activity, simple composition and easy quality control; simultaneously, the preparation method has the advantages of simplicity, easy implementation, low production cost and strong practicability, and successfully solves the problem of preparation.
Description
The present invention relates to from anticancer effective site medicine of a kind of annonaceous acetogenins (AnnonaCeous acetogenins) of Sirikaya (Annona squamosa L.) seed preparation and preparation method thereof.
Annonaceousacetogenicompounds material (Annonaceous acetogenins) is a class natural product that is derived by the long-chain fatty acid gamma lactone.The construction features of this class material is: the α that the monomethyl replacement is arranged at an end of a long aliphatic chain, β-unsaturated gamma lactone ring, 1～3 oxolane ring and some other oxygen-containing substituents are arranged on aliphatic chain, as hydroxyl, acetoxyl group, ketone group, epoxy radicals, and carbon-carbon double bond etc.This class natural product exists only in the plant of some genus of annonaceae (Annonaceae).
The Annonaceousacetogenicompounds material has multiple biological activity, and wherein most important biological activity is extremely strong cell in vitro poison and anti-tumor in vivo effect.Its mechanism of action is by NADH oxidoreductase in the anticancer mitochondrion optionally, stop the transmission of respiratory chain electronics, make ADP can not change into ATP, thereby cut off the energy supply that cancerous cell is depended on for existence and bred, and then inducing cancer cell moves towards apoptosis (Apoptosis); Simultaneously, the Annonaceousacetogenicompounds material can also overcome the multidrug resistance (MDR) of cancerous cell.Therefore, the Annonaceousacetogenicompounds material becomes hot research in recent years.Since reporting first annonaceous acetogenins Uvaricin in nineteen eighty-two, about 300 these compounds have been found so far.
External work is mainly aspect monomeric compound, but still rest on separation, structure, the synthetic research that reaches aspects such as biological activity so far, still very remote apart from practical application, reason has: first, in about 300 chemical compounds of having found, real in vivo effectively high-activity compound is also few; The second, owing to numerous isomer, homologue coexist as in the same plant, nearly more than 30 homologue in some plant, and the physicochemical property of each homologue and isomer is very similar, and therefore, the separation of monomeric compound, purification be difficulty very; The 3rd, the content of individualized compound in plant is relatively low, and plant resources is limited; The 4th, have a plurality of chiral centres in the molecule of Annonaceousacetogenicompounds material, also be difficult to obtain the specific monomer thing by chemosynthesis; The 5th, the toxicity of sugar apple lactone monomeric compound is higher, and therapeutic index is lower.
The domestic people of having proposes with sirikaya total lactones as medicine material, but so total lactone component complexity, be difficult to set up the quality standard and the quality control method of medicine, thereby can't guarantee the quality and the curative effect of medicine, be difficult to reach new drug due " effective's, safe, controlled " target.Therefore, sirikaya total lactones also will be difficult to enter practical application.And also there are some problems in existing known sirikaya total lactones preparation method, for example the CN1224016A disclosed method is to be raw material with the Sirikaya seed, at first with hexane or defat with petroleum ether, use alcohol extraction, chloroform extraction and hexane-ethanol allocation process then, obtain total lactone through the silica gel adsorption chromatography more at last.There is following shortcoming in this method: (1) at first the amount of organic solvent such as used hexane of defat or petroleum ether is very big, and solvent loss is big, and the processing time is long, causes cost to increase; (2) owing to hexane, petroleum ether equal solvent energy stripping part effective ingredient, therefore at first the defat meeting makes the part loss of effective components.
In addition, the Annonaceousacetogenicompounds material has extremely strong fat-soluble, and preparation also is a difficult point.
The object of the invention is to solve following problems: (1) does not still have the actual application value problem with single annonaceous acetogenins as medicine material; (2) with sirikaya total lactones during as medicine material, component is too complicated, can't guarantee the quality of medicine, i.e. the quality controllability problem; (3) problem that exists in the sirikaya total lactones preparation method; (4) formulation problems.To develop a kind of is the anticancer effective site medicine with practical value of effective ingredient with the annonaceous acetogenins.
