CN102079739B - Daidzein derivative, preparation method and application thereof - Google Patents
Daidzein derivative, preparation method and application thereof Download PDFInfo
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- CN102079739B CN102079739B CN2010105894394A CN201010589439A CN102079739B CN 102079739 B CN102079739 B CN 102079739B CN 2010105894394 A CN2010105894394 A CN 2010105894394A CN 201010589439 A CN201010589439 A CN 201010589439A CN 102079739 B CN102079739 B CN 102079739B
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Abstract
The invention discloses a daidzein derivative, a preparation method and application thereof, relating to the daidzein and providing a daidzein derivative which is shaped as yellow gel and has a chemical name of 3',8-diallyl-4',7-dyhydroxyl isoflavone and the molecular weight of 334.1. The daidzein derivative can be conveniently and rapidly prepared through a Claisen rearrangement reaction, the preparation method is simple, and the used raw materials are low in price, thus the daidzein derivative can be widely applied to the industrial production. The 3',8-diallyl-4',7-dyhydroxyl isoflavone has a similar structural characteristics to the daidzein, but has remarkably improved antitumor activity compared with the daidzein. The daidzein derivative can remarkably inhibit the growth of tumor cells and can be widely applied to the preparation of the antitumor drugs.
Description
Technical field
The present invention relates to a kind of compound, particularly a kind of daidzein verivate.
Background technology
The chemical structural formula of daidzein is:
Daidzein (4 ', the 7-dihydroxy isoflavone daidzein), is claimed Daidzein, daizeol, Daidzein or big legumin again, is a kind of isoflavonoid.Mainly be present in leguminous plants such as soybean, the root of kudzu vine, especially in fermented bean products, have higher content.The source of daidzein is very abundant, and pharmacological action is extensive, has broad application prospects; Has pharmacologically active such as antitumor, anti-oxidant widely, the effect of this external cerebullar and cardiac system also fairly obvious (Foti, P; Erba; D, Riso, P.et al.Arch Biochem Biophys (2005) 433:421-427).
Summary of the invention
First purpose of the present invention is to provide a kind of daidzein verivate.
Second purpose of the present invention is to provide a kind of preparation method of daidzein verivate.
The 3rd purpose of the present invention is to provide the application of a kind of daidzein verivate in the preparation antitumor drug.
The chemistry of said a kind of daidzein verivate is by name 3 ', 8-diallyl-4 ', 7-dihydroxy isoflavone, molecular weight are 334.1, structural formula is:
It is yellow gluey that said daidzein verivate is.
The preparation method of said a kind of daidzein verivate may further comprise the steps:
1) under nitrogen protection, with daidzein and Anhydrous potassium carbonate join in the organic solvent solution A; With allyl bromide 98 add in the organic solvent solution B, solution B is added in the solution A react again, reaction finishes promptly to get mixing solutions;
2) step 1) gained mixing solutions is filtered, filtrate decompression concentrates, and spissated residuum is carried out silica gel column chromatography separate, promptly get intermediate product 4 ', 7-two allyloxy NOVASOY 400;
3) with step 2) intermediate product 4 of gained ', 7-two allyloxy NOVASOY 400 rearrangement reactions are carried out column chromatography for separation with reaction product, promptly get 3 ', 8-diallyl-4 ', the 7-dihydroxy isoflavone.
In step 1); Said organic solvent can be N or acetone etc.; The volumetric molar concentration of daidzein can be 0.1～1.0mmol/L in the said solution A; The volumetric molar concentration of Anhydrous potassium carbonate can be 0.2～2.0mmol/L, and to can be 0.2～2.0mmol/L to the volumetric molar concentration of allyl bromide 98 in the said solution B; The condition of said reaction: temperature can be 20～28 ℃, and the time can be 16～20h, and stir speed (S.S.) can be 100～400rpm.
In step 2) in, the silica gel of said plastic column chromatography can be 200～400 orders.
In step 3), the condition of said rearrangement reaction is: 160～200 ℃ of temperature, time 4～6h.
