CN102532154A - Angelica oncosepala linear furocoumarins compound and application thereof - Google Patents
Angelica oncosepala linear furocoumarins compound and application thereof Download PDFInfo
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- CN102532154A CN102532154A CN2012100065223A CN201210006522A CN102532154A CN 102532154 A CN102532154 A CN 102532154A CN 2012100065223 A CN2012100065223 A CN 2012100065223A CN 201210006522 A CN201210006522 A CN 201210006522A CN 102532154 A CN102532154 A CN 102532154A
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Abstract
The invention relates to new compounds, in particular linear furanocoumarin compounds with antitumor activity and pharmaceutical application thereof. The general formula of an angelica oncosepala linear furocoumarins compound is shown in the description, wherein R is -H or -CH(CH3)2. The invention relates to the application of the angelica oncosepala linear furocoumarins compound in preparation of tumor cell inhibiting medicines.
Description
Technical field
The present invention relates to one type of new compound, especially have the linear furocoumarins compounds of anti-tumor activity, and their application in pharmacy.
Background technology
Umbelliferae (Umbelliferae) the plant whole world have approximately 275 belong to 2850 surplus kind, be bordering on distribution on global, the abundantest with the north temperate zone, China distributes has 96 to belong to 525 kinds approximately, Yunnan has 51 to belong to 259 kind of 21 mutation approximately.The research of Yunnan umbelliferae medicinal plant mainly starts from the seventies in 20th century; Result of study shows; The chemical ingredients of Yunnan umbelliferae medicinal plant is mainly tonka bean camphor, and its main structure type has 4 types: simple coumarin type, linear furocoumarins type; The angle-furocoumarins type, angle type dihydropyrane coumarin type.Modern pharmacology research shows that the umbelliferae tonka bean camphor has physiology and pharmacologically active widely; It is the focus of studying both at home and abroad always; Wherein anti-tumor activity is one of main pharmacologically active of umbelliferae tonka bean camphor; And for being applied to other clinical natural anti-cancer drugs, coumarin compound is synthetic and structural modification is simple relatively and ripe, has the potential pharmaceutical use.The report that two new linear furocoumarins compounds that the present invention relates to are not arranged in the prior art.
Summary of the invention
The object of the present invention is to provide from Yunnan grand calyx Radix Angelicae Sinensis (
Angelicaoncosepala) separate two grand calyx Radix Angelicae Sinensis linear furocoumarins compounds that obtain in the plant with anti-tumor activity.
Another object of the present invention is to provide the application of this grand calyx Radix Angelicae Sinensis linear furocoumarins compound in pharmacy.
Grand calyx Radix Angelicae Sinensis linear furocoumarins compound of the present invention is the compound with following general structure:
Wherein: R Wei – H Huo – CH (CH
3)
2
When R Wei – H is compound I, as R Wei – CH (CH
3)
2The time be compound I I, its structural formula is respectively:
Compound I compound I I
The preparation method of grand calyx Radix Angelicae Sinensis linear furocoumarins compound of the present invention is: with acetone or methanol solvate; The grand calyx angelica root meal in cold soaking or thermal backflow lixiviate Yunnan obtains total medicinal extract; Total medicinal extract with water-dispersion after with organic solvent ETHYLE ACETATE or chloroform or ether or sherwood oil or benzene extract extract, extract is through column chromatography and must said compound after partly preparing HPLC and separating.
It is material that the present invention selects the grand calyx angelica root meal in Yunnan, extracts, separation, structure is identified and system works such as screening active ingredients, has therefrom obtained 2 new linear furocoumarins compounds: compound I and compound I I.
The preparation of compound I of the present invention and compound I I:
Dry grand calyx Radix Angelicae Sinensis plant root 1.0 kg pulverize the back and repeat to extract (each 3 liters, soaking at room temperature 24 hours) 3 times with pure methyl alcohol, and extracting solution merges; Filter, methyl alcohol is removed in underpressure distillation, leaves standstill; Be scattered in 0.5 premium on currency, the aqueous solution is used the EtOAc extracted several times, and evaporate to dryness EtOAc gets medicinal extract 20.0 g.This medicinal extract adds 30.0 g silica gel (100 order) and mixes the appearance back with 200.0 g silica gel (200-300 order) column chromatography, chloroform-acetone solvent gradient elution (1:0-0:1), and TLC detects, and merges identical cut, gets cut section I-IV.Cut section IV is an acetone wash-out part, does not do further to separate.
