CN102070573B - Mono-tetrahydrofuran type sugar apple lactone compound with anti-tumor activity and application thereof - Google Patents
Mono-tetrahydrofuran type sugar apple lactone compound with anti-tumor activity and application thereof Download PDFInfo
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- CN102070573B CN102070573B CN2011100470893A CN201110047089A CN102070573B CN 102070573 B CN102070573 B CN 102070573B CN 2011100470893 A CN2011100470893 A CN 2011100470893A CN 201110047089 A CN201110047089 A CN 201110047089A CN 102070573 B CN102070573 B CN 102070573B
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- nuoshikemomin
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Abstract
The invention discloses a new mono-tetrahydrofuran type sugar apple lactone compound with anti-tumor activity, through systematic in-depth research of chemical ingredients of sugar apple seeds, the analysis of wave spectrum and mass spectrum data shows that the new mono-tetrahydrofuran type sugar apple lactone compound (Anno Shikemominbing) can be separated from the sugar apple seeds, in vivo and in vitro anti-tumor activity researches show that mono-tetrahydrofuran type sugar apple lactone provided by the invention has very strong anti-tumor activity for a variety of tumor cells, including lung cancer, breast cancer, liver cancer, cervical cancer and gastric cancer, and the toxicity test research shows that the mono-tetrahydrofuran type sugar apple lactone compound with the anti-tumor activity provided by the invention is expected to be developed into new anti-tumor medicaments.
Description
Technical field
The present invention relates to have the compound of anti-tumor activity, be specifically related to a kind of new single THF type annonaceous acetogenins and purposes in prevention and treatment tumor disease thereof, belong to medical technical field with anti-tumor activity.
Background technology
Malignant tumour is the frequently-occurring disease and the common disease of serious harm human health and life, the Egyptian and existing record about tumour of China before 2000～3000 years.The a lot of countries, the especially medium-developed country that comprise China, caused by malignant tumors death accounts for first place or second in all causes of death; And sickness rate is worldwide still in rising trend, and in the art treatment of tumour, radiotherapy, chemotherapy, biotherapy four big therapies, chemotherapy is still main treat-ment; But well-known, existing chemotherapy medicine antitumor activity is limited, and toxic side effect is bigger; Patient's tolerance is poor, and costs an arm and a leg.Therefore, generation and development through the chemical cancer-resisting substance preventing cancer in the research natural phant have become a key areas of cancer chemoprophylaxis research, and receive the common concern and the research focus of countries in the world scientific circles.
Annona lactone is one type of natural compounds that extraction separation obtains from the annonaceae plant; Annonaceousacetogenicompounds compounds has wide biological activity, and most typical is that desinsection and antitumor cell are active, and research shows that Annona lactone has powerful cytotoxicity in vivo and in vitro; And kinds of tumor cells all shown biological activity preferably; Research shows that the mechanism of action of Annona lactone anti-tumor activity is through blocking-up DNA mitochondrial DNA NADH oxydo-reductase, thereby stops the transmission of respiratory chain electronics, suppresses the generation of tumour cell ATP; Make tumour cell because of hungry dead; Its mechanism of action is unique, is different from the mechanism of action of general antitumor drug, is called " star that tomorrow is anticancer ".
The waste that Sirikaya seed abandons after edible for sweetsop pulp; Wherein Annonaceousacetogenicompounds compounds content is higher; In order to utilize this waste fully; It is turned waste into wealth, and the present invention carries out system's further investigation to the Sirikaya seed chemical ingredients, from Sirikaya seed, separates obtaining a new single THF type annonaceous acetogenins.
Summary of the invention
Goal of the invention: the objective of the invention is in order to overcome the deficiency of prior art, a kind of new single THF type annonaceous acetogenins and purposes in prevention and treatment tumor disease thereof with powerful antitumor activity is provided
Technical scheme: in order to realize above purpose, the technical scheme that the present invention takes is:
Have single THF type Annonaceousacetogenicompounds compounds of anti-tumor activity, its structural formula is following:
Molecular formula is C
35H
64O
5, the structure end has α, and β-γ unsaturated lactone ring has a single THF ring in the molecular chain, and with its called after An Nuoshikemomin third.