The present invention utilizes the Claisen rearrangement reaction, prepares a kind of daidzein verivate easily and quickly, and the preparation method is simple, and raw materials used price is inexpensive, can be widely used in the industrial production.Among the present invention 3 ', 8-diallyl-4 ', the 7-dihydroxy isoflavone has the constitutional features similar with daidzein, but its anti-tumor activity is compared tangible raising with daidzein.Can suppress the growth of nasopharyngeal carcinoma CNE2 cell, the thin HeLa cell of human cervical carcinoma, human fibrosarcoma HT1080 cell and people's liver cancer Bel-7402 cell significantly, can on the preparation antitumor drug, have widely and use.
Description of drawings
Fig. 1 be daidzein and 3 ', 8-diallyl-4 ', the anti-nasopharyngeal carcinoma CNE2 cell-proliferation activity comparison diagram of 7-dihydroxy isoflavone.In Fig. 1, X-coordinate is drug level (μ mol/L), and ordinate zou is inhibiting rate (%), and wherein a is a daidzein, b is 3 ', 8-diallyl-4 ', the 7-dihydroxy isoflavone.
Fig. 2 be daidzein and 3 ', 8-diallyl-4 ', the anti-human fibrosarcoma HT 1080 cell-proliferation activity comparison diagrams of 7-dihydroxy isoflavone.In Fig. 2, X-coordinate is drug level (μ mol/L), and ordinate zou is inhibiting rate (%), and wherein a is a daidzein, b is 3 ', 8-diallyl-4 ', the 7-dihydroxy isoflavone.
Fig. 3 be daidzein and 3 ', 8-diallyl-4 ', the anti-HeLa Cells proliferation activity comparison diagram of 7-dihydroxy isoflavone.In Fig. 3, X-coordinate is drug level (μ mol/L), and ordinate zou is inhibiting rate (%), and wherein a is a daidzein, b is 3 ', 8-diallyl-4 ', the 7-dihydroxy isoflavone.
Fig. 4 be daidzein and 3 ', 8-diallyl-4 ', the anti-human liver cancer Bel-7402 cell-proliferation activity comparison diagram of 7-dihydroxy isoflavone.In Fig. 4, X-coordinate is drug level (μ mol/L), and ordinate zou is inhibiting rate (%), and wherein a is a daidzein, b is 3 ', 8-diallyl-4 ', the 7-dihydroxy isoflavone.
Embodiment
Embodiment 1
1) under nitrogen protection, daidzein 2.54g and Anhydrous potassium carbonate 2.76g are joined in the 30mL anhydrous propanone, stir 0.5h and get the oyster white turbid solution.
2) the anhydrous propanone solution that 30mL is contained the 2.4g allyl bromide 98 slowly drops to above-mentioned reaction solution, and 0.5h adds, stirred overnight under the nitrogen protection.
3) remove by filter insolubles, filtrating is removed in decompression.Spissated residuum is carried out silica gel column chromatography separate, V (sherwood oil): V (ETHYLE ACETATE)=10: 1 is as eluent, obtain intermediate product 4 ', 7-two allyloxy NOVASOY 400 2.61g, yellow chip solid, productive rate 78.1%.
4) with this intermediate product tube sealing of packing into, under the nitrogen protection, 200 ℃ of rearrangements.Behind the 5h, monitoring reaction till do not observe raw material point, stopped reaction.After treating that tube sealing is cooled to room temperature, reaction residual is carried out silica gel column chromatography separate, V (sherwood oil): V (ETHYLE ACETATE)=5: 1 is as eluent; Obtain title product 3 ', 8-diallyl-4 ', 7-dihydroxy isoflavone 1.27g; Yellow gluey, productive rate 48.7%.Product is identified with mass spectrum.
Daidzein is bought from Baoji time bio tech ltd.
