CN104529810A - Preparation method and application of arctigenin derivatives - Google Patents

Preparation method and application of arctigenin derivatives Download PDF

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CN104529810A
CN104529810A CN201410441786.0A CN201410441786A CN104529810A CN 104529810 A CN104529810 A CN 104529810A CN 201410441786 A CN201410441786 A CN 201410441786A CN 104529810 A CN104529810 A CN 104529810A
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aretigenin
derivative
compound
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窦德强
陈桂荣
康廷国
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Liaoning University of Traditional Chinese Medicine
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Liaoning University of Traditional Chinese Medicine
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Abstract

The method of the invention adopts arctigenin as a lead compound, carries out structure modification of arctigenin by chemical methods of demethylation, oxygen atom acylation, aminomethylation, ester aminolysis and hydrolysis, and the like, synthesizes 15 arctigenin structure derivatives, seven of which are new compounds. In the structural formula, R, R'=O or R=NHR'', R'=O or R=R'=OH, R1=OCH3 or H, R2=H or COCH3 or COC6H5 or COCH2CH2COOH, R3=H or CH2NR1'R2', R4=R5=H or SO3Na, R6=OCH3 or H, R7=OCH3 or H. The invention relates to the preparation process of the derivatives and research of the antineoplastic activity of the derivatives.

Description

The Preparation method and use of aretigenin derivative
Technical field
The present invention relates to the Preparation method and use of aretigenin derivative.
Background technology
Great Burdock Achene be composite family (Compositae) Arctium (Arctium) plant burdock ( arctium lappa) dry mature fruit.Great Burdock Achene has wind-dispelling heat-dissipating, a surname's lung promoting eruption, resolving toxin and disinhibiting the throat, the effect of the intestines defaecation that disappears, for common cold due to wind-heat, and coughing with a lot of sputum, measles, rubella, swelling and pain in the throat, mumps erysipelas, the diseases such as carbuncle sore tumefacting virus.The main pharmacodynamics composition of Great Burdock Achene is Arctiin, and our result of study and external report all show that Arctiin plays its drug effect by being metabolized to aretigenin in the gastrointestinal tract.But aretigenin belongs to Lignanoids compounds, water-soluble little, bioavailability is low, and this brings certain difficulty to the exploitation of the PTS of aretigenin.Therefore, the present invention relates to and carry out structure of modification with Chinese medicine aretigenin for lead compound and then carry out new drug development, expect to improve aretigenin water-soluble, improve bioavailability, facilitate formulation, find safer, effective, low toxicity and facilitate the anti-cancer agent of medication.
Summary of the invention
Object of the present invention, be to provide the preparation method of aretigenin derivative, its general structure is formula (), formula () compound is that lead compound synthetic obtains with aretigenin, carries out synthesis aretigenin derivative by hydroxyl, aromatic ring, lactonic ring reaction site.
(I)
Another object of the present invention, is to provide the purposes of aretigenin derivative, studies its antineoplastic activity.
The technical scheme adopted is:
R=NHR'', R'=OH, R in structural formula 1=CH 3, R 2=R 3=R 4=R 5=H, R 6=R 7=CH 3, adopt chemical process, by the method for ammonia solution the lactonic ring of aretigenin opened and obtain ammonia solution derivative.
R, R'=O, R in structural formula 1=R 2=R 3=R 4=R 5=H, R 6=CH 3or H, R 7=CH 3or H, be adopt chemical process in formula, aretigenin be converted into half demethylation or full demethylation derivative.
R, R'=O, R in structural formula 1=CH 3, R 2=H, R 3=CH 2nR 1' R 2', R 4=R 5=H, R 6=R 7=CH 3, adopt chemical process, be converted into the nitrogen containing derivative of aretigenin by aminomethylation (Mannich reaction).
Be R in structural formula 1'=CH 3, CH 2cH 3, R 2'=CH 3, CH 2cH; Or .This compounds is except the nitrogen containing derivative of piperidine ring, and other compounds are new compound.