Extraction and separation method with single THF type annonaceous acetogenins of anti-tumor activity provided by the invention may further comprise the steps:
A, get Sirikaya seed and pulverize the back and use solvent extraction, the recovery extracting solution obtains liquid concentrator;
B, with liquid concentrator through the normal-phase chromatography chromatographic separation, obtain target compound An Nuoshikemomin third.
Among the above preparation method, the used extraction solvent of step a can be the mixed solvent of one of them or they such as sherwood oil, chloroform, ETHYLE ACETATE, preferred chloroform; Process for extracting can be cold soaking, diacolation, microwave extraction or supersound extraction, preferred diacolation and supersound extraction.
Among the above preparation method; Can pass through chromatography after step b extracting solution concentrates, used chromatography parting material can be silica gel, aluminum oxide, contain cyanic acid or amino silane group silica gel, wherein preferred silica gel; Used eluting solvent is sherwood oil and ETHYLE ACETATE; Collect the elutriant contain target compound respectively and concentrate, the refined liquid after concentrating respectively can be at silica gel, aluminum oxide, contain in cyanic acid or the amino materials such as silane group silica gel and carry out chromatographic separation, sherwood oil and ETHYLE ACETATE gradient elution; Collect elutriant, the elutriant recrystallization obtains new single THF type Annona lactone An Nuoshikemomin third respectively.
Single THF type annonaceous acetogenins with anti-tumor activity provided by the invention becomes formulations such as tablet, capsule, injection, powder injection, granule, lipomul, micro-capsule, dripping pill, ointment or skin-permeable and control-released plaster with single THF type Annonaceousacetogenicompounds compounds (An Nuoshikemomin third) with pharmaceutically acceptable preparing carriers.
When single THF type Annona lactone provided by the invention is processed tablet,, add magnesium stearate lubricant when needing, mix single THF type Annona lactone and lactose or W-Gum, whole grain, compressing tablet is processed tablet then.
When processing capsule, single THF type Annona lactone provided by the invention mixes single THF type Annona lactone and carrier lactose or W-Gum whole grain, the encapsulated then capsule of processing.
When single THF type Annona lactone provided by the invention is processed granule, single THF type Annona lactone and thinner lactose or W-Gum, mix, whole grain, drying is processed granule.
When single THF type Annona lactone provided by the invention was processed powder injection, the lyophilize of single THF type Annona lactone, powder injection was processed in sterilization.
When single THF type Annona lactone provided by the invention is processed injection liquid, get single THF type Annona lactone adding physiological saline solution and add activated carbon then, stir; 80 ℃ were heated 30 minutes; Filter, regulate the pH value, be filtered to clear and bright with sintered glass funnel or other filter; Can was processed injection liquid in 30 minutes 100 to 115 ℃ of sterilizations.
Adding carrier when single THF type Annona lactone provided by the invention is processed formulation such as lipomul, ointment or skin-permeable and control-released plaster prepares by the pharmacy ordinary method.
The application of single THF type Annonaceousacetogenicompounds compounds (An Nuoshikemomin third) with anti-tumor activity provided by the invention in the preparation antitumor drug.
As preferred version, the application of single THF type Annonaceousacetogenicompounds compounds in the preparation antitumor drug with anti-tumor activity provided by the invention, described tumour is lung cancer, mammary cancer, liver cancer, cervical cancer and cancer of the stomach.
Beneficial effect: the single THF type Annonaceousacetogenicompounds compounds with anti-tumor activity provided by the invention is compared with prior art and is had the following advantages:
The present invention is through carrying out system's further investigation to the Sirikaya seed chemical ingredients; Show from Sirikaya seed, to separate with MASS SPECTRAL DATA ANALYSIS and obtain a single THF type Annonaceousacetogenicompounds compounds (An Nuoshikemomin third) through wave spectrum, be new compound.And through research shows with anti tumor activity in vitro in the body; Single THF type Annona lactone provided by the invention comprises lung cancer, mammary cancer, liver cancer to kinds of tumor cells; Cervical cancer and cancer of the stomach all have very strong anti-tumor activity; And show that through toxicity test research the single THF type Annonaceousacetogenicompounds compounds toxicity with anti-tumor activity provided by the invention is lower, is a kind of good antineoplastic novel compound.