The present invention is raw material with the Sirikaya seed, Sirikaya (Annona squamosay L.) is a kind of medicinal plants that originates in China's southern area, and its fruit is famous fruit, aboundresources, is easy to get, its seed contains a large amount of annonaceous acetogenins, wherein is no lack of active very strong composition.The present invention earlier prepares sirikaya total lactones by Sirikaya seed, then with total lactone through refinement treatment, purpose is to remove the lactone composition of the not high or non-activity of a large amount of activity, only keeps high activity lactone composition and becomes an efficient position medicine.This efficient position is enrichment high activity lactone composition only owing to removed a large amount of useless lactone compositions, thereby not only activity is stronger, and forms simply, is easy to carry out quality control; Simultaneously, its preparation method simple, easily implement, production cost is low; The present invention has done improvement to the sirikaya total lactones preparation method in addition, at first use alcohol extraction, ethanol extraction is with organic solvent defat with petroleum ether for example, and goes out for example effective ingredient in the petroleum ether of organic solvent with alcohol extraction, reduce solvent load, improved the effective ingredient yield; The present invention as its dosage form, has successfully solved formulation problems with fat milk in addition.Therefore the present invention has extremely strong practicality.
Anticancer lichee lectone medicine of the present invention is by following two materials that operation makes: the sirikaya total lactones preparation section is at first arranged, and is the feedstock production sirikaya total lactones with the Sirikaya seed; It is characterized in that refining step in addition, sirikaya total lactones prepared in the preceding step operation through silica gel column chromatography, the silica gel granularity of filling in the described silicagel column is 80～300 orders, best 100～200 orders, with the mass ratio of described sirikaya total lactones be 15: 1～50: 1, be preferably 30: 1, it behind the chromatography is petroleum ether-acetone eluting of 3: 1～3: 2 with volume ratio, check with thin layer chromatography, when flowing out, peaceful-6 (the Annonin VI) of Arnold begin to be collected into till whole outflow of peaceful-1 (the Annonin I) of Arnold, the consumption of eluant petroleum ether acetone just decides thus, the described fraction of collecting is concentrated, drying promptly gets anticancer lichee lectone medicine of the present invention.
Described sirikaya total lactones preparation section can adopt existing various known method, for example method of CN1224016A.But in order to improve the effective ingredient yield and to reduce solvent load, the present invention has done improvement to this operation.The preparation section of sirikaya total lactones of the present invention is: the Sirikaya seed coarse powder is extracted with 80%～97% soak with ethanol, consumption of ethanol, soak time and number of times choose at random, ethanol extract concentrates back organic solvent extracting extracting degreasing, use chloroform extraction then, chloroform extract is through silica gel column chromatography, the silica gel granularity of filling in the described silicagel column is 80～300 orders, best 100～200 orders, with the mass ratio of chloroform extract be 5: 1～20: 1, be preferably 10: 1, it behind the chromatography is 100: 0～90: 10 chloroform-methanol eluting with volume ratio, use the thin layer chromatography inspection, when the Annonaceousacetogenicompounds material flows out in a large number, begin to collect, when not having the Annonaceousacetogenicompounds material and flow out till, the described fraction of collecting is concentrated, drying obtains sirikaya total lactones.
Above-mentioned each time used solvent load and extraction times of extraction all can choose at random.Degreasing process can use known organic solvent for example petroleum ether, hexane etc.For example boiling off before the petroleum ether extraction defat at described organic solvent and preferably to add water in the alcoholic acid extract earlier; Organic solvent after the defat for example the most handy volume fraction of petroleum ether layer is 60%～97% alcohol extraction, and in the aqueous solution alcohol extraction liquid is incorporated defat into after concentrating after, concrete preparation technology's flow process sees accompanying drawing 1 for details.
Described thin layer chromatography inspection is a control anticancer lichee lectone medicine method for quality of the present invention, can adopt common thin layer chromatography board, for making things convenient for the present invention to adopt self-control silica gel H hardboard (CMC is a binding agent), with volume ratio be petroleum ether-acetone of 3: 1 as developing solvent, can select a kind of colour developing the in following three kinds of developers for use:
(1) Kedde reagent is 3, and the 5-dinitrobenzoic acid: speckle takes on a red color, and mottle disappears very soon and takes off;
(2) Dragendorff reagent is Dragendorff's reagent: be orange-yellow speckle, color is lasting;
(3) iodine steam: be the brown speckle, color is lasting.
The result: sirikaya total lactones effective site medicine of the present invention all shows two speckles to three kinds of developers after pressing above-mentioned condition expansion on the TLC, and mapping is in reference substance Arnold peaceful-1 and Arnold peaceful-6 respectively.