Though the nitrogen containing derivative of piperidine ring is for report compound, but the present invention is the method that solvent replacement bibliographical information oil of mirbane is solvent first with Glacial acetic acid prepares this compound, and aftertreatment is easy, and reduce Financial cost, preparation technology is easy.
R, R'=O, R in structural formula 1=CH 3, R 2=R 3=H, R 4=R 5=SO 3na, R 6=R 7=CH 3, adopt chemical process, be converted into the sulfonate derivatives of aretigenin by the sulfonylation on aromatic ring.
R, R'=O, R in structural formula 1=CH 3, R 2=COCH 3or COC 6h 5or COCH 2cH 2cOOH, R 3=R 4=R 5=H, R 6=R 7=CH 3, R in formula 2be the pendant moiety of aretigenin molecular formula hydroxyl, adopt chemical process, be converted into fat-soluble derivant or the soluble derivative of aretigenin by the acidylate of Sauerstoffatom.Compared with the reaction method being solvent stirred overnight at room temperature with bibliographical information triethylamine, Reaction time shorten, methylene dichloride is solvent, and aftertreatment is easy, reduces Financial cost, Simplified flowsheet condition.
R=R'=OH, R in structural formula 1=CH 3, R 2=R 3=R 4=R 5=H, R 6=R 7=CH 3, adopt chemical process, the hydrolysis derivative of aretigenin will be obtained after the lactonic ring open loop of aretigenin by the method for basic hydrolysis.Though this compound is for report compound, but the present invention adopts the method for aretigenin basic hydrolysis to prepare this compound first.This compound polarity is greater than aretigenin, can be used as the prodrug of aretigenin.
The preparation technology of aretigenin ammonia solution derivative: aretigenin and mono-substituted primary amine solutions join in round-bottomed flask, stirring at room temperature, stopped reaction, after reaction solution concentrating under reduced pressure, preparation liquid phase separation or recrystallization obtain target compound.
The constitutional features of the ammonia solution derivative of aretigenin is R=NHR'', R''=CH 2cH 2cH 3, CH 2cH 2oH and CH 2c 6h 5, the propylamine of replacement, thanomin and benzylamine are generated corresponding p-Coumaric acid to the ammonolysis reaction of the lactonic ring generation ester of aretigenin and polarity is greater than aretigenin, can be used as the prodrug of aretigenin;
It is new compound that aretigenin and propylamine and thanomin react the ammonia solution derivative generated, the benzylamine ammonia solution derivative of aretigenin is for report compound, the present invention adopts benzylamine not only to make reaction raw materials but also the novel method making solvent prepares the benzylamine ammonia solution derivative of aretigenin, economize desolventizing, reduce Financial cost.
The preparation technology of aretigenin list demethylation derivative: aretigenin, anhydrous pyridine join in round-bottomed flask, gradation adds Aluminum chloride anhydrous in flask, finishes, backflow, stopped reaction.Reaction solution concentrating under reduced pressure, ethyl acetate and alcohol mixed solution dissolved residue, pumping rate, filtrate reduced in volume, silica gel column chromatography is separated and obtains target compound.
The preparation technology of the full demethylation derivative of aretigenin: add aretigenin, Glacial acetic acid, demethylating agent hydrobromic acid solution in round-bottomed flask, reflux, react complete.Be poured into water by reaction solution, use sodium bicarbonate adjust pH, use appropriate extraction into ethyl acetate, add anhydrous sodium sulfate drying, filter, filtrate reduced in volume, silica gel column chromatography is separated and obtains target compound.
Though aretigenin half demethylation and full demethylation derivative are for report compound, but the present invention adopts aretigenin to be reaction raw materials first, adopts Hydrogen bromide to be the full demethylation derivative that demethylation reagent prepares aretigenin; Adopt pyridine not only to prepare half demethylation derivative of aretigenin as alkali but also as the novel method of solvent, economize desolventizing, reduce Financial cost.
The preparation technology of aretigenin aminomethylation derivative: aretigenin, paraformaldehyde, dibasic secondary amine and Glacial acetic acid join in round-bottomed flask, reacting by heating.After reaction stops, underpressure distillation removing glacial acetic acid solvent, then in reaction flask, add appropriate water, filter, filtrate uses aqueous sodium carbonate adjust pH, and filter, crude product obtains target compound through Preparative TLC chromatographic separation or recrystallization.