Description of drawings
Fig. 1 is the structural representation of An Nuoshikemomin third;
Fig. 2 is the high resolution mass spectrum figure of An Nuoshikemomin third;
Fig. 3 is An Nuoshikemomin's third
1H NMR figure;
Fig. 4 is An Nuoshikemomin's third
13C NMR figure.
Embodiment
According to following embodiment, can understand the present invention better.Yet, those skilled in the art will readily understand that the described concrete material proportion of embodiment, processing condition and result thereof only are used to explain the present invention, and the present invention that should also can not limit in claims to be described in detail.
The preparation of embodiment 1 single THF type Annonaceousacetogenicompounds compounds (An Nuoshikemomin third)
Get 10 kilograms of dry Sirikaya seeds, pulverize the back and use the chloroform diacolation, reclaim the merging percolate; Filter, filtrate decompression reclaims and obtains 1 kilogram of liquid concentrator, and liquid concentrator carries out column chromatography for separation with purification on normal-phase silica gel; With petroleum ether-ethyl acetate-methyl alcohol gradient elution, collect 400 parts of cuts altogether, be merged into five parts (F1 ~ F5) according to the thin-layer chromatography situation; Get F2 (63 gram) and carry out column chromatography for separation through purification on normal-phase silica gel, (gradient elution of 20:1 ~ 0:1) is divided into 8 parts (F6 ~ F13) according to the thin-layer chromatography situation with petroleum ether-ethyl acetate; Get F9 amalgamation liquid precipitate through the petroleum ether-ethyl acetate recrystallization, obtain compound An Nuoshikemomin the third, structural formula is as shown in Figure 1; Detect through performance liquid, purity is 99.1%.
The structure elucidation of An Nuoshikemomin third: white powder, molecular formula: C
35H
64O
5Fusing point: 64-65 ° C; Specific rotation: [α]
25 D+ 12.8 (
c0.10, MeOH); Ultraviolet: (MeOH)
λ Max(log
ε) 218 (3.71) nm; Infrared: IR (KBr)
ν Max3424,2918,2852,1743 and 1070 cm
-1 1H NMR with
13C NMR data are seen table 1, Fig. 3 and 4; High resolution electrospray ionization mass spectrum (HRESIMS) like Fig. 2: quasi-molecular ion peak
M/z[565.4808 M+H]
+(calculated value 585.4832) and
M/z[587.4665 M+Na]
+(calculated value 587.4651).Confirm that in conjunction with ultimate analysis relative molecular weight is 580, confirm that molecular formula is C
35H
64O
5, compound UV λ
Max=215 nm and keed reagent react are red-purple, and α has been described, the existence of β-γ unsaturated lactone ring.Its
1δ among the H-NMR
H6.97 (H-33), 4.99 (H-34), 1.39 (H-35) and
13δ among the C-NMR
C173.54 (C-1), 134.02 (C-2), 148.49 (C-33), 77.05 (C-34), 18.88 (C-35), these are characteristic signals of α, β-γ unsaturated lactone ring;
1δ among the H-NMR
H2.26 the triplet of locating shows that the C-4 position does not have oxy radical to replace,
1δ 3.38 (H-11) among the H-NMR, δ 3.89 (H-16), 3.83 (H-12,15) and
13C-NMR δ 74.01 (C-11), 82.90 (C-12/15), 81.83 (C-12/15), the peak of 71.24 (C-16) shows that existence that single THF ring is arranged in the structure and the both sides of THF respectively have a hydroxyl adjacent, because its δ
C74.01 (C-11), 71.24 (C-16); δ
H3.38 (H-11), δ 3.89 (H-16) is so be respectively erythro form and Su Shi.The position of substitution of inferring THF according to ESI-MS/MS data (m/z=209,221,289,303,317,307,237) is between C-11 and the C-16.The NMR data of binding compounds Annonacin A and Reticulatain-1 infer that its relative configuration is th/t/er, are Annonacin A hypotype.In sum; In conjunction with various physics and chemistry and spectral data; Be accredited as the new ring-like sweetsop branch of a single THF lactone compound; Called after An Nuoshikemomin the third, cycle chemistry is by name: (S)-3-((R)-9-hydroxyl-9-((2R, 5R)-5-((S)-1-hydroxyl heptadecyl)-2-tetrahydrofuran base) nonyl)-5-methyl furan-2 (5H)-ketone.
