CN103275051B - A kind of 7,3 ', 4 '-trihydroxyflavone derivative and preparing the application in Hepatoma therapy medicine - Google Patents
A kind of 7,3 ', 4 '-trihydroxyflavone derivative and preparing the application in Hepatoma therapy medicine Download PDFInfo
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- 0 CC*(C(C(C1*)O)[C@@](C)OC1C(CC1)=CC(N)=C1N)I Chemical compound CC*(C(C(C1*)O)[C@@](C)OC1C(CC1)=CC(N)=C1N)I 0.000 description 1
Abstract
The invention discloses a kind of 7,3 ', 4 '-trihydroxyflavone derivative and preparing the application in Hepatoma therapy medicine, 7, the compound of 3 ', 4 '-trihydroxyflavone derivative used as anti-tumor medicine, particularly have clear and definite curative effect to liver cancer to malignant tumour, its general structure is:
external pharmacological evaluation shows, described in said structure general formula I 7, and 3 ', 4 '-trihydroxyflavone derivative used as anti-tumor medicine, has obvious anti-tumor activity, has good antitumor drug development prospect.
Description
Technical field
The invention belongs to medical art, relate to a kind of 7,3 ', 4 '-trihydroxyflavone derivative and preparing the application in Hepatoma therapy medicine.
Background technology
Malignant tumour is a kind of common disease of serious threat human health, and the mortality ratio ranking the second that malignant tumour causes, is only second to cardiovascular disorder.According to incompletely statistics, the whole world has nearly new cases of 2,000 ten thousand every year.Updated statistics shows, and the annual tumour new cases of China are about 2,200,000, because tumor mortality number is about 1,600,000, account for 1/5th of disease death number.Treatment at present for tumour mainly contains pharmacotherapy, operative therapy and radiotherapy.Pharmacological agent has become the important means of current clinical cancer therapy.The antitumor drug of clinical main use roughly can be divided into the medicine (as: endoxan destroying DNA structure and function, oxaliplatin etc.), affect the medicine of Nucleic acid (as Fluracil, gemcitabine, methotrexate etc.), interference transcription suppresses the medicine (as Zorubicin), antitumor antibiotics (as dactinomycin) etc. of RNA synthesis.Its pharmacological action is all " cytocide " substantially, and they non-specifically block cell fission thus cause necrocytosis, while killing tumour cell, also destroys human normal cell.In order to overcome the poor selectivity of conventional cell cytotoxic drug, toxic side effect comparatively strong, easily produce the shortcomings such as resistance, antitumor drug is transitioned into according to the specific effect of clear and definite mechanism of action in the medicament research and development of dysfunction cell from the research of conventional cell cytotoxic drug.Flavones take C6-C3-C6 as a series of compounds of basic carbon skeleton, vegitabilia's distribution is very wide and pharmaceutical use is extensive.As the rutin in the sophora bud and the dried orange peel glycosides in dried orange peel, the fragility of blood vessel can be reduced, and improve blood vessel permeability, reduce blood fat and cholesterol, for preventing and treating senile hypertension and Intracerebral hemorrhage.The SHUXUENING PIAN be made up of Ginkgo Leaf contains flavones and bisflavones, for the treatment of coronary heart diseases and angina pectoris.The efloxate of synthesis has another name called efloxate or Li Keding, has expansion coronary vasodilator, increases the effect of coronary flow.Many flavones ingredients have cough-relieving, eliminate the phlegm, relieving asthma, antibacterial activity.Protect liver, separate liver malicious, antimycotic, treat acute hepatitis, chronic hepatitis, liver cirrhosis.