Cut section II (3.5 g) is through silica gel column chromatography (sherwood oil/acetone 8:2; 7:3) carry out gradient elution; Detect to merge identical cut through TLC, Sephadex LH-20 (methyl alcohol) chromatography and partly prepare HPLC (45% methanol-water) and obtain compound I (5.0 mg).
Cut section III (4.0 g) through silica gel column chromatography (chloroform: methyl alcohol 30:1,20:1,15:1,9:1 8:2) carries out gradient elution, Sephadex LH-20 (methyl alcohol) chromatography obtains compound I I (6.0 mg).
The wave spectrum analysis process of 2 compounds wherein:
Compound
I, pale yellow powder; EIMS (positive) provides quasi-molecular ion peak m/z 404 [M]
+, corresponding to a molecular formula C
21H
24O
8, HREIMS (positive) has confirmed this molecular composition (m/z 404.1470 [M]
+, calcd 404.1471 for C
21H
24O
8).
1H NMR spectrum (seeing table 1) has provided two couples of alkene methyne signal: δ
H(6.31 J 9.65 for 1H, d) and 8.18 (J 9.65 for 1H, d); δ
H6.99 (1H, and s) with 7.65 (1H, s);
13Observe four methyne (δ on the C NMR spectrum (seeing table 1)
C105.0,113.4,139.3,145.5) and seven quaternary carbons totally 11 carbon signals.And ultraviolet spectrum data 221,248,268,311 nm data show compound
IIt is a linear furocoumarins compounds.Chemical shift with the corresponding carbon of psoralene is a radix, characteristic carbon signal δ
C127.0 (s, (s C-5) points out that compound I is that C-5, C-8 two replace the linear furocoumarins compounds C-8) with 143.8.In the HMBC test (Fig. 1), contain oxygen methene proton δ
HThen supported 1 4.37 (1H, dd, J=3.18,9.76) are relevant with C-5 " position methylene radical ownership; δ
H" the ownership of ' position methylene radical that (4.62 1H, dd, J=2.40,8.17) are relevant with C-8, support 1.Like this, compound
IBe accredited as 5-(2 ", 3 " dihydroxy-3 "-methylbutyloxy)-8-(2 " '-hydroxy-3 " '-methyl-3 " '-
Butyleneoxy)-psoralen, and the grand calyx Radix Angelicae Sinensis linear furocoumarins A of called after.
Table 1 compound
I 1H with
13C NMR spectral data (measuring among the MeOD)
Compound I I, pale yellow powder; EIMS (positive) provides quasi-molecular ion peak m/z 446 [M]
+, in conjunction with
13C spectrum and DEPT spectrum are corresponding to a molecular formula C
24H
30O
8, HREIMS (positive) has confirmed this molecular composition (m/z 446.1933 [M]
+, calcd 446.1941 for C
24H
30O
8).
1H NMR spectrum (seeing table 2) has provided two couples of alkene methyne signal: δ
H(6.29 J 9.65 for 1H, d) and 8.16 (J 9.65 for 1H, d); δ
H6.97 (1H, and s) with 7.63 (1H, s);
13C NMR spectrum (is seen table
2) on observe four methynes and seven quaternary carbons totally 11 carbon signals.And ultraviolet spectrum data 220,241,248,267,311 nm show that compound I I also is a linear furocoumarins compounds.Comparative compound II and compound
ITwo compounds
1H NMR with
13C NMR spectrogram finds that the data of 2 compounds are most of consistent, only at C-3 " (δ
C77.2, s) position to low field displacement 5.6 ppm, and in HMBC tests (Fig. 2), contain sec.-propyl methyne signal δ
H3.9 (1H, m, H-6
") be isopropoxy rather than compound with the substituting group of C-3 " relevant then supported 3 " position
IMiddle hydroxyl; Contain oxygen methene proton δ
H4.34 (1H m) relevantly with C-5 has then supported
1 " ownership of position methylene radical; δ
H4.59 (1H, m) relevant with C-8, support to 1 " the ownership of ' position methylene radical.So, compound I I be accredited as 5-(2 ", hydroxy-3 " isopropoxy-3 "-methylbutyloxy)-8-(2 " '-
Hydroxy-3 " '-methyl-3 " '-butyleneoxy)-psoralen, and the grand calyx Radix Angelicae Sinensis linear furocoumarins B of called after.