(solvent is CDCl to the NMR data of table 1. An Nuoshikemomin third compound
3, test be 300MHz)
The acute toxicity test of embodiment 2 An Nuoshikemomin third
Press the Bliss method and calculate mouse medium lethal dose(LD&-{50}) LD
50Value, it is as shown in table 2 to measure the result:
The acute toxicity test data of table 2 An Nuoshikemomin third
By table 2 experiment gained LD
50Value explains that the acute toxicity of compound An Nuoshikemomin third provided by the invention is lower, and the toxicity of compound An Nuoshikemomin third oral administration is minimum in the route of administration.
The embodiment 3 An Nuoshikemomin third external restraining effect to human tumor cells
With people's lung cancer (MCF-7); Mammary cancer (A-5408), people's liver cancer (SMMC-7451), human cervical carcinoma (Hela) and 5 kinds of knurl strains of people's cancer of the stomach (SGC-7901); Adopt tetrazolium bromide reduction method (MTT) to carry out anticancer experiment in vitro; Compound An Nuoshikemomin third establishes 5 concentration, with the positive control group of taxol (Taxol), is the negative control group of methyl-sulphoxide with the solvent of sample.Used mouse is cleaning level kunming mice.Can find out the different restraining effect of demonstration of third pair 5 strain human tumor cells of compound An Nuoshikemomin by the experimental result of table 3; The anticancer experiment in vitro data show that compound An Nuoshikemomin third provided by the invention has shown very strong anti-tumor activity, wherein lung cancer (MCF-7) tumour cell are compared with the positive drug taxol to have stronger tumour cell selection inhibition activity.
Table 3 An Nuoshikemomin third and the restraining effect of taxol to 5 strain tumour cells
The restraining effect of in embodiment 4 compound An Nuoshikemomin third body mouse transplantability hepatoma Heps being produced
Carry out the inhibition experiment that mouse interior tumor is produced with mouse transplantability hepatoma Heps, compound An Nuoshikemomin third establishes 3 dose groups, and promptly high, medium and low 3 groups, with the positive control group of taxol; Solvent with sample is the negative control group of VT 18, establishes 10 mouse for every group, every group of mouse peritoneal injection every day 0.2ml; Continuous 7 days, put to death mouse in the 8th day, get tumour; Weigh, calculate tumour inhibiting rate, concrete experimental result is seen shown in the table 4.
Table 4 compound An Nuoshikemomin third intraperitoneal administration is to the inhibition experimental result of rat liver cancer HepS
Ratio of outflow (%)=(1-drug group knurl weight/feminine gender group knurl is heavy) * 100% * gives the solution with the same amount sample dissolution, down together.
Draw the show strong inhibition activity of third pair of mouse hepatoma of compound An Nuoshikemomin Heps growth by experimental result table 4; The height of An Nuoshikemomin third, middle concentration all have statistical significance with respect to the feminine gender group; Wherein the high density group of An Nuoshikemomin third is 58.7% to mouse hepatoma Heps inhibiting rate, demonstrates good antitumor activity.
With murine sarcoma S
180Carry out the inhibition experiment that mouse interior tumor is produced, compound An Nuoshikemomin third respectively establishes 3 dose groups, promptly high, medium and low 3 groups; With the positive control group of taxol, be the negative control group of VT 18 with the solvent of sample, establish 10 mouse for every group; Every group of mouse peritoneal injection every day 0.2ml continuous 7 days, put to death mouse in the 8th day; Getting tumour, weigh, calculate tumour inhibiting rate. the result sees table 5.
Table 5 compound An Nuoshikemomin third intraperitoneal administration is to the inhibition experimental result of mouse meat cancer S180
Tumour inhibiting rate (%)=(1-drug group knurl weight/feminine gender group knurl is heavy) * 100% * gives the solution with the same amount sample dissolution, down together.