Summary of the invention
The object of the present invention is to provide a kind of 7,3 ', 4 '-trihydroxyflavone derivative and preparing the application in Hepatoma therapy medicine, 7, the compound of 3 ', 4 '-trihydroxyflavone derivative used as anti-tumor medicine, particularly have clear and definite curative effect to liver cancer to malignant tumour, its general structure is:
R
1h, CH
2cH
2cl, CH
2cH
2br and (CH
2cH
2x) any one in nY, wherein X=NH, O; Y=H, CH
3, CH
2cH
3, Oac; N=1 ~ 10; R
2and R
4h, CH
3, CH
2cH
3, CH
2oH, CH
2oAc, CH
2oCH
3, CH
2cH
2oH, COOH, COOC, COOCH
2cH
3, CONH
2, CONHCH
3, CONHCH
2ph, CONHPh, OH, OAc, OCH
3, OCH
2cH
3, NHAc, NHCOPh any one, R
2and R
5can be identical or different; R
3h, Cl, Br, NO
2, CH
3, CH
2cH
3, CH (CH
3)
2, C (CH
3)
3with any one in Ac;
External pharmacological evaluation shows, described in said structure general formula I 7, and 3 ', 4 '-trihydroxyflavone derivative used as anti-tumor medicine, has obvious anti-tumor activity (the results are shown in Table 1), has good antitumor drug development prospect.
Table 1 is the anti tumor activity in vitro test-results of part of compounds.
Compound I a in table 1 is to the IC of human hepatoma cell
50for 0.52ug/mL, and the IC to human normal liver epithelial cell
50for 2.76ug/mL, be that difference of them is fairly obvious to normally Cytotoxic 5.3 times to the toxicity of liver cancer cell, therefore visual compounds I is expected to play an important role in Hepatoma therapy.
Accompanying drawing explanation
Fig. 1 is the H-NMR collection of illustrative plates of embodiment 1 final product;
Fig. 2 is the H-NMR collection of illustrative plates of embodiment 1 final product;
Fig. 3 is the H-NMR collection of illustrative plates of embodiment 1 final product;
Fig. 4 is the H-NMR collection of illustrative plates of embodiment 1 final product;
Fig. 5 is the H-NMR collection of illustrative plates of embodiment 1 final product;
Embodiment
Below in conjunction with specific embodiment, the present invention is described in detail.
The synthesis of example I-01:2-(3,4-dihydroxyl)-2,7-dihydroxyl-5-methoxyl group-4H-benzopyran-4-one
Under nitrogen protection condition, by 2-(3,4-dihydroxyl) 3; 5; 7-trihydroxy--4H-chromene-4 ketone (1g, 3.31mmol), bromotoluene (1.98g; 11.58mmol); the DMF of salt of wormwood (1.60g, 11.58mmol) and 20mL is placed in 100mL round-bottomed flask; after stirring at room temperature 12h, in this reaction system, add 100mL water.Use ethyl acetate (100mL × 3) to extract again, merge organic layer.After this organic phase uses saturated common salt water washing again, with anhydrous sodium sulfate drying, vacuum concentration organic phase.Residue silica gel chromatography, chloroform is eluent, obtains 450mg yellow powder solid, productive rate 21%.
By 3,7-bis-(benzyloxy)-2-[3, the two benzyl oxy phenyl of 4-]-5-hydroxyl-4H-benzo pyrrole-4-ketone (420mg, 0.63mmol) with the N of 5mL, dinethylformamide is dissolved in 50mL round-bottomed flask, adds methyl iodide (270mg, 1.90mmol) in this flask simultaneously, salt of wormwood (262.5mg, 1.90mmol).This system is detected by LCMS, TLC (ethyl acetate/petroleum ether=1:2), stirred overnight at room temperature, and reaction is finished.Add the dilution of 10mL water, then use ethyl acetate (10mL × 3) to extract, merge organic layer.This organic phase uses saturated common salt water washing again, anhydrous magnesium sulfate drying, and vacuum concentration obtains 400mg yellow oil 3,7-bis-(benzyloxy)-2-[3,4-bis-benzyl oxy phenyl]-5-methoxyl group-4H-benzopyran-4-one, productive rate 93%.