Table 2 compound I I
1H with
13C NMR spectral data (measuring among the MeOD)
The present invention relates to described grand calyx Radix Angelicae Sinensis linear furocoumarins compound and suppress the application in the tumour cell medicine in preparation.
The present invention relates to described grand calyx Radix Angelicae Sinensis linear furocoumarins compound and suppress the application in leukemia cell's medicine in preparation.
The present invention relates to described grand calyx Radix Angelicae Sinensis linear furocoumarins compound and suppress the application in the liver cancer cell medicine in preparation.
The present invention relates to described grand calyx Radix Angelicae Sinensis linear furocoumarins compound and suppress the application in the lung carcinoma cell medicine in preparation.
The present invention relates to described grand calyx Radix Angelicae Sinensis linear furocoumarins compound and suppress the application in the breast cancer cell medicine in preparation.
The present invention relates to described grand calyx Radix Angelicae Sinensis linear furocoumarins compound and suppress the application in the colon cancer cell medicine in preparation.
Compound I of the present invention and compound I I through to five kinds of cell strains (HL-60, SMMC-7721, A-549, MCF-7, anti tumor activity in vitro experiment SW480) has all shown cytotoxic activity preferably to five kinds of tumour cells.Experimental result shows; Compound ii is individual all to have very strong restraining effect to human leukemia cell, liver cancer cell, lung carcinoma cell, breast cancer cell, colon cancer cell; Half growth inhibitory concentration scope is 1.99～3.69 μ Μ, has showed significant cytotoxic activity.Compound I has strong restraining effect to colon cancer cell, and the half growth inhibitory concentration is 10.77 μ Μ.
The extracorporeal anti-tumor function of compound of the present invention:
Through to five kinds of cell strains (HL-60, SMMC-7721, A-549, MCF-7, the experiment of SW480) anti tumor activity in vitro, compound I and compound I I have all shown cytotoxic activity preferably to five kinds of tumour cells.Experimental result shows; Compound I I all has very strong restraining effect to human leukemia cell, liver cancer cell, lung carcinoma cell, breast cancer cell, colon cancer cell; Half growth inhibitory concentration scope is 1.99～3.69 μ Μ, has showed significant cytotoxic activity.Compound
IColon cancer cell is had strong restraining effect, and the half growth inhibitory concentration is 10.77 μ Μ.
The anti tumor activity in vitro experimental technique:
1. experimental design:
Cell and different concns compound (are respectively 0.064,0.32,1.6,8,40
μM) incubation is 72 hours, adopts the inhibition degree of MTT method assessing compound on cell proliferation, calculates inhibiting rate, adopts the Logit method to calculate IC according to inhibiting rate
50, the anti tumor activity in vitro of comparative compound.
2. inhibiting rate method of calculation:
Inhibiting rate (%)=(control group OD value-medication group OD value)/control group OD group * 100%
3. experimental technique
(1), inoculating cell: the nutrient solution (DMEM or RMPI1640) with containing 10% foetal calf serum is made into the individual cells suspension, with every hole 5000-10000 cell inoculation to 96 orifice plates, every pore volume 100
μL, attached cell is 12 hours inoculation culture in advance.
(2), add testing compound solution (fixed concentration 40
μThe M primary dcreening operation is suppressed near 50% compound in this concentration to growth of tumour cell and establishes 5 concentration and get into gradients and sieve again), every hole final volume 200
μL, 3 multiple holes are all established in every kind of processing.