The preparation technology of aretigenin Sauerstoffatom acylated derivatives: aretigenin and diacetyl oxide or Benzoyl chloride or Succinic anhydried react under the condition of heating, and reaction process is monitored by thin-layer chromatography.Question response terminates, and reaction solution is through aftertreatment, and Preparative TLC or silica gel chromatography, obtain corresponding acylate.
The preparation technology of aretigenin basic hydrolysis derivative: aretigenin and diethylamine react at ambient temperature, stopped reaction.Concentrating under reduced pressure, residue adds appropriate water, is extracted with ethyl acetate, combining extraction liquid, anhydrous sodium sulfate drying, and filter, filtrate reduced in volume, obtains aretigenin hydrolysis derivative.
The purposes of aretigenin derivative:
The present invention is preparing the application in cancer therapy drug, and these compounds have the effect of antiproliferative effect, separately or can combine with other drug and be applied in the preparation of cancer therapy drug as raw material.
The present invention take aretigenin as derivative preparation and the antitumor activity thereof of lead compound.Through aretigenin structural modification and antitumor activity carried out to its derivative show, the demethylation derivative compound of aretigenin 4-5aretigenin is better than to the effect of people cancer of the stomach SGC7901 growth-inhibiting; The aminomethylation compound of aretigenin 10aretigenin is better than to the growth-inhibiting effect of people cancer of the stomach SGC7901 and human prostata cancer Du154 cell, the growth-inhibiting effect of people liver cancer HEPG-2 cell and aretigenin are close; The sulfonate derivatives compound of aretigenin 11aretigenin is better than to the growth-inhibiting effect of people cancer of the stomach SGC7901 and people liver cancer HEPG-2 cell, the growth-inhibiting effect of human prostata cancer Du154 cell and aretigenin are close; The acylated derivatives compound of aretigenin 13-14all aretigenin is better than to the growth-inhibiting effect of people cancer of the stomach SGC7901, people liver cancer HEPG-2 and human prostata cancer Du154 cell.So, compound 4-5, compound 10-11and compound 13-14at anti-tumor aspect, there is good Development volue, wherein compound 11for water miscible compound, can be used as the injection of cancer therapy drug; Compound 13- 14obviously aretigenin is better than to the inhibiting rate of people cancer of the stomach SGC7901, in anti-cancer of the stomach, there is good DEVELOPMENT PROSPECT.
preparation example1
74.8.mg aretigenin and 2mL ethanolamine solutions add in round-bottomed flask, stirring at room temperature, stopped reaction.Reaction solution concentrating under reduced pressure, raffinate obtains the ammonia solution derivative of aretigenin through efficient preparation liquid phase separation 1,wherein compound 1for new compound.
Condition determination: INSTROM AV500
Solvent: CDCl 3
table 1 compound 1 13 c-NMR and 1 h-NMR nuclear magnetic resonance data
preparation example 2
111.6mg aretigenin is placed in 25mL round-bottomed flask, adds Tri N-Propyl Amine solution 6.0mL, stirring and dissolving at 25 DEG C, reacts stopped reaction after 24 hours.Reaction solution concentrating under reduced pressure, recrystallizing methanol, namely obtains compound 2, wherein compound 2for new compound.
Condition determination: INSTROM AV500
Solvent: CDCl 3
table 2 compound 2 13 c-NMR and 1 h-NMR nuclear magnetic resonance data
preparation example 3
96mg aretigenin and 1mL benzylamine solution join in round-bottomed flask, and 160 DEG C are reacted 12 hours.Reaction solution is chilled to room temperature, in reaction solution, adds 10% dilute hydrochloric acid, extraction into ethyl acetate 3-5 time, combining extraction liquid, concentrated, and then utilize efficient preparation liquid phase to be separated, obtain compound 3.