By 3,7-bis-(benzyloxy)-2-[3,4-bis-benzyl oxy phenyl]-5-methoxyl group-4H-benzopyran-4-one (200mg, 0.30mmol), Pd (OH)
2/ C (200mg), tetrahydrofuran (THF) 2mL and ethanol 2mL are placed in 50mL round-bottomed flask.Hydrogen imports in this reaction solution simultaneously.Whole reaction is by LCMS, TLC (methylene dichloride: methyl alcohol=5:1), and stirred overnight at room temperature, reaction is finished.Mother liquor after filtration concentrates to obtain the thick product of 100mg under vacuo, obtains 9.9mg yellow solid 2-(3,4-dihydroxyl)-3,7-dihydroxyl-5-methoxyl group-4H-benzopyran-4-one, productive rate 11% with preparative high performance liquid phase separating-purifying.Preparative high performance liquid phase condition (Pre-HPLC-001 (SHIMADZU)): chromatographic column, SunFirePrepC18,19*150mm5um; Moving phase, water and acetonitrile (20%CH
3cNupto38%in10min, upto100%in1min, downto20%in1min); Detector: Waters2545UvDector254 & 220nm. (ESI, m/z): 317 [M+H]
+; HNMR (300MHz, DMSO) δ: 10.71 (s, 1H), 9.46 (s, 1H), 9.25 (s, 1H), 8.63 (s, 1H), 7.64 (s, 1H), 7.50 (d, J=9.0Hz, 1H), 6.89 (d, J=9.0Hz, 1H), 6.48 (s, 1H), 6.37 (s, 1H), 3.85 (s, 3H).
Example I-02: the tertiary butyl-N-[synthesis of 2-[2-(2-[3-[2-(3,4-dihydroxy phenyl)-3,5,7-trihydroxy--4-oxygen-4H-chromene-6] propoxy-] oxyethyl group) ethyl] carbamate
By 2-(3,4-dihydroxyl) 3,5,7-trihydroxy--4H-chromene-4 ketone (1.0g, the 3.31mmol) DMF of 100mL is dissolved in the round-bottomed flask of 250mL, add salt of wormwood (1.82g, 13.17mmol) simultaneously.Stirred overnight at room temperature, reaction is finished.Add 200mL water and dilute this system, then be extracted with ethyl acetate (100mL × 2), merge organic phase, vacuum concentration.By residue column chromatography separating purification, developping agent is ethyl acetate/petroleum ether=1:20 ~ 1:10, obtains 1.2g yellow solid 3,7-bis-(benzyloxy)-2-[3,4-bis-(benzyloxy) phenyl]-5-hydroxyl-4H-benzopyran-4-one, productive rate 55%.
By 3,7-bis-(benzyloxy)-2-[3,4-bis-(benzyloxy) phenyl]-5-hydroxyl-4H-benzopyran-4-one (7.0g, 10.56mmol) be dissolved in 1000mL three-necked bottle with the mixed solvent of methylene chloride/methanol=45/9, add calcium carbonate (7.7g, 76.92mmol) again.This system is instilled BTMA.ICl2 (3.7g at 0 DEG C in batches, 10.63mmol), after stirred overnight at room temperature, in this system, add 300mL water, extract with methylene dichloride (300mL × 2), merge organic phase, vacuum concentration, anhydrous magnesium sulfate drying, obtain 7.8g yellow powder solid 3,7-bis-(benzyloxy)-2-[two (benzyloxy) phenyl of 3,4-]-5-hydroxyl-6-iodo-4H-benzopyran-4-one, productive rate 94%.
By 3,7-bis-(benzyloxy)-2-[3, two (benzyloxy) phenyl of 4-] the iodo-4H-benzopyran-4-one of-5-hydroxyl-6-(7.8g, 9.89mmol) with the N of 150mL, dinethylformamide is dissolved in 250mL round-bottomed flask, then adds salt of wormwood (2.1g, 15.19mmol) and bromotoluene (2.5g, 14.62mmol), stirred overnight at room temperature.Add the dilution of 250mL water, ethyl acetate (200mL × 3) extracts, and merges organic phase, saturated common salt water washing, vacuum concentration.Thick product silica gel column chromatography separating-purifying, moving phase is ethyl acetate/petroleum ether=1:20 ~ 1:5, obtains 8.0g light yellow solid 3,5, the iodo-4H-benzopyran-4-one of 7-tri-(benzyloxy)-2-[3,4-bis-(benzyloxy) phenyl]-6-, productive rate 92%.