(3), colour developing: cultivate after 48 hours for 37 degrees centigrade, every hole adds MTT solution 20
μL.Continued to hatch 4 hours, and stopped cultivating, inhale and abandon culture supernatant liquid in the hole, every hole adds 200
μThe SDS solution (10%) of l, night incubation (37 ℃ of temperature) is fully melted crystallisate.
(4), colorimetric: select the 595nm wavelength; Enzyme-linked immunosorbent assay instrument (Bio-Rad 680) reads each hole absorbance value; The record result; With concentration is X-coordinate, and cell survival rate is that ordinate zou is drawn cell growth curve, uses the IC50 value of two-point method (Reed and Muench method) computerized compound.
Table 3 compound I
,II is to the cytotoxic activity of five kinds of cell strains
Remarks: cis-platinum and taxol are positive controls.
Compound of the present invention can be used for preparing the medicine of treating cancer, especially for the medicine of preparation treatment white blood disease, liver cancer, lung cancer, mammary cancer, colorectal carcinoma.
Above-mentioned pharmaceutically acceptable carrier is meant the pharmaceutical carrier that pharmaceutical field is conventional, for example: thinner, vehicle such as water etc., weighting agent such as starch, sucrose etc.; Tamanori such as derivatived cellulose, alginate, gelatin and Vinylpyrrolidone polymer; Wetting agent such as glycerine; Disintegrating agent such as agar, lime carbonate and sodium hydrogencarbonate; Absorption enhancer such as quaternary ammonium compound; Tensio-active agent such as cetyl alcohol; Absorption carrier such as kaolin and soap clay; Lubricant such as talcum powder, calcium stearate and magnesium and and polyoxyethylene glycol etc.Can also add other assistant agent such as flavouring agent, sweeting agent etc. therein in addition.
The compounds of this invention administered through oral, snuffing are gone into, the mode of rectum or administered parenterally is applied to the patient who needs this treatment.Be used for when oral, can be made into conventional solid preparation such as tablet, pulvis, granula, capsule etc., process liquid preparation such as water or oil-suspending agent or other liquid preparations such as syrup, elixir etc.; When being used for administered parenterally, can be made into solution, water or the oiliness suspension agent etc. of injection.Preferred form is tablet, capsule and injection.
The various formulations of medicine according to the invention can be according to the conventional working method preparation of pharmaceutical field.Activeconstituents is mixed with one or more carriers, be made into required formulation then.
Description of drawings
Fig. 1 is the two-dimentional HMBC correlogram of compound I of the present invention.
Fig. 2 is the two-dimentional HMBC correlogram of compound ii of the present invention.
Fig. 3 is a compound separation schema of the present invention.
Embodiment
Use below in conjunction with accompanying drawing the present invention is done further description, but content of the present invention is not limited thereto.
Embodiment 1:
Tablet: compound I 10mg lactose 180mg starch 55mg Magnesium Stearate 5mg.
The preparation method: compound I, lactose and starch are mixed, and water is evenly moistening, sieves the mixture after moistening and drying, after sieve, adds Magnesium Stearate, then with the mixture compressing tablet, and every heavy 250 mg, active component content is 10 mg.
Embodiment 2:
Ampulla: compound ii 2mg sodium-chlor 10mg.
Preparing method: compound ii and sodium-chlor are dissolved in the proper amount of water for injection, filter gained solution, in the ampoule of under aseptic condition, packing into.
Embodiment 3:
Capsule: compound ii 10mg lactose 187mg Magnesium Stearate 3mg.
The preparation method: compound ii is mixed with auxiliary agent, sieve, uniform mixing, the mixture that the obtains hard gelatin capsule of packing into, the heavy 200mg of each capsule, active component content is 10mg.
Claims (7)
1. grand calyx Radix Angelicae Sinensis linear furocoumarins compound is characterized in that it being the compound with following general structure:
Wherein: R Wei – H Huo – CH (CH
3)
2
2. the present invention relates to the described grand calyx Radix Angelicae Sinensis linear furocoumarins compound of claim 1 and suppress the application in the tumour cell medicine in preparation.