Condition determination: INSTROM AV500
Solvent: CDCl 3
table 3 compound 3 13 c-NMR and 1 h-NMR nuclear magnetic resonance data
preparation example 4
372mg aretigenin and 3.0mL anhydrous pyridine join in reaction flask, are warming up to 115 DEG C gradually, divide and in flask, add 399mg Aluminum chloride anhydrous three times, react 3 hours, terminate reaction.Reaction solution concentrating under reduced pressure, raffinate is through ethyl acetate: ethanol (2:1) extracts three times, united extraction liquid, concentrating under reduced pressure, silica gel column chromatography methylene dichloride: methyl alcohol system gradient elution, obtains compound 4.
Condition determination: INSTROM AV500
Solvent: MeOD
table 4 compound 4 13 c-NMR and 1 h-NMR nuclear magnetic resonance data
preparation example 5
100mg aretigenin and 2mL Glacial acetic acid join in reaction flask, stir and make it dissolve, be warming up to 70 DEG C, add demethylating agent 48% hydrobromic acid aqueous solution 0.2mL, are then warming up to 110 DEG C of reactions 16 hours, terminate reaction, be cooled to room temperature.Reaction solution is poured in equal-volume water, pH to 6-7 is adjusted with saturated sodium bicarbonate, extraction into ethyl acetate 3 times, combining extraction liquid, add anhydrous sodium sulfate drying, filter, filtrate reduced in volume, raffinate is through silica gel column chromatography methylene dichloride: methyl alcohol (40:1) system gradient elution, obtains compound 5.
Condition determination: INSTROM AV500
Solvent: DMSO
table 5 compound 5 13 c-NMR and 1 h-NMR nuclear magnetic resonance data
No C H
1 128.84
2 115.57 6.62 (1H, d, J=1.95 Hz)
3 145.10
4 143.79
5 116.58 6.62 (1H, d, J=7.90 Hz)
6 120.13 6.34 (1H, dd, J=7.98, 1.95 Hz)
7 33.35 2.72 (2H, m)
8 45.64 2.59 (1H, dd, J=3.25, 3.25 Hz)
9 178.47
1’ 129.56
2’ 115.44 6.48 (1H, d, J=1.95 Hz)
3’ 145.10
4’ 143.63
5’ 115.95 6.65 (1H, d, J=7.95 Hz)
6’ 119.19 6.43 (1H, dd, J=7.98, 1.95 Hz)
7’ 36.65 2.32 (2H, m)
8’ 40.80 2.45 (1H, dd, J=3.80, 3.95 Hz)
9’ 70.58 3.97 (1H, t), 3.80 (1H, t)
preparation example 6
Aretigenin, paraformaldehyde and Glacial acetic acid, add in reaction flask, then in reaction flask, add dimethylamine hydrochloride, diethylamine hydrochloride, piperidines, hydroxyethyl piperazine and Piperazine anhydrous respectively, reacting by heating, thin-layer chromatography (TLC) monitors reaction process.After stopped reaction, underpressure distillation removing glacial acetic acid solvent, then adds suitable quantity of water solution, filter, filtrate, with 5% aqueous sodium carbonate adjust pH 7-8, is filtered, solids with methanol recrystallization or Preparative TLC carry out purifying, obtain aminomethylation (Mannich reaction) product 6- 10, compound 6-7and compound 9- 10be new compound.
Condition determination: INSTROM AV500
Solvent: CDCl 3
table 6 compound 6 13 c-NMR and 1 h-NMR nuclear magnetic resonance data
Condition determination: INSTROM AV500
Solvent: CDCl 3
table 7 compound 7 13 c-NMR and 1 h-NMR nuclear magnetic resonance data
Condition determination: INSTROM AV500
Solvent: CDCl 3
table 8 compound 8 13 c-NMR and 1 h-NMR nuclear magnetic resonance data (CDCl 3 )
Condition determination: INSTROM AV500
Solvent: CDCl 3
table 9 compound 9 13 c-NMR and 1 h-NMR nuclear magnetic resonance data (CDCl 3 )
Condition determination: INSTROM AV500
Solvent: CDCl 3
table 10 compound 10 13 c-NMR and 1 h-NMR nuclear magnetic resonance data (CDCl 3 )
preparation example 7
111.6mg aretigenin, 1.2mL acetic anhydride and 0.6mL Glacial acetic acid join in round-bottomed flask, drip 0.12mL nitration mixture (Glacial acetic acid: sulfuric acid=1:1), stirring and dissolving.Stirring at room temperature 12 hours, stopped reaction.Reaction solution 5%NaCO 3adjust pH to 6-7, concentrating under reduced pressure, adds three volumes ethanol, supersound extraction, filters, and ethyl alcohol recrystallization after filtrate is concentrated, obtains the sulfonylation derivative compound of aretigenin 11, compound 11for new compound.