Under nitrogen protection condition; by (300mg; 0.34mmol) 3; 5; 7-tri-(benzyloxy)-2-[3; 4-bis-(benzyloxy) phenyl] N of-6-iodo-4H-benzopyran-4-one 3mL; dinethylformamide is dissolved in the three-necked bottle of 50mL; add tertiary butyl N-(2-[2-[2-(propyl group 2-titanium carbide base-1-base) oxyethyl group] oxyethyl group] ethyl) carbamate (300mg again; 1.04mmol), Pd (PPh
3)
2cl
2(16.7mg, 0.02mmol), cuprous iodide (3.8mg, 0.02mmol) and piperidines (57.9mg, 0.68mmol).Stir at 80 DEG C and spend the night, reaction is finished.Add 10mL water, then use ethyl acetate (10mL × 4) to extract, merge organic phase, saturated common salt water washing, anhydrous sodium sulfate drying, vacuum concentration.Gained thick product silica gel column chromatography separating-purifying, moving phase is ethyl acetate: sherwood oil=1:5 ~ 1:2, obtain 150mg white solid tertiary butyl N-(2-[2-[2-([3-[3,5,7-tri-(benzyloxy)-2-[3,4-bis-(benzyloxy) phenyl]-4-oxygen-4H-chromene-6-base] propyl group-2-titanium carbide base-1-base] oxygen) oxyethyl group] oxyethyl group] ethyl) carbamate, productive rate 42%.
By 4.8g palladium/carbon, tertiary butyl N-(2-[2-[2-([3-[3,5,7-tri-(benzyloxy)-2-[3,4-bis-(benzyloxy) phenyl]-4-oxygen-4H-chromene-6-base] propyl group-2-titanium carbide base-1-base] oxygen) oxyethyl group] oxyethyl group] ethyl) carbamate (1.6g, 1.54mmol) be placed in 50mL round-bottomed flask with the mixed solvent of ethanol/water (150/3.0mL), import hydrogen simultaneously.Stirred overnight at room temperature, filter, mother liquid obtained vacuum concentration recycle silicon glue pillar layer separation is purified, moving phase is methylene chloride/methanol 50:1 ~ 5:1), obtain the 0.5g light yellow solid tertiary butyl-N-[2-[2-(2-[3-[2-(3,4-dihydroxy phenyl)-3,5,7-trihydroxy--4-oxygen-4H-chromenes-6] propoxy-] oxyethyl group) ethyl] carbamate.Productive rate 55%.(ES,m/z):[M+Na]
+＝614,[M-Boc+H]
+＝492；HNMR(300MHz,CDCl
3):δ:7.762(s,1H),7.643～7.668(d,J＝7.5Hz),6.891～6.920(d,J＝8.7Hz,1H),6.462(s,1H),3.505～3.655(m,12H),3.213～3.248(t,J1＝5.1Hz,J2＝10.5Hz,2H),2.716～2.764(t,J1＝6.9Hz,J2＝14.4Hz,2H),1.848～1.919(m,2H),1.437(s,9H).
The synthesis of the bromo-2-of example I-03:8-(3,4-dihydroxy phenyl)-3,5,7-trihydroxy--4H-benzopyran-4-one
By 2-(3,4-dihydroxy phenyl)-3,5,7-trihydroxy--4H-benzopyran-4-one (500mg, 1.65mmol) be dissolved in the round-bottomed flask of 50mL with 10mL methylene dichloride, add diacetyl oxide (760mg, 7.44mmol) and pyridine (262mg, 3.31mmol) again.Stirring at room temperature 3h, reaction is finished.Directly by reaction solution vacuum concentration, the mixing solutions crystallization of the thick product ethanol/water=10:1 of gained, obtain 0.5g light yellow solid 3-(acetoxyl group)-2-[3,4-bis-(acetoxyl group) phenyl]-5-hydroxyl-4-oxygen-4H-chromene-7-acetic ester, productive rate 64%.