Suppress the application in leukemia cell's medicine 3.3. the present invention relates to the described grand calyx Radix Angelicae Sinensis linear furocoumarins compound of claim 1 in preparation.
4. the present invention relates to the described grand calyx Radix Angelicae Sinensis linear furocoumarins compound of claim 1 and suppress the application in the liver cancer cell medicine in preparation.
5. the present invention relates to the described grand calyx Radix Angelicae Sinensis linear furocoumarins compound of claim 1 and suppress the application in the lung carcinoma cell medicine in preparation.
6. the present invention relates to the described grand calyx Radix Angelicae Sinensis linear furocoumarins compound of claim 1 and suppress the application in the breast cancer cell medicine in preparation.
7. the present invention relates to the described grand calyx Radix Angelicae Sinensis linear furocoumarins compound of claim 1 and suppress the application in the colon cancer cell medicine in preparation.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210006522.3A CN102532154B (en) | 2012-01-11 | 2012-01-11 | Angelica oncosepala linear furocoumarins compound and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210006522.3A CN102532154B (en) | 2012-01-11 | 2012-01-11 | Angelica oncosepala linear furocoumarins compound and application thereof |
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| CN102532154A true CN102532154A (en) | 2012-07-04 |
| CN102532154B CN102532154B (en) | 2014-05-14 |
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|---|---|---|---|
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11304902B2 (en) * | 2014-11-25 | 2022-04-19 | Curadigm Sas | Pharmaceutical compositions, preparation and uses thereof |
| US11357724B2 (en) | 2013-05-30 | 2022-06-14 | Curadigm Sas | Pharmaceutical composition, preparation and uses thereof |
| US11471410B2 (en) | 2014-11-25 | 2022-10-18 | Curadigm Sas | Pharmaceutical composition combining at least two distinct nanoparticles and a pharmaceutical compound, preparation and uses thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0578066A1 (en) * | 1992-07-07 | 1994-01-12 | Bayer Ag | Photochemical labelling of nucleic acids with digoxigenin-reagents and their use in gene probe systems |
| EP0607091A1 (en) * | 1993-01-15 | 1994-07-20 | Jean Jacques Goupil | Method of dosage of furocoumarines, and especially of psoralene and its derivatives, compounds and kits for processing this method |
-
2012
- 2012-01-11 CN CN201210006522.3A patent/CN102532154B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0578066A1 (en) * | 1992-07-07 | 1994-01-12 | Bayer Ag | Photochemical labelling of nucleic acids with digoxigenin-reagents and their use in gene probe systems |
| EP0607091A1 (en) * | 1993-01-15 | 1994-07-20 | Jean Jacques Goupil | Method of dosage of furocoumarines, and especially of psoralene and its derivatives, compounds and kits for processing this method |
Non-Patent Citations (3)
| Title |
|---|
| TORU OKUYAMA,等: "Studies on the antitumor-promoting activity of naturally occurring substances. II. Inhibition of tumor-promoterenhanced phospholipid metabolism by Umbelliferous materials", 《CHEMICAL & PHARMACEUTICAL BULLETIN》 * |
| 熊友健，等: "呋喃香豆素类成分及其药理作用研究进展", 《中成药》 * |
| 韩莎,等: "呋喃香豆素药理活性研究进展", 《齐鲁药事》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11357724B2 (en) | 2013-05-30 | 2022-06-14 | Curadigm Sas | Pharmaceutical composition, preparation and uses thereof |
| US11304902B2 (en) * | 2014-11-25 | 2022-04-19 | Curadigm Sas | Pharmaceutical compositions, preparation and uses thereof |
| US11471410B2 (en) | 2014-11-25 | 2022-10-18 | Curadigm Sas | Pharmaceutical composition combining at least two distinct nanoparticles and a pharmaceutical compound, preparation and uses thereof |
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| Publication number | Publication date |
|---|---|
| CN102532154B (en) | 2014-05-14 |
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