The content of two main components in the high effective liquid chromatography for measuring anticancer lichee lectone medicine of the present invention: usefulness ODS post (6mm * 15cm), methanol-water (volume ratio 9: 1) is a mobile phase, flow velocity 1mL/min, use Ultraviolet Detector, detect wavelength 210nm, naphthalene is interior mark, and by the content of peak area integrated value by internal standard method or external standard method Arnold peaceful-1 and Arnold peaceful-6, the regression equation of the two is as follows:
Peaceful-1 (Annonin I): the y=5065.05x-6902.7r=0.9998 of Arnold;
Peaceful-6 (Annonin VI): the y=4975.92x-4179.8r=0.9998 of Arnold.
The result: Arnold peaceful-1 content is mass fraction 42%～55%, and representative value is 52.3%, and Arnold peaceful-6 content is mass fraction 8%～15%, and typical content is 10.5%, and the content sum of the two is a mass fraction 50%～70%, and representative value is 63.1%.
Anticancer lichee lectone medicine of the present invention can be made into Emulsion, its formula proportion and manufacture method are as follows: in every 1000mg anticancer lichee lectone medicine of the present invention, add 50～200g soybean oil (optimum dose is 100g) and 10～20g (optimum dose is 12g) lecithin, heating mixes, dissolving, adding injection water to cumulative volume after treating all to dissolve is 500～1500mL, best 1000mL, behind emulsifying, filter, embedding, sterilization, Emulsion of the present invention, described emulsifying can adopt general emulsification method, and for example available multistage ultrasonic emulsification is handled.
Anticancer lichee lectone medicine of the present invention carries out following pharmacology test.
(1) acute toxicity test
Acute toxicity test in mice calculates LD with the Bliss method
50, the result is as follows:
Lumbar injection ip * 1 time LD
50=1.124 (1.017～1.242) mg/kg;
Irritate stomach po * 1 LD
50=74.754 (58.662～95.260) mg/kg.
(2) cell in vitro poison test
Anticancer lichee lectone medicine body of the present invention is external to have carried out cellulotoxic experiment to pulmonary carcinoma (A-549), nasopharyngeal carcinoma (CNE2, SUNE1), hepatocarcinoma (BEL-7402), HT-29 (colon cancer), breast carcinoma (MCF-7) and adenocarcinoma of lung 7 kinds of human cancer cells such as (GLC-82), with Taxol as positive control medicine, result such as table 1.Show that effective site medicine of the present invention all has cytotoxicity to 7 kinds of cell strains of test, wherein the strongest to the effect of three kinds of cell strains such as A-549, CNE2, BEL-7402, effect is better than taxol or suitable with taxol.
Cell in vitro toxic action (the IC of table 1 pair various human cancer cells
50Half-inhibition concentration)
| Cell strain | Medicine IC of the present invention 50(μg/mL) | Control drug Taxol IC 50(μg/mL) |
| HT-29 CNE2 SUNE1 BEL-7402 A-549 MCF-7 GLC-82 | 0.446 4.369×10 -2 1.617 3.873×10 -2 4.413×10 -3 1.857 3.491 | 0.295 4.444×10 -3 0.2209×10 -2 9.846×10 -2 1.373×10 -2 6.058×10 -3 2.091 |
(3) to the anti-tumor effect of mice transplanted tumor
Adopt lumbar injection (ip) and irritate two kinds of route of administration of stomach (po), ip also increases reticulosarcoma (L with rat liver cancer HepS and two kinds of animal transplanting tumors of murine sarcoma S-180, po
2) carry out inhibition test in the body.Anticancer lichee lectone medicine of the present invention is established 3～4 dosage groups, matched group is not for containing the fat milk of medicine, and the positive drug matched group is cyclophosphamide (CTX) when the ip administration, is fluorouracil (5-Fu) when the po administration, each organized successive administration 10 days, and each test repeats 3～4 batches.Result's (seeing Table 2～table 6) shows: when the ip dosage is 0.03～0.09mg/ (kg.d), tumour inhibiting rate still can show certain inhibitory action near the tumour inhibiting rate of chemotherapeutics CTX 18mg/kg dosage group when dosage is low to moderate 0.01mg/ (kg.d) * 10 day; Adopt and irritate stomach through medicine, also demonstrate extremely strong anti-tumor in vivo effect, but compare with intraperitoneal injection, the dosage of gastric infusion is bigger, illustrates that the absorbability of gastric infusion approach medicine is relatively poor.Batch have 10% the mice with tumor death except that high dose (0.09mg/ (kg.d)) group has part in the experiment, the mice with tumor behavioral activity of other effective dose groups is normal, do not see obviously become thin, toxicity performances such as Folium Pini, diarrhoea.