Condition determination: INSTROM AV500
Solvent: D 2o
table 11 compound 11 13 c-NMR and 1 h-NMR nuclear magnetic resonance data
preparation example 8
111.6mg aretigenin and 3mL Benzoyl chloride join in round-bottomed flask, react 2 hours at 40 DEG C.After question response terminates, add 2mL methylene dichloride, then wash 2 times with isopyknic 10% aqueous sodium hydroxide solution, organic over anhydrous dried over mgso, filter, through Preparative TLC chromatogram purification after filtrate is concentrated, obtain compound 12.
Condition determination: INSTROM AV500
Solvent: CDCl 3
table 12 compound 12 13 c-NMR and 1 h-NMR nuclear magnetic resonance data
preparation example 9
372mg aretigenin, 50mg sodium acetate, 3mL diacetyl oxide and 3mL methylene dichloride join in reaction flask, and 38 DEG C are reacted 5 hours, stopped reaction, cool to room temperature.In reaction soln, add isopyknic 10% dilute hydrochloric acid, saturated sodium hydrogen carbonate solution, saturated nacl aqueous solution and water respectively wash once, anhydrous sodium sulfate drying, filter, concentrated, raffinate is through silica gel column chromatography methylene dichloride: methyl alcohol (60:1) system carries out gradient elution, obtains compounds 13.
Condition determination: INSTROM AV500
Solvent: CDCl 3
table 13 compound 13 13 c-NMR and 1 h-NMR nuclear magnetic resonance data
preparation example 10
372mg aretigenin, 3mL triethylamine and 15mL CH 2cl 2join in reaction flask, under the condition stirred, add 1g Succinic anhydried, 40 DEG C are reacted stopped reaction after 7 minutes.Reaction solution first uses appropriate 10%HCl solution washing 2 times, then washes with water once, and anhydrous sodium sulfate drying is overanxious, and filtrate concentrates, dry, obtains compound 14.
Condition determination: INSTROM AV500
Solvent: CDCl 3
table 14 compound 14 13 c-NMR nuclear magnetic resonance data
No. δ C
1 138.55
2 111.52
3 151.11
4 136.75
5 122.54
6 120.57
7 34.62
8 46.37
9 178.59
1’ 130.32
2’ 111.99
3’ 149.06
4’ 147.89
5’ 113.38
6’ 121.40
7’ 38.08
8’ 40.99
9’ 71.26
10 170.30
11 28.7
12 28.9
13 176. 89
-OCH 3*3 55.89,55.86,55.84
preparation example 11
500mg aretigenin, 0.1mL diethylamine and 10mL methyl alcohol add in reaction flask, stirring at room temperature 24 hours, stopped reaction.Reaction solution concentrating under reduced pressure, adds equal-volume water, is extracted with ethyl acetate 3 times, combining extraction liquid, acetic acid ethyl acetate extract water washing 2 times, anhydrous sodium sulfate drying, and filter, filtrate reduced in volume, obtains compound 15.
Condition determination: INSTROM AV500
Solvent: Pyridine
table 15 compound 15 13 c-NMR nuclear magnetic resonance data (Pyr)
No. δ C
1 132.16
2 112.69
3 148.33
4 146.55
5 116.34
6 122.11
7 35.27
8 48.61
9 177.89
1’ 134.39
2’ 113.49
3’ 149.68
4’ 148.52
5’ 114.04
6’ 122.37
7’ 35.37
8’ 45.92
9’ 62.18
-OCH 3*3 55.76, 55.73, 56.02
experimental example 1
(Ι) of the present invention formula compound and antitumor activity thereof, compare (Ι) formula compound and the growth-inhibiting effect to different malignant cells.
