CN101700995A - Polyvinylarene substituted beta-diketones with anti-tumor effects - Google Patents
Polyvinylarene substituted beta-diketones with anti-tumor effects Download PDFInfo
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- CN101700995A CN101700995A CN200810220580A CN200810220580A CN101700995A CN 101700995 A CN101700995 A CN 101700995A CN 200810220580 A CN200810220580 A CN 200810220580A CN 200810220580 A CN200810220580 A CN 200810220580A CN 101700995 A CN101700995 A CN 101700995A
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- cancer
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- diketones
- heptadione
- diene
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- 238000002360 preparation method Methods 0.000 claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims description 15
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- 208000026310 Breast neoplasm Diseases 0.000 claims description 9
- 239000002246 antineoplastic agent Substances 0.000 claims description 7
- 229940041181 antineoplastic drug Drugs 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 201000005202 lung cancer Diseases 0.000 claims description 7
- 208000020816 lung neoplasm Diseases 0.000 claims description 7
- -1 methoxyl group Chemical group 0.000 claims description 7
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- 125000003118 aryl group Chemical group 0.000 claims description 4
- 206010008342 Cervix carcinoma Diseases 0.000 claims description 3
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
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Abstract
The invention relates to polyvinylarene substituted beta-diketones with anti-tumor effects and application thereof in the preparation of anti-tumor medicaments. The polyvinylarene substituted beta-diketones can inhibit the activation of an NF-Kb path, thereby leading to the apoptosis of tumor cells, overcoming the defects of low activity and poor availability of turmerone in treatment of cancer, and greatly improving the anti-tumor activity of the medicaments. The chemical structural formula I of the polyvinylarene substituted beta-diketones is shown as follows, wherein R1, R2 and R3 are defined as a specification.
Description
Technical field
The present invention relates to the application of a kind of antineoplastic compound in the preparation antitumor drug, particularly, relate to polyvinylarene substituted beta-diketones and the application in the preparation antitumor drug thereof.
Background technology
Cancer is mainly one of deadly disease of modern society, the pathogenesis complexity, and result of treatment is poor, and cancer cells produces resistance to chemotherapeutics easily.Therefore, cancer therapy drug is the emphasis of current drug development, and at present, many experts of medical circle just are being devoted to seek efficient, hang down toxic side effect, drug-resistant tumor are had the cancer therapy drug of good lethal effect.
Studies show that from molecular biological angle most of tumours cause that because of about 500 improper regulation and control of gene this just needs to seek and can prevent and treat tumour to all activated compound of a plurality of gene expression products.Curcumine is a kind of yellow compound in the edible spices, show after deliberation curcumine can with protein-interacting widely, thereby regulation and control Expression of Related Genes and protein-active.Wherein, these albumen comprise transcription factor, and the albumen relevant with cell survival, increment, invasion and attack and new vessel.Discover that curcumine can suppress the propagation of kinds of tumors, can prevent the tumour that causes by carcinogens, use separately or share the growth of human tumor cells that can suppress to be transplanted to animal model with other anticarcinogen; And several first phases and the second stage of clinical experiment show that curcumine is quite safe to tumour patient, have the characteristics of low toxic side effect, can show result of treatment.
But clinical experiment finds that the curcumine activity is lower, and reach result of treatment needs patient with heavy dose of curcumine and relative medicine, has brought great inconvenience therefore for the clinical use of curcumine.In addition, the oral availability of curcumine is low, and this also is the major reason that causes needs of patients large dose oral administration curcumine when clinical treatment.For these reasons, carried out a lot of work at the structure of modification of curcumine in recent years, it is higher that its purpose is to seek activity, and oral availability is higher and keep the curcumin derivate of the low toxic side effect advantage of curcumine.
Summary of the invention
In view of this, problem to be solved by this invention is to provide a kind of polyvinylarene substituted beta-diketones, overcomes active low that curcumine exists when the treatment cancer, the deficiency that availability is not high.
To be solved by this invention being problematic in that provides the application of above-mentioned polyvinylarene substituted beta-diketones in the preparation antitumor drug.
In order to address the above problem, polyvinylarene substituted beta-diketones provided by the invention, its structure is suc as formula shown in (I):
In the formula (I)
R
1, R
2, R
3For the aromatic series group or contain substituent aromatic series group, described aromatic series group comprises benzene, furans, thiophene, pyridine, thiazole, imidazoles.
Described substituting group comprises a kind of in hydroxyl, methoxyl group, oxyethyl group, methyl, ethyl, trifluoromethyl, fluorine, chlorine, bromine, amino, methylamino, dimethylin, diethylin, the nitro at least.