Table 2 intraperitoneal injection is to the inhibitory action of mouse bearing liver cancer HepS
| Group | Dosage administration time mg/ (kgd) d | Average tumour inhibiting rate (x ± s)/% | The P value |
| Cyclophosphamide group CTX medicine of the present invention: dosage group 2 high dose group in the dosage group 1 in the dosage group | 18 10 0.01 10 0.03 10 0.06 10 0.09 10 | 65.80±0.90 30.93±0.73 44.97±5.17 58.26±3.39 66.68±5.46 | ＜0.01 ＜0.01 ＜0.01 ＜0.01 ＜0.01 |
Table 3 intraperitoneal injection is to the inhibitory action of murine sarcoma S-180
| Group | Dosage administration time mg/ (kgd) d | Average tumour inhibiting rate (x ± s)/% | The P value |
| Cyclophosphamide group CTX medicine of the present invention: dosage group high dose group in the low dose group | 18 10 0.01 10 0.03 10 0.09 10 | 56.11±2.59 30.93±0.73 38.43±2.35 50.70±4.08 | ＜0.01 ＜0.01 ＜0.01 ＜0.01 |
Table 4 gastric infusion is to the inhibitory action of mouse bearing liver cancer HepS
| Group | Dosage administration time mg/ (kgd) d | Average tumour inhibiting rate (x ± s)/% | The P value |
| Fluorouracil 5-Fu medicine of the present invention: dosage group high dose group in the low dose group | 30 10 4 10 8 10 16 10 | 63.30±8.63 36.61±3.87 46.42±11.39 57.53±11.55 | ＜0.01 ＜0.01 ＜0.01 ＜0.01 |
Table 5 gastric infusion is to the inhibitory action of murine sarcoma S-180
| Group | Dosage administration time mg/ (kgd) d | Average tumour inhibiting rate (x ± s)/% | The P value |
| Fluorouracil 5-Fu medicine of the present invention: dosage group high dose group in the low dose group | 30 10 4 10 8 10 16 10 | 65.36±15.47 35.97±14.72 47.46±9.83 52.57±11.66 | ＜0.01 ＜0.01 ＜0.01 ＜0.01 |
Table 6 gastric infusion is to mice reticulosarcoma L
2Inhibitory action
| Group | Dosage administration time mg (kgd) d | Average tumour inhibiting rate (x ± s)/% | The P value |
| Fluorouracil 5-Fu medicine of the present invention: dosage group high dose group in the low dose group | 30 10 4 10 8 10 16 10 | 60.33±0.7 37.64±0.01 46.76±2.15 60.75±1.65 | ＜0.01 ＜0.01 ＜0.01 ＜0.01 |
Reach following technique effect through above-mentioned pharmacology test explanation the present invention:
(1) antitumor action is strong and since the present invention be with sirikaya total lactones through further refinement treatment, get rid of the lactone composition of a large amount of active lower or non-activities, only enrichment the high activity composition, thereby its effect is higher;
(2) component is simple, clear and definite, is easy to carry out quality control;
(3) simple, the easily enforcement of preparation method, cost is low;
(4) use fat milk as its pharmaceutical dosage form, successfully solved formulation problems.
Accompanying drawing 1 is anticancer lichee lectone medicine preparation technology flow chart of the present invention.
Anticancer lichee lectone medicine embodiment of the present invention is as follows:
Embodiment 1
The extraction of total lactone: get 1 kilogram of Sirikaya seed, pulverize, seed meal is extracted three times with 95% soak with ethanol, each 24 hours, adds alcoholic acid amount and is: the first time 1500mL, second, third time 1000mL.Merge three times extracting solution, be evaporated to 150mL, add water 150mL, add petroleum ether extraction behind the mixing three times, each 150mL merges, add 80% alcohol extraction three times in petroleum ether extraction liquid, each 100mL merges the rare pure liquid behind 80% ethanol liquid and the petroleum ether extraction, remove ethanol under reduced pressure, add water to 200mL, chloroform extraction three times of this aqueous solution, each 100mL, be concentrated into dried brown syrup thing (30.0g) after chloroform extraction liquid merges, be total lactone extract.
The separation of total lactone: with silica gel G (300g on the above-mentioned total lactone extract that obtains, 100～200 orders, Haiyang Chemical Plant, Qingdao) post, use the chloroform-methanol gradient elution, every part receives 200mL, the pure chloroform eluting of initial usefulness, and flow point is 1～13 part, being changed to chloroform-methanol (98: 2) then, is 14～21 parts; Change (97: 3) again, 22～26 parts; Use (90: 10) eluting at last, 27～36 parts.Check with TLC, the 19th～29 part of merging is concentrated, dry, get total lactone (15.15g).