Select and to aretigenin and derivative thereof, MTT experiment is carried out respectively to the tumour cell of aretigenin sensitivity.The strain of people's cancer is containing the RPMI-1640 nutrient solution of 10% calf serum, 37 DEG C, 5%CO 2cultivate under condition, within 48 hours, change liquid, go down to posterity with 0.25% tryptic digestion after cell covers with individual layer.With 2 × 10 4the cell suspension inoculation of/mL cell concn in 96 porocyte culture plates, every pore volume 200 μ L, 37 DEG C, 5%CO 2cultivate after 24 hours, add the medicine of different concns, each dosage establishes 3 multiple holes; Separately establish contrast 1 group (the RPMI-1640 nutrient solution with containing equivalent DMSO, 10% calf serum).Cultivate after 72 hours, sucking-off nutrient solution, every hole adds the RPMI-1640 nutrient solution 200 μ L of the serum-free containing MTT (final concentration 0.5 mg/mL), continue cultivation after 4 hours, supernatant solution is abandoned in suction, add 100 μ L DMSO, micro-oscillator vibrates 5 minutes, it is made fully to mix, microplate reader (Tecan Infinite M200) measures its absorbancy (A value), absorbing wavelength is 570 nm, cell proliferation inhibition rate=(1-treatment group A value/control group A value) × 100 ﹪.
1, aretigenin structural derivative compound 1and aretigenin, adopt human colon cancer cell strain HCT116, the human gastric carcinoma cell line MGC803, human lung carcinoma cell line NCI-H460, human pancreas cancer cell strain PANC-1 and esophageal cancer cell strain TE-1 to evaluate its activity.All cells strain is all purchased from Shanghai Inst. of Life Science, CAS Institute of Cell Biology.Half-inhibition concentration (the IC recorded when being below administration 3 days 50): unit (μm ol/L)
table 16 aretigenin and compound 1 anti-tumor activity result
Compound HCT116 MGC-803 NCI-H460 PANC-1 TE-1
Aretigenin 4.99 20 100 19.51 2.78
Compound 1 72.03 83.82 120.97 68.75 >100
Result shows: aretigenin is high to HCT116, TE-1, PANC-1, MGC-803 inhibit activities, IC 50be respectively 4.99 μm of ol/L, 2.78 μm of ol/L, 19.51 μm of ol/L, 20 μm of ol/L, and it is poor to NCI-H460 restraining effect, the inhibiting rate of 100 μm of ol/L aretigenins to NCI-H460 is 29.8%, illustrates that the antitumour activity of aretigenin has cell selective.Aretigenin structural modification compounds 1have restraining effect to HCT116, NCI-H460, PANC-1 tri-kinds of cell proliferations, and to the restraining effect of TE-1 more weak (see table 16).
2,14 aretigenin structural modification compounds 2-15and aretigenin, adopt human hepatoma cell strain Bel7402, human stomach cancer cell line SGC7901, human lung carcinoma cell line NCI-H460, human prostate cancer cell line Du145 and human hepatoma cell strain HEPG-2 to evaluate its activity.All cells strain is all purchased from Shanghai Inst. of Life Science, CAS Institute of Cell Biology.