1H-NMR,
13C-NMR is by measuring on the Bruker av400 NMR spectrometer with superconducting magnet, is marked on deuterium for recording in the organic solvent in TMS being.Mass spectrum system uses Applied Biosystems3200Q TRAP LC/MS/MS System quadrupole mass spectrometer to record.Infraredly on infrared absorption spectrometer Nicolet Avatar360, record.ELIASA uses the product of Bio-Rad company.Below provide test result:
3 ', 8-diallyl-4 ', the spectral data of 7-dihydroxy isoflavone is: IR (film): 3326,1621,1507,1436,1277,1120,1021,914,824,797,685cm
-1 1H?NMR(DMSO-d
6)，δ3.30(d，J＝6.6Hz，2H)，3.50(d，J＝6.1Hz，2H)，4.95(dd，J＝12.0Hz，2.0Hz，1H)，4.99(m，2H)，5.06(dd，J＝16.0Hz，1.9Hz，1H)，5.95(m，2H)，6.83(d，J＝8.3Hz，1H)，7.01(d，J＝8.8Hz，1H)，7.22(dd，J＝8.0Hz，2.2Hz，1H)，7.25(d，J＝2.2Hz，1H)，7.86(d，J＝8.8Hz，1H)，8.29(s，1H)，9.53(s，1H)，10.73(s，1H)。
13C?NMR(DMSO-d
6)：26.49，33.82，112.73，114.10，114.55，115.14，115.38，116.67，122.56，123.22，124.54，125.60，127.65，130.32，135.28，136.92，152.76，154.72，155.26，159.76，175.03。MS-ESI，m/z?333.2[M-H]
-。
Prepared product is a kind of daidzein verivate, is yellow gluey, its chemistry is by name 3 ', 8-diallyl-4 ', 7-dihydroxy isoflavone, molecular weight are 334.1, structural formula is:
Embodiment 2
The present invention to 3 ', 8-diallyl-4 ', the anti-tumor activity of 7-dihydroxy isoflavone is studied, and finds all to have tangible anti-tumor activity.The tumor cell line of being studied comprises nasopharyngeal carcinoma CNE2 cell, human fibrosarcoma HT 1080 cells, HeLa Cells and people's liver cancer Bel-7402 cell.
The tumour cell of taking the logarithm vegetative period is processed single cell suspension, by every hole 1 * 10
4Individual cell inoculation places 37 ℃, contains 5%CO in 3 96 orifice plates
2Cultivate 24h in the cell culture incubator of saturated humidity; Treat that cell attachment growth fusion was to 80% o'clock; Add final concentration respectively and be 2-allyl group-5-[(E)-2-(3-allyl group-4-hydroxy phenyl) vinyl] benzene-1 of 6.25,12.5,25,50,100,200 μ mol/L, the 3-diphenol is not to contain 2-allyl group-5-[(E)-2-(3-allyl group-4-hydroxy phenyl) vinyl] benzene-1; The cell of 3-diphenol substratum is the blank well zeroing as negative control.37 ℃ on cell transposition contains 1%O
2, 5%CO
2And 95%N
2In the incubator of saturated humidity, continue to cultivate 48h.Measure the light absorption value (A) in each hole again at ELIASA 475nm place.Calculate inhibiting rate by following formula: inhibiting rate (%)=[1-(average light absorption value is organized in the average light absorption value-zeroing of experimental group)]/(average light absorption value is organized in the average light absorption value-zeroing of control group) * 100%.
1) 3 ', 8-diallyl-4 ', the 7-dihydroxy isoflavone is to the effect of nasopharyngeal carcinoma CNE2 cell inhibiting
Experimental result shows: 3 ', 8-diallyl-4 ', the 7-dihydroxy isoflavone all has remarkable restraining effect to the propagation of nasopharyngeal carcinoma CNE2 cell, and is the significant concn dependency.Do the time spent (≤50 μ mol/L) at lower concentration, compound 3 ', 8-diallyl-4 ', 7-dihydroxy isoflavone antagonism nasopharyngeal carcinoma CNE2 cell does not have obvious effect, and daidzein shows faint inhibition activity; Do the time spent (>=100 μ mol/L) in high density, 3 ', 8-diallyl-4 ', the active of 7-dihydroxy isoflavone significantly increases, and shows the activity (referring to Fig. 1) of the inhibition nasopharyngeal carcinoma CNE2 cell proliferation that far is better than daidzein.