Total lactone refining: get total lactone 10g of above-mentioned preparation, go up silica gel G (300g, 100～2000 orders, Haiyang Chemical Plant, Qingdao) post again, usefulness petroleum ether-acetone is in following ratio eluting: 3: 1, and 6000mL; 7: 3,2000mL; 65: 35,1500mL; 1: 1,1000mL; Receive with every part of 100mL.Check with TLC, till when Arnold peaceful-6 is flowed out, beginning to collect when Arnold peaceful 1 is all flowed out (the 43rd～93 part), with this part flow point merging, concentrated, dry, obtain the little yellow waxy solid of 6.6g, be anticancer lichee lectone medicine thing (lot number: 981225).The content of its main component sees Table 7.
Embodiment 2
Press embodiment 1 and extract total lactone, obtain the 29.7g total lactone extract from 1 kilogram of raw material, the separation of total lactone is also undertaken by embodiment 1, altogether the total lactone of 15.23g.Get total lactone 10g, last silica gel G (300g, 100～200 orders, Haiyang Chemical Plant, Qingdao) post, use petroleum ether-acetone successively in following ratio eluting: 3: 1,9500mL; 7: 3,1500mL; Receive with every part of 100mL.Check with TLC, when Arnold peaceful-6 is flowed out, begin to collect when Arnold peaceful-1 is all flowed out till (the 35th～102 part), with this part flow point merge, concentrate, dry, obtain 6.2g anticancer lichee lectone medicine thing (lot number: 990108).The content of its main component sees Table 7.
Embodiment 3
Extract and separate total lactone by embodiment 1, from the 1.05kg raw material the 32.5g total lactone extract, this extract through separate the total lactone of 15.07g.Get the total lactone of 10g, last silica gel G (300g, 100～200 orders, Haiyang Chemical Plant, Qingdao) post, use petroleum ether-acetone successively in following ratio eluting: 3: 1,5000mL:65: 35,3500mL; Receive with every part of 100mL.Check with TLC, when Arnold peaceful-6 is flowed out, begin to collect when Arnold peaceful-1 is all flowed out till (the 41st～76 part), with this part flow point merge, concentrate, dry, obtain 6.13g anticancer lichee lectone medicine thing (lot number: 990120).The content of its main component sees Table 7.
The content of main component in the table 7 different batches annonaceous acetogenins effective site medicine
Embodiment 4
| The sample lot number | Content (mass fraction)/% | ||
| Arnold peaceful-1 | Arnold peaceful-6 | Arnold is peaceful-1+ Arnold peaceful-6 | |
| 981225 990108 990120 | 52.06 51.42 53.55 | 10.88 11.66 9.85 | 62.94 63.10 63.40 |
The preparation of Emulsion: get anticancer lichee lectone medicine 1000mg of the present invention, add injection soybean oil 100g, add 12g lecithin again, heating is dissolved in the soybean oil all solids thing in 90 ℃ water-bath, add the injection water to 1000mL, after multistage ultrasonic emulsification is handled, filtration, embedding, sterilization, annonaceous acetogenins effective site medicine Emulsion.
Embodiment 5
The test of cell in vitro poison: used human cancer cell strain has: 7 kinds of pulmonary carcinoma (A-549), nasopharyngeal carcinoma (CNE2, SUNE1), hepatocarcinoma (BEL-7402), HT-29 (colon cancer), breast carcinoma (MCF-7) and adenocarcinomas of lung (GLC-82) etc.Adopt tetrazolium bromide reducing process (mtt assay), if negative control group, solvent control group, positive controls and variable concentrations drug dose group of the present invention, medicine of the present invention is with the 10%DMSO dissolving and be diluted to variable concentrations, and solvent control is 10%DMSO, and the positive control medicine is paclitaxel (Taxol).Result such as table 1.
Embodiment 6
Effect to mice transplanted tumor: test by health " antitumor drug pharmacodynamics test guideline " promulgated by the ministries or commissions of the Central Government.With cleaning level kunming mice, transplanted tumor is mice hepatoma HepS, murine sarcoma S-180 and reticulosarcoma L2, and lumbar injection (ip) and two kinds of administering modes of filling stomach (po) are established negative control group, positive drug matched group and medicine group of the present invention.The positive control medicine is cyclophosphamide (CTX) when intraperitoneal injection, is fluorouracil (5-Fu) when gastric infusion; Medicine of the present invention is established 3～4 dosage groups with the Emulsion of 1.0mg/mL, and every group of test repeats three batches, calculates average tumour inhibiting rate.The results are shown in Table 2～6.