table 17 aretigenin and structural derivative thereof are to the inhibiting comparison of different sorts growth of tumour cell
Result shows: with under aretigenin same concentrations condition, and the structural modification thing of 14 kinds of aretigenins all can the growth of T suppression cell in various degree, and the growth-inhibiting effect size of each sample to different types of tumour cell is also different.As can be seen from experimental result, the growth-inhibiting effect of each sample to human liver cancer cell Bel7402 cell is all weaker than aretigenin.Compared with Bel7402 cell, compound 4, compound 5, compound 8- 11compound 13-14comparatively strong to the growth-inhibiting effect of gastric carcinoma cells SGC7901 cell, inhibiting rate is respectively 57.03 ± 2.14,62.51 ± 5.54,55.26 ± 1.89,51.26 ± 2.47,56.26 ± 2.68,57.18 ± 2.33,68.50 ± 1.16 and 70.13 ± 2.05; Compared with Bel7402 cell, compound 9-11and compound 13-14be close to the growth-inhibiting effect of human prostata cancer Du145 cell and aretigenin, inhibiting rate is respectively 68.74 ± 4.19,74.95 ± 5.63,70.46 ± 5.19,72.35 ± 3.17 and 75.61 ± 2.88, compound 4and compound 5slightly be weaker than aretigenin to the growth-inhibiting effect of Du145, inhibiting rate is respectively 50.86 ± 6.42 and 61.62 ± 2.22, but other derivatives to the growth-inhibiting effect of Du145 all lower than aretigenin; Compound 10-11and compound 13-14all show stronger growth-inhibiting effect to people liver cancer HEPG-2 cell, inhibiting rate is respectively 52.37 ± 1.72,59.35 ± 2.31,63.23 ± 2.74 and 69.74 ± 2.92; Compound 4- 5and compound 8- 9the growth-inhibiting effect of people liver cancer HEPG-2 cells show and aretigenin are close, and inhibiting rate is respectively 45.65 ± 5.32,47.83 ± 3.29,47.19 ± 2.13 and 50.78 ± 1.84; Other derivatives be all weaker than aretigenin (see table 17).
Above-mentioned per-cent is volume percent.
The invention has the advantages that:
The present invention carries out structure of modification with Chinese medicine aretigenin for lead compound and then carries out new drug development, expect to improve aretigenin water-soluble, improve bioavailability, facilitate formulation, find safer, effective, low toxicity and facilitate the anti-cancer agent of medication.The restraining effect of the present invention to the growth of the stomach cancer cell of people, liver cancer cell, prostate cancer cell has the effect being obviously better than aretigenin itself.
Accompanying drawing explanation
Fig. 1 is the proton nmr spectra of aretigenin.
Fig. 2 is the carbon-13 nmr spectra of aretigenin.
Fig. 3 is the ammonia solution derivative compound of aretigenin 1hydrogen spectrum.
Fig. 4 is the ammonia solution derivative compound of aretigenin 1carbon spectrum.
Fig. 5 is the ammonia solution derivative compound of aretigenin 2hydrogen spectrum.
Fig. 6 is the ammonia solution derivative compound of aretigenin 2carbon spectrum.
Fig. 7 is the ammonia solution derivative compound of aretigenin 3hydrogen spectrum.
Fig. 8 is the ammonia solution derivative compound of aretigenin 3carbon spectrum.
Fig. 9 is single demethylation derivative compound of aretigenin 4hydrogen spectrum.
Figure 10 is single demethylation derivative compound of aretigenin 4carbon spectrum.
Figure 11 is the full demethylation derivative compound of aretigenin 5hydrogen spectrum.
Figure 12 is the full demethylation derivative compound of aretigenin 5carbon spectrum.
Figure 13 is the aminomethylation derivative compound of aretigenin 6hydrogen spectrum.
Figure 14 is the aminomethylation derivative compound of aretigenin 6carbon spectrum.
Figure 15 is the aminomethylation derivative compound of aretigenin 7hydrogen spectrum.
Figure 16 is the aminomethylation derivative compound of aretigenin 7carbon spectrum.
Figure 17 is the aminomethylation derivative compound of aretigenin 8hydrogen spectrum.
Figure 18 is the aminomethylation derivative compound of aretigenin 8carbon spectrum.
Figure 19 is the aminomethylation derivative compound of aretigenin 9hydrogen spectrum.
Figure 20 is the aminomethylation derivative compound of aretigenin 9carbon spectrum.
Figure 21 is the aminomethylation derivative compound of aretigenin 10hydrogen spectrum.
Figure 22 is the aminomethylation derivative compound of aretigenin 10carbon spectrum.
Figure 23 is the sulfonylation derivative compound of aretigenin 11hydrogen spectrum.
Figure 24 is the sulfonylation derivative compound of aretigenin 11carbon spectrum.