By 3-(acetoxyl group)-2-[3,4-bis-(acetoxyl group) phenyl]-5-hydroxyl-4-oxygen-4H-chromene-7-acetic ester (50mg, 0.11mmol) be dissolved in 50mL round-bottomed flask with 5mL tetracol phenixin, add N-bromo-succinimide (19mg again, 0.11mmol) with (3mg, 0.01mmol) succimide.Whole reaction system stirs 2h at 80 DEG C, and reaction is finished.Vacuum concentration obtains 150mg yellow solid 3-(acetoxyl group)-2-[3,4-bis-(acetoxyl group) phenyl] the bromo-5-hydroxyl of-8--4-oxygen-4H-chromene-7-acetic ester, productive rate 86%.
By 3-(acetoxyl group)-2-[3,4-bis-(acetoxyl group) phenyl] the bromo-5-hydroxyl of-8--4-oxygen-4H-chromene-7-acetic ester (30mg, 0.05mmol) use 5mL dissolve with methanol in the round-bottomed flask of 10mL, add sulfuric acid (30mg, 0.31mmol) again.Stirred overnight at room temperature, reaction is finished.Vacuum concentration reaction solution, gained 30mg thick product preparation HPLC separating-purifying obtains the bromo-2-of 10mg light yellow solid 8-(3,4-dihydroxy phenyl)-3,5,7-trihydroxy--4H-benzopyran-4-one, productive rate 48%.Preparation HPLC (HPLC-001 (SHIMADZU)) condition is: chromatographic column, SunFirePrepC18,19*150mm5um; Moving phase, water, 0.05% trifluoroacetic acid and acetonitrile (35%CH
3cNupto48%in10min, upto100%in1min, downto35%in1min); Detector, Waters2545UvDector254 & 220nm. (ES, m/z): [M+1]: 383; HNMR (CD
3oD): δ: 7.74 (d, J=16.0Hz, 1H), 7.66 (d, J=8.4Hz, 1H), 6.91 (d, J=8.4Hz, 1H), 6.58 (s, 1H).
The synthesis of example I-04:3-butoxy-2-(3,4-dihydroxy phenyl)-5,7-dihydroxyl-4H-benzopyran-4-one
By 2-(3,4-dihydroxyl) 3,5,7-trihydroxy--4H-chromene-4 ketone (5g, 16.54mmol) and ditan (11.8g, 49.76mmol) are placed in 100mL round-bottomed flask, stir 10min at 180 DEG C after, reaction is finished.Whole process is by LCMS, TLC (methylene dichloride: ethyl acetate=6:1) detection control.The thick product silica gel column chromatogram separating purification of gained, moving phase is dichloromethane/ethyl acetate (30:1), obtains 1.8g yellow solid 2-(2,2-phenylbenzene-2H-1,3-dihydroxy-benzene-5)-3,5,7-trihydroxy--4H-benzopyran-4-one, productive rate 23%.
By 2-(2,2-phenylbenzene-2H-1,3-dihydroxy-benzene-5)-3,5,7-trihydroxy--4H-benzopyran-4-one (200mg, 0.43mmol) N, dinethylformamide 5mL is dissolved in 50mL round-bottomed flask, add 1-n-butyl bromide (47mg, 0.34mmol) and salt of wormwood (59mg, 0.43mmol) again.Whole reaction process is by LCMS, TLC (dichloromethane/ethyl acetate=6:1) detection control, and stirred overnight at room temperature, reaction is finished.Add the dilution of 10mL water, then use ethyl acetate (10mL × 3) to extract, merge organic phase, anhydrous sodium sulfate drying, vacuum concentration.Gained thick product silica gel column chromatography separating-purifying, moving phase is dichloromethane/ethyl acetate (40:1 ~ 20:1), obtain 130mg yellow oil 3-butoxy-2-(2,2-phenylbenzene-2H-1,3-dihydroxy-benzene-5)-5,7-dihydroxyl-4H-benzopyran-4-one, productive rate 58%.