Embodiment 7
Acute toxicity test: carry out acute toxicity test in mice by former Ministry of Public Health bureau of drug administration " new drug toxicology guideline ", press the Bliss method measure anticancer lichee lectone medicine Emulsion lumbar injection of the present invention (ip) once with irritate stomach (po) LD once
50
Claims (11)
1, a kind of anticancer lichee lectone medicine is that the mass fraction sum that contains Arnold peaceful-1 and Arnold peaceful-6 is 50%～70% and by following two materials that operation makes: the sirikaya total lactones preparation section is at first arranged, and is the feedstock production sirikaya total lactones with the Sirikaya seed; It is characterized in that refining step in addition, sirikaya total lactones prepared in the preceding step operation through silica gel column chromatography, the silica gel granularity of filling in the described silicagel column is 80～300 orders, with the mass ratio of described sirikaya total lactones be 15: 1～50: 1, it behind the chromatography is petroleum ether-acetone eluting of 3: 1～3: 2 with volume ratio, use the thin layer chromatography inspection, when Arnold peaceful-6 is flowed out, begin to be collected into when Arnold peaceful-1 is all flowed out and end, with the described fraction of collecting concentrate, dry.
2, anticancer lichee lectone medicine according to claim 1, it is characterized in that described sirikaya total lactones preparation section is as follows: the Sirikaya seed coarse powder is extracted with 80%～97% soak with ethanol, ethanol extract concentrates back organic solvent extracting extracting degreasing, use chloroform extraction then, chloroform extract is through silica gel column chromatography, the silica gel granularity of filling in the described silicagel column is 80～300 orders, with the mass ratio of chloroform extract be 5: 1～20: 1, it behind the chromatography is 100: 0～90: 10 chloroform-methanol eluting with volume ratio, check with thin layer chromatography, when flowing out in a large number, the Annonaceousacetogenicompounds material begins to collect, till when not having the Annonaceousacetogenicompounds material and flow out, the described fraction of collecting is concentrated, dry.
3, anticancer lichee lectone medicine according to claim 1, it is characterized in that described sirikaya total lactones preparation section is as follows: the Sirikaya seed coarse powder is extracted with the soak with ethanol of volume fraction 80%～97%, after ethanol extract concentrates, add water, use the organic solvent extracting extracting degreasing, the organic solvent layer alcohol extraction of volume fraction 60%～97%, rare pure liquid behind ethanol liquid and the organic solvent extraction merges, steam and remove ethanol, the aqueous solution chloroform extraction, chloroform extract is through silica gel column chromatography, the silica gel granularity of filling in the described silicagel column is 80～300 orders, with the mass ratio of chloroform extract be 5: 1～20: 1, behind the chromatography be 100: 0～90: 10 chloroform-methanol eluting, use the thin layer chromatography inspection, when the Annonaceousacetogenicompounds material flows out in a large number, begin to collect with volume ratio, till when not having the Annonaceousacetogenicompounds material and flow out, the described fraction of collecting is concentrated, dry.
4, anticancer lichee lectone medicine according to claim 1, it is characterized in that described silica gel granularity is 100～200 orders, with the mass ratio of sirikaya total lactones be 30: 1, described Arnold peaceful 1 content is mass fraction 42%～55%, described Arnold peaceful-6 content is mass fraction 8%～15%, and described Arnold peaceful-1 is a mass fraction 50%～70% with peaceful-6 content sums of Arnold.
5, according to claims 4 described anticancer lichee lectone medicines, it is characterized in that peaceful-1 content of described Arnold is mass fraction 52.3%, peaceful-6 content of described Arnold are mass fraction 10.5%, and described Arnold peaceful-6 is a mass fraction 63.1% with Arnold peaceful 1 content sum.
6, a kind of preparation method of anticancer lichee lectone medicine has following two operations: the sirikaya total lactones preparation section is at first arranged, and is the feedstock production sirikaya total lactones with the Sirikaya seed; It is characterized in that refining step in addition, sirikaya total lactones prepared in the preceding step operation through silica gel column chromatography, the silica gel granularity of filling in the described silicagel column is 80～300 orders, with the mass ratio of described sirikaya total lactones be 15: 1～50: 1, it behind the chromatography is petroleum ether-acetone eluting of 3: 1～3: 2 with volume ratio, use the thin layer chromatography inspection, when Arnold rather-6 outflows, begin to be collected into till Arnold's peaceful-1 whole outflow, the described fraction of collection is concentrated, dry.