2) 3 ', 8-diallyl-4 ', the 7-dihydroxy isoflavone is to the restraining effect of human fibrosarcoma HT1080 cell and HeLa Cells
Can find out from active comparison diagram; Daidzein and 3 ', 8-diallyl-4 ', the 7-dihydroxy isoflavone has evident regularity to the restraining effect of human fibrosarcoma HT1080 cell, HeLa Cells: do the time spent (≤50 μ mol/L) at lower concentration; Compound 3 '; 8-diallyl-4 ', 7-dihydroxy isoflavone antagonism nasopharyngeal carcinoma CNE2 cell does not almost have effect, and daidzein shows more weak inhibition activity; Do the time spent (>=100 μ mol/L) in high density, 3 ', 8-diallyl-4 ', the active of 7-dihydroxy isoflavone significantly increases, and shows the activity (referring to Fig. 2 and 3) of the inhibition tumor cell proliferation that far is better than daidzein.
3) 3 ', 8-diallyl-4 ', the 7-dihydroxy isoflavone is to people's liver cancer Bel-7402 cyto-inhibition
Can find out from active comparison diagram, do the time spent (≤50 μ mol/L) at lower concentration, 3 '; 8-diallyl-4 ', 7-dihydroxy isoflavone and daidzein are done the time spent (>=100 μ mol/L) to people's liver cancer Bel-7402 cell unrestraint effect in high density; 3 '; 8-diallyl-4 ', the 7-dihydroxy isoflavone shows remarkable antitumor effect, and effect will obviously be better than daidzein (referring to Fig. 4).
Claims (8)
1. daidzein verivate, it is characterized in that its chemistry by name 3 ', 8-diallyl-4 ', 7-dihydroxy isoflavone, molecular weight are 334.1, structural formula is:
2. the preparation method of a kind of daidzein verivate as claimed in claim 1 is characterized in that may further comprise the steps:
1) under nitrogen protection, with daidzein and Anhydrous potassium carbonate join in the organic solvent solution A; With allyl bromide 98 add in the organic solvent solution B, solution B is added in the solution A react again, reaction finishes promptly to get mixing solutions;
2) step 1) gained mixing solutions is filtered, filtrate decompression concentrates, and spissated residuum is carried out silica gel column chromatography separate, promptly get intermediate product 4 ', 7-two allyloxy NOVASOY 400;
3) with the intermediate product 4 of step 2 gained ', 7-two allyloxy NOVASOY 400 rearrangement reactions are carried out column chromatography for separation with reaction product, promptly get 3 ', 8-diallyl-4 ', the 7-dihydroxy isoflavone.
3. the preparation method of a kind of daidzein verivate as claimed in claim 2 is characterized in that in step 1), and said organic solvent is N or acetone.
4. the preparation method of a kind of daidzein verivate as claimed in claim 2; It is characterized in that in step 1); The volumetric molar concentration of daidzein is 0.1～1.0mmol/L in the said solution A; The volumetric molar concentration of Anhydrous potassium carbonate is 0.2～2.0mmol/L, and the volumetric molar concentration of allyl bromide 98 is for being 0.2～2.0mmol/L in the said solution B.
5. the preparation method of a kind of daidzein verivate as claimed in claim 2 is characterized in that in step 1), the condition of said reaction: temperature is 20～28 ℃, and the time is 16～20h, and stir speed (S.S.) is 50～100rpm.
6. the preparation method of a kind of daidzein verivate as claimed in claim 2 is characterized in that in step 2) in, the silica gel of said silica gel column chromatography is 200～400 orders.
7. the preparation method of a kind of daidzein verivate as claimed in claim 2 is characterized in that in step 3), the condition of said rearrangement reaction: temperature is 160～200 ℃, and the time is 4～6h.
8. the application of a kind of daidzein verivate as claimed in claim 1 in the anti-nasopharyngeal carcinoma of preparation, human cervical carcinoma, human fibrosarcoma and people's liver-cancer medicine.
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| Guodong Xiao, et al..Isolation of antioxidants from Psoralea corylifolia fruits using high-speed counter-current chromatography guided by thin layer chromatography-antioxidant autographic assay.《Journal of Chromatography A》.2010,第1217卷5470-5476. * |
| Taro Nomura, et al..Chemistry of phenolic compounds of licorice (Glycyrrhiza species) and their estrogenic and cytotoxic activities.《Pure Appl. Chem.》.2002,第74卷(第7期),1199-1206. * |
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