Figure 25 is the acylated derivatives compound of aretigenin 12hydrogen spectrum.
Figure 26 is the acylated derivatives compound of aretigenin 12carbon spectrum.
Figure 27 is the acylated derivatives compound of aretigenin 13hydrogen spectrum.
Figure 28 is the acylated derivatives compound of aretigenin 13carbon spectrum.
Figure 29 is the acylated derivatives compound of aretigenin 14carbon spectrum.
Figure 30 is the hydrolysis derivative compound of aretigenin 15carbon spectrum.

Claims (10)

1. aretigenin derivative, is characterized in that: be that lead compound carries out structural modification and obtains with aretigenin, its general structure is ();
(?)。
2. aretigenin derivative according to claim 1, its constitutional features is R=NHR'', R'=OH, R 1=CH 3, R 2=R 3=R 4=R 5=H, R 6=R 7=CH 3, adopt chemical process, after can being opened by the lactonic ring of aretigenin by the method for ammonia solution, obtain ammonia solution derivative;
The structure of the ammonia solution derivative of aretigenin is R=NHR'', R''=CH 2cH 2cH 3, CH 2cH 2oH and CH 2c 6h 5, the propylamine of replacement, thanomin and benzylamine are generated corresponding p-Coumaric acid to the ammonolysis reaction of the lactonic ring generation ester of aretigenin and polarity is greater than aretigenin, can be used as the prodrug of aretigenin.
3. aretigenin derivative according to claim 1, its constitutional features is R, R'=O, R 1=R 2=R 3=R 4=R 5=H, R 6=CH 3or H, R 7=CH 3or H, be adopt chemical process aretigenin to be converted into half demethylation or full demethylation derivative in formula.
4. aretigenin derivative according to claim 1, its constitutional features is R, R'=O, R 1=CH 3, R 2=H, R 3=CH 2nR 1' R 2', R 4=R 5=H, R 6=R 7=CH 3, adopt chemical process, be converted into the nitrogen containing derivative of aretigenin by aminomethylation reaction.
5. aretigenin derivative according to claim 4, its constitutional features is R 1'=CH 3, CH 2cH 3, R 2'=CH 3, CH 2cH; Or , this compounds is except the nitrogen containing derivative of piperidine ring, and other compounds are new compound.
6. aretigenin derivative according to claim 1, its constitutional features is R, R'=O, R 1=CH 3, R 2=R 3=H, R 4=R 5=SO 3na, R 6=R 7=CH 3, adopt chemical process, be converted into the sulfonate derivatives of aretigenin by the sulfonylation on aromatic ring.
7. aretigenin derivative according to claim 1, its constitutional features is R, R'=O, R 1=CH 3, R 2=COCH 3, COC 6h 5or COCH 2cH 2cOOH, R 3=R 4=R 5=H, R 6=R 7=CH 3, R in formula 2be the pendant moiety of aretigenin molecular formula hydroxyl, adopt chemical process, be converted into fat-soluble derivant or water miscible derivative by the acidylate of Sauerstoffatom.
8. aretigenin derivative according to claim 7, it is characterized in that: the Sauerstoffatom acylated derivatives of aretigenin, employing methylene dichloride is solvent, adds appropriate triethylamine and sodium acetate, and reflux prepared this analog derivative by 5 hours in 7 minutes.
9. aretigenin derivative according to claim 1, the constitutional features of the hydrolysis derivative of aretigenin is R=R'=OH, R 1=CH 3, R 2=R 3=R 4=R 5=H, R 6=R 7=CH 3, be there is hydrolysis reaction in the basic conditions in aretigenin, obtains the basic hydrolysis derivative of aretigenin lactonic ring open loop.
10. aretigenin derivative according to claim 1, is preparing the application in cancer therapy drug, it is characterized in that: these compounds have the effect of antiproliferative effect, separately or can combine with other drug and be applied in the preparation of cancer therapy drug as raw material.
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CN105732598B (en) * 2016-02-03 2018-07-27 辽宁中医药大学 Arctigenin ether derivative and its preparation method and application

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