7, according to the preparation method of claim 6 with described anticancer lichee lectone medicine, it is characterized in that described sirikaya total lactones preparation section is as follows: the Sirikaya seed coarse powder is extracted with the soak with ethanol of volume fraction 80%～97%, ethanol extract concentrates back organic solvent extracting extracting degreasing, use chloroform extraction then, chloroform extract is through silica gel column chromatography, the silica gel granularity of filling in the described silicagel column is 80～300 orders, with the mass ratio of chloroform extract be 5: 1～20: 1, it behind the chromatography is 100: 0～90: 10 chloroform-methanol eluting with volume ratio, check with thin layer chromatography, when flowing out in a large number, the Annonaceousacetogenicompounds material begins to collect, till when not having the Annonaceousacetogenicompounds material and flow out, the described fraction of collecting is concentrated, dry.
8, the preparation method of anticancer lichee lectone medicine according to claim 6, it is characterized in that described sirikaya total lactones preparation section is as follows: the Sirikaya seed coarse powder is extracted with the soak with ethanol of volume fraction 80%～97%, after ethanol extract concentrates, add water, use the organic solvent extracting extracting degreasing, the organic solvent layer alcohol extraction of volume fraction 60%～97%, rare pure liquid behind ethanol liquid and the organic solvent extraction merges, steam and remove ethanol, the aqueous solution chloroform extraction, chloroform extract is through silica gel column chromatography, the silica gel granularity of filling in the described silicagel column is 80～300 orders, with the mass ratio of chloroform extract be 5: 1～20: 1, behind the chromatography be 100: 0～90: 10 chloroform-methanol eluting, use the thin layer chromatography inspection, when the Annonaceousacetogenicompounds material flows out in a large number, begin to collect with volume ratio, till when not having the Annonaceousacetogenicompounds material and flow out, the described fraction of collecting is concentrated, dry.
9, the preparation method of anticancer lichee lectone medicine according to claim 6, it is characterized in that described silica gel granularity is 100～200 orders, with the mass ratio of described sirikaya total lactones be 30: 1, described thin layer chromatography inspection silica gel H hardboard, with petroleum ether-acetone of 3: 1 of volume ratio is developing solvent, develops the color with Dragendorff's reagent.
10, a kind of preparation method of anticancer lichee lectone medicine Emulsion, it is characterized in that described anticancer lichee lectone medicine Emulsion proportioning is as follows: add 50～200g soybean oil and 10～20g lecithin in the described anticancer lichee lectone medicine of one of every 1000mg claim 1～5, heating according to the above ratio is mixed to that to add injection water to cumulative volume after the substance dissolves be 500～1500mL, through the emulsifying after-filtration, embedding, sterilization.
11, the preparation method of anticancer lichee lectone medicine Emulsion according to claim 10 is characterized in that described soybean oil is 100g, and described lecithin is 12g, and described cumulative volume is 1000mL.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011075945A CN1141093C (en) | 2001-02-27 | 2001-02-27 | Anticancer lichee lectone medicine and its prepn |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB011075945A CN1141093C (en) | 2001-02-27 | 2001-02-27 | Anticancer lichee lectone medicine and its prepn |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1370530A CN1370530A (en) | 2002-09-25 |
| CN1141093C true CN1141093C (en) | 2004-03-10 |
Family
ID=4656511
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB011075945A Expired - Lifetime CN1141093C (en) | 2001-02-27 | 2001-02-27 | Anticancer lichee lectone medicine and its prepn |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1141093C (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101375936B (en) * | 2007-08-29 | 2012-02-29 | 北京星昊医药股份有限公司 | Anti-tumor compound cherimoya formulation and preparation method thereof |
| CN101575324B (en) * | 2009-05-15 | 2011-05-25 | 贵州正鑫药业有限公司 | Preparation method for extracting anticancer valid-position medicine SHIKEMOXIN from sweetsop |
| CN109528785A (en) * | 2019-01-31 | 2019-03-29 | 中国医学科学院药用植物研究所 | The pharmaceutical composition and its application of a kind of pair of drug-resistant tumor selective killing or the horizontal Efficient killing effect of nM |
| CN110526883A (en) * | 2019-07-22 | 2019-12-03 | 苏州农业职业技术学院 | A method of it is pungent to extract bubble manaca from sugar apple seed |