By 3-butoxy-2-(2,2-phenylbenzene-2H-1,3-dihydroxy-benzene-5)-5,7-dihydroxyl-4H-benzopyran-4-one (130mg, 0.25mmol), acetic acid 4mL and water 1mL is placed in 50mL round-bottomed flask, whole reaction process passes through LCMS, TLC (dichloromethane/ethyl acetate=6:1) detection control, stirs and spends the night at 110 DEG C, and reaction is finished.By reaction solution vacuum concentration, gained 100mg thick product preparation HPLC separating-purifying obtains 6.6mg yellow solid 3-butoxy-2-(3,4-dihydroxy phenyl)-5,7-dihydroxyl-4H-benzopyran-4-one productive rate 7%.Preparation HPLC (HPLC-001 (SHIMADZU)) condition is: chromatographic column, C18,19*150mm5um; Moving phase, water 0.05% trifluoroacetic acid and acetonitrile (55.0%CH
3cNupto65.0%in10min, upto100.0%in1min, downto55.0%in1min); Detector, Waters2545UvDector254 & 220nm. (ESI, m/z): 359 [M+H]
+; HNMR (300MHz, CD
3oD): δ: 7.60 (d, J=2.1Hz, 1H), 7.52 ~ 7.55 (m, 1H), 6.92 (d, J=8.4Hz, 1H), 6.42 (d, J=2.1Hz, 1H), 6.22 (d, J=2.1Hz, 1H), 3.94 (t, J=6.6Hz, 2H), 1.67 ~ 1.74 (m, 2H), 1.41 ~ 1.48 (m, 2H), 0.93 (t, J=7.5Hz, 3H).
The synthesis of example I-05:2-(3,4-dihydroxy phenyl)-5,7-dihydroxyl-3-(2-methoxyethoxy)-4H-benzopyran-4-one
By 2-(3,4-dihydroxyl) 3,5,7-trihydroxy--4H-chromene-4 ketone (5g, 16.54mmol) and ditan (11.8g, 49.76mmol) are placed in 100mL round-bottomed flask, stir 10min at 180 DEG C after, reaction is finished.Whole process is by LCMS, TLC (methylene dichloride: ethyl acetate=6:1) detection control.The thick product silica gel column chromatogram separating purification of gained, moving phase is dichloromethane/ethyl acetate (30:1), obtains 1.8g yellow solid 2-(2,2-phenylbenzene-2H-1,3-dihydroxy-benzene-5)-3,5,7-trihydroxy--4H-benzopyran-4-one, productive rate 23%.
By 2-(2,2-phenylbenzene-2H-1,3-dihydroxy-benzene-5)-3,5,7-trihydroxy--4H-benzopyran-4-one (200mg, 0.43mmol) N, dinethylformamide 5mL is dissolved in 50mL round-bottomed flask, add the bromo-2-methyl ethyl ether (47.25mg, 0.34mmol) of 1-and salt of wormwood (59mg, 0.43mmol) again.Whole reaction process is by LCMS, TLC (dichloromethane/ethyl acetate=6:1) detection control, and stirred overnight at room temperature, reaction is finished.Add the dilution of 10mL water, then use ethyl acetate (10mL × 3) to extract, merge organic phase, anhydrous sodium sulfate drying, vacuum concentration.Gained thick product silica gel column chromatography separating-purifying, moving phase is dichloromethane/ethyl acetate (40:1 ~ 20:1), obtain 130mg yellow oil 3-methoxy ethyl-2-(2,2-phenylbenzene-2H-1,3-dihydroxy-benzene-5)-5,7-dihydroxyl-4H-benzopyran-4-one, productive rate 58%.