Draw third pair of Mouse Liver sarcoma of compound An Nuoshikemomin S by experimental result table 5
180Show that also stronger inhibition is active, with respect to the height of feminine gender group compound, middle concentration group all has statistical significance, and the high density group of An Nuoshikemomin third is to murine sarcoma S
180Inhibiting rate is 57.8%, demonstrates than taxol to have better antitumor activity.The experiment of above anti-tumor in vivo shows that further the ring-like sweetsop branch of single THF provided by the invention lactone cpd has high anti-tumor activity, low toxic side effect, and being expected to develop becomes new antitumor drug.
The preparation of embodiment 6 tablets
Get above-mentioned An Nuoshikemomin third and add medicinal supplementary product starch, Magnesium Stearate etc. in right amount, fully behind the mixing, compressing tablet is processed every tablet of tablet that contains the above-mentioned An Nuoshikemomin third of 1mg and is orally used.
The preparation of embodiment 7 capsules
Getting above-mentioned An Nuoshikemomin third, to add medicinal supplementary product starch an amount of, fully behind the mixing, incapsulates, and processes every capsule that contains the above-mentioned An Nuoshikemomin third of 1mg and orally use.
The preparation of embodiment 8 micro-capsules
It is an amount of to get gummi arabicum pulveratum, add get above-mentioned An Nuoshikemomin third, zero(ppm) water is processed colostrum in right amount, and is processed emulsion in right amount with 3% Arabic glue; Emulsion is heated to 45, and to add 3% gelatin solution when spending an amount of and with 10% acetate solution accent pH4.1 ~ 4.3; Add zero(ppm) water, 3% formaldehyde is an amount of, stir to make it solidify setting, with 5% sodium hydroxide accent pH7.0 ~ 7.5; It is an amount of to add 10% starch at last, processes the micro-capsule that every gram contains 1mg An Nuoshikemomin third.
Above embodiment only is explanation technical conceive of the present invention and characteristics; Its purpose is to let the people that is familiar with this technology understand content of the present invention and implements; Can not limit protection scope of the present invention with this; All equivalences that spirit is done according to the present invention change or modify, and all should be encompassed in protection scope of the present invention.
Claims (3)
1. single THF type annonaceous acetogenins with anti-tumor activity is characterized in that its structural formula is following:
2. the described application of single THF type annonaceous acetogenins in the preparation antitumor drug of claim 1 with anti-tumor activity.
3. the application of single THF type annonaceous acetogenins in the preparation antitumor drug with anti-tumor activity according to claim 2 is characterized in that described tumour is lung cancer, mammary cancer, liver cancer, cervical cancer and cancer of the stomach.
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| CN106309516B (en) * | 2016-11-02 | 2020-02-21 | 南京中医药大学 | Annona squamosa pericarp volatile oil extract with anti-tumor activity and preparation method and application thereof |
| CN107007826B (en) * | 2017-04-19 | 2020-03-31 | 南京中医药大学 | Active protein of isatis root and its preparing process and application |
| CN107674065A (en) * | 2017-10-13 | 2018-02-09 | 江苏建康职业学院 | Annonaceous acetogenins and its application with antitumor activity |
Citations (3)
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| CN1861597A (en) * | 2006-06-16 | 2006-11-15 | 南京中医药大学 | Internal ester monomer compound and its application in preparing anti cancer medicine |
| CN1869031A (en) * | 2006-06-30 | 2006-11-29 | 南京中医药大学 | Lactone monomer compound and its application in preparing anticancer medicine |
| CN101108840A (en) * | 2007-07-06 | 2008-01-23 | 中国科学院上海有机化学研究所 | Chirality anona squamosa L. lactone compound with conformation limitation structure and synthesizing method and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1861597A (en) * | 2006-06-16 | 2006-11-15 | 南京中医药大学 | Internal ester monomer compound and its application in preparing anti cancer medicine |
| CN1869031A (en) * | 2006-06-30 | 2006-11-29 | 南京中医药大学 | Lactone monomer compound and its application in preparing anticancer medicine |
| CN101108840A (en) * | 2007-07-06 | 2008-01-23 | 中国科学院上海有机化学研究所 | Chirality anona squamosa L. lactone compound with conformation limitation structure and synthesizing method and use thereof |
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