-
2001
- 2001-02-27 CN CNB011075945A patent/CN1141093C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CN1370530A (en) | 2002-09-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101904968B (en) | Preparation method of Chinese paris rhizome yam type saponin and anti-tumor medicinal preparation thereof | |
| CN102652792A (en) | Anti-cancer application of composition containing garlic oil, garlic total polysaccharide and garlic total saponin | |
| Hajimehdipoor et al. | The cytotoxic effects of Ferula persica var. persica and Ferula hezarlalehzarica against HepG2, A549, HT29, MCF7 and MDBK cell lines | |
| CN105017345B (en) | The method of four kinds of compounds of extraction and the application simultaneously from selfheal | |
| CN101979366A (en) | Diarylheptanoid compounds in curcuma zedoary and medicinal application thereof | |
| CN101485700B (en) | Refined cherimoya total inner ester with anti-tumor activity and preparation method thereof | |
| CN1141093C (en) | Anticancer lichee lectone medicine and its prepn | |
| CN1247855A (en) | Preparation and application of tanshinpolyphenolic salt | |
| CN102827001A (en) | Ilex kudingcha C.J.Tseng extract | |
| CN102908340B (en) | Isolicoflavonol-containing antitumor drug and application thereof | |
| Hajimehdipoor et al. | The Cytotoxic Effects of Ferula Persica var. Persica and Ferula Hezarlalehzarica against HepG2, A549, HT29, MCF7 and MDBK Cell Lines: Cytotoxicity of Ferula species | |
| CN102805829B (en) | Preparation method of rhizoma smilacis glabrae extract and applications thereof in tumor treatment | |
| Altinyay et al. | Quantification of shikimic acid in the methanolic extracts of three alnus taxons growing in Turkey | |
| CN103833823A (en) | Diterpene dimer compounds and pharmaceutical compositions and preparation method and application thereof | |
| CN101721434B (en) | Active ingredients of fomes officinalis, preparation method thereof and use thereof | |
| CN1165545C (en) | Method for separating and extracting total flavone from goldenrain tree plant and its application | |
| CN102961440A (en) | Pharmaceutical composition containing cyclooxygenase and natural doxorubicin or doxorubicin-like substances, its preparation method and application in preparation of multiple drugs | |
| CN104374890B (en) | A kind of Ilex kudincha C. J. Tseng extract | |
| CN106008641A (en) | Withania somnifera lactide compound, method for extracting same and application of withania somnifera lactide compound | |
| CN104546952A (en) | Active component of selaginella doederleinii hieron as well as preparation method and use thereof | |
| CN111978309B (en) | Tripterygium wilfordii source compound, application and preparation method thereof, pharmaceutical composition and pesticide | |
| CN105796548B (en) | Flavonoid pharmaceutical composition, preparation method and application | |
| CN102114065B (en) | Longhairy antenoron herb and common threewingnut root Chinese medicinal composition with effect of preventing and treating cancer and application thereof | |
| CN1068782C (en) | Anti-cancer medicine with extracts from goldenrain and the preparation thereof | |
| CN104288169B (en) | A kind of flavonoid glycoside compound and its production and use |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| 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 | ||
| C56 | Change in the name or address of the patentee |
Owner name: GUILIN SANJIN PHARMACEUTICAL CO., LTD. Free format text: FORMER NAME OR ADDRESS: SOUTH CHINA BOTANICAL GARDEN CHINESE ACADEMY OF SCIENCES Owner name: SOUTH CHINA BOTANICAL GARDEN CHINESE ACADEMY OF SC Free format text: FORMER NAME OR ADDRESS: SOUTH-CHINA INST. OF BOTANY, CHINESE ACADEMY OF SCIENCES |
|
| CP03 | Change of name, title or address |
Address after: No. 1, Jinxing Road, Guilin, the Guangxi Zhuang Autonomous Region: 541004 Patentee after: GUILIN SANJIN PHARMACEUTICAL Co.,Ltd. Address before: Guangdong city of Guangzhou province Shahe Chang ban happy home zip code: 510650 Patentee before: South China Botanical Garden, Chinese Academy of Sciences Address after: Guangdong city of Guangzhou province Shahe Chang ban happy home zip code: 510650 Patentee after: SOUTH CHINA BOTANICAL GARDEN, CHINESE ACADEMY OF SCIENCES Address before: Guangdong city of Guangzhou province Shahe Chang ban happy home zip code: 510650 Patentee before: SOUTH CHINA INST OF BOTANY CHI |
|
| CX01 | Expiry of patent term |
Granted publication date: 20040310 |
|
| CX01 | Expiry of patent term | ||
| DD01 | Delivery of document by public notice |
Addressee: Xiong Qiling Document name: Notice of termination of patent right |
|
| DD01 | Delivery of document by public notice |