By 3-methoxy ethyl-2-(2,2-phenylbenzene-2H-1,3-dihydroxy-benzene-5)-5,7-dihydroxyl-4H-benzopyran-4-one (130mg, 0.25mmol), acetic acid 4mL and water 1mL is placed in 50mL round-bottomed flask, whole reaction process passes through LCMS, TLC (dichloromethane/ethyl acetate=6:1) detection control, stirs and spends the night at 110 DEG C, and reaction is finished.By reaction solution vacuum concentration, gained 100mg thick product preparation HPLC separating-purifying obtains 6.6mg yellow solid 3-methoxy ethyl oxygen base-2-(3,4-dihydroxy phenyl)-5,7-dihydroxyl-4H-benzopyran-4-one productive rate 7%.Preparation HPLC (HPLC-001 (SHIMADZU)) condition is: chromatographic column, C18,19*150mm5um; Moving phase, water 0.05% trifluoroacetic acid and acetonitrile (55.0%CH
3cNupto65.0%in10min, upto100.0%in1min, downto55.0%in1min); Detector, Waters2545UvDector254 & 220nm. (ESI, m/z): 361 [M+H]
+; HNMR (300MHz, CD
3oD, ppm): δ: δ 7.62 ~ 7.66 (m, 1H), 6.92 (d, J=8.4Hz, 1H), 6.42 (s, 1H), 6.27 (s, 1H), 4.13 ~ 4.16 (m, 2H), 3.57 ~ 3.67 (m, 2H), 1.32 (s, 3H).
Embodiment 6: vitro Drug anticancer test (MTT colorimetry)
3 × 10
4the hepatoma cell strain 7402 of/mL is inoculated in 96 well culture plates, and every hole adds 200u1, uses 10%MEM culture medium culturing.Remove nutrient solution after cultivating 24h in incubator, add and newly prepare nutrient solution, and add the DMSO solution of the medicine to be measured of a series of concentration respectively, every hole adds 200u1, every dosage group establishes three parallel models, and after cultivating 48h, every hole adds the MTT solution 20u1 of 2mg/mL, cultivates 4h.Nutrient solution in complete sucking-off hole, the DMSO respectively adding 150u1 shakes and crystallisate was dissolved in 10 minutes.Each hole OD value (λ=-570nm) is detected with enzyme connection detector; With OD value, the logarithm of drug level is mapped, obtain from figure the drug level and IC that make half necrocytosis
50, the results are shown in Table 1.
Should be understood that, for those of ordinary skills, can be improved according to the above description or convert, and all these improve and convert the protection domain that all should belong to claims of the present invention.
Claims (1)
1. one kind 7,3 ', 4 '-trihydroxyflavone derivative, is characterized in that, its general structure is:
Wherein, R
1for H, R
2for H, R
3for H, R
4for CH
3(CH
2)
2cH
2o; Or
R
1for H, R
2for H, R
3for H, R
4for CH
3oCH
2cH
2o; Or
R
1for H, R
2for (CH
3)
3oCONH (CH
2oCH
2)
3(CH
2)
2, R
3for H, R
4for OH;
Described in general structure I 7,3 ', 4 '-trihydroxyflavone derivative used as anti-tumor medicine, has obvious anti-tumor activity.
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| CN104003968A (en) * | 2014-06-17 | 2014-08-27 | 广西师范学院 | Natural product 3-prenyl Iuteolin analogue (I)/(II), preparation method of natural product 3-prenyl Iuteolin analogue (I)/(II), and application of natural product 3-prenyl Iuteolin analogue (I)/(II) |
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| CN102698275A (en) * | 2012-06-19 | 2012-10-03 | 中国人民解放军第二军医大学 | Application of myricetin similar flavonol compound to preparation of antitumor medicament |
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2013
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102698275A (en) * | 2012-06-19 | 2012-10-03 | 中国人民解放军第二军医大学 | Application of myricetin similar flavonol compound to preparation of antitumor medicament |
Non-Patent Citations (2)
| Title |
|---|
| Metabolism-based synthesis,biologic evaluation and SARs analysis of O-methylated analogs of quercetin as thrombin as thrombin inhibitors;Zhi-Hao Shi et al.;《European Journal of Medicinal Chemistry》;20120514;第54卷;210-222 * |
| 槲皮素衍生物的合成及生物活性研究进展;渠文涛等;《化学研究》;20120731;第23卷(第4期);101-110 * |
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