Preferably, R in the formula (I)
1, R
2, R
3Be selected from following substituting group:
More preferably, above-mentioned polyvinylarene substituted beta-diketones is preferably:
(1E, 6E)-1,7-two (3, the 4-Dimethoxyphenyl)-4-(4-hydroxy 3-methoxybenzene methylene radical)-1,6-diene-3,5-heptadione;
(1E, 6E)-1,7-two (4-p-methoxy-phenyl)-4-(4-hydroxy 3-methoxybenzene methylene radical)-1,6-diene-3,5-heptadione;
(1E, 6E)-1,7-two (5-methoxyl group furans-2-yl)-4-(4-dimethylin Ben Yajiaji)-1,6-diene-3,5-heptadione;
(1E, 6E)-1,7-two (3, the 4-Dimethoxyphenyl)-4-(3,4,5-trimethoxy Ben Yajiaji)-1,6-diene-3,5-heptadione;
(1E, 6E)-1,7-two (3,4, the 5-trimethoxyphenyl)-4-(3,4-dimethoxy Ben Yajiaji)-1,6-diene-3,5-heptadione.
Correspondingly, the present invention also provides the application of compound in the preparation antitumor drug of formula (I).
More preferably, described antitumor drug comprises the medicine of treatment cancer of the stomach, esophagus cancer, colorectal carcinoma, lung cancer, mammary cancer, ovarian cancer, cervical cancer, prostate cancer, carcinoma of the pancreas, uterus carcinoma.
More preferably, described antitumor drug is treatment mammary cancer and lung cancer drugs.
Correspondingly, the present invention also provides the preparation method of compound shown in the formula (I), is specially according to following reaction formula 1～3 preparation:
Reaction formula 1:
This reaction formula is applicable to 1,4,7 three replacements 1 that synthetic 1,7 bit substituent is identical, 6-diene-3,5-heptadione.
The chemical reaction concrete steps of representing in this formula are:
1eq methyl ethyl diketone and 0.6eq boric anhydride in adding the reflux of drying tube are solvent 70 degree heated and stirred 2h with the ethyl acetate.Add the 4eq tributyl borate again, 0.05eq n-Butyl Amine 99 and 2eq R
1Aldehyde 70 degree that replace reflux and spend the night.Add 1N HCl again and transfer PH to acid, 60 degree stir 1h.Collected organic layer, it is neutral washing with water to water layer PH.The dried over sodium sulfate organic layer, be spin-dried for thick product, get 1,7-R through re-crystallizing in ethyl acetate or ethyl acetate, sherwood oil mixed solvent for the eluent column chromatography
1Replace-1,6-diene-3,5-heptadione (intermediate 1).Equivalent intermediate 1 and R
2The aldehyde that replaces adds the 0.1eq piperidines, and 0.12eq acetate is that solvent reflux in the reflux of water trap is housed is spent the night with toluene, reaction solution be spin-dried for thick product, it is pure 1 to be with ethyl acetate, sherwood oil mixed solvent that the eluent column chromatography gets, 7-R
1Replacement-4-R
2Methylene radical replaces-1,6-diene-3,5-heptadione.
Reaction formula 2:
This reaction formula is applicable to 1,4,7 three replacements-1 that synthetic 1,7 bit substituent difference, 4,7 bit substituent raw materials are identical, 6-diene-3,5-heptadione.
The chemical reaction concrete steps of expression are in the reaction formula 2:
The 5eq methyl ethyl diketone, 4eq tributyl borate and 2.6eq boric anhydride are solvent 70 degree heated and stirred 2h in adding the reflux of drying tube with the ethyl acetate.0.05eq n-Butyl Amine 99,1eq R
1The aldehyde that replaces is dissolved in and slowly drops to flask in the ethyl acetate, and 0.5h drips, and 70 degree reflux and spend the night.Add 1N HCl again and transfer PH to acid, 60 degree stir 1h.Collected organic layer, it is neutral washing with water to water layer PH.The dried over sodium sulfate organic layer, be spin-dried for thick product, get 1-R through ethyl acetate, sherwood oil mixed solvent for the eluent column chromatography
1Replacement-1-alkene-3,5-diacetylmethane (intermediate 2).1eq intermediate 2 and 2eq R
2The aldehyde that replaces adds the 0.1eq piperidines, and 0.12eq acetate is that solvent reflux in the reflux of water trap is housed is spent the night with toluene, reaction solution be spin-dried for thick product, be that the eluent column chromatography gets pure 1-R with ethyl acetate, sherwood oil mixed solvent
1Replacement-7-R
2Replacement-4-R
2Methylene radical replaces-1,6-diene-3,5-heptadione.
Reaction formula 3:
This reaction formula is applicable to 1,4,7 three replacements-1 that synthetic 1,4,7 raw materials are all inequality, 6-diene-3,5-heptadione.
The chemical reaction concrete steps of expression are in the reaction formula 3:
1eq intermediate 2,0.6eq boric anhydride are solvent 70 degree heated and stirred 2h in adding the reflux of drying tube with the ethyl acetate.Add the 4eq tributyl borate again, 0.05eq n-Butyl Amine 99 and 1eq R
1The aldehyde that replaces, 70 degree reflux and spend the night.Add 1N HCl again and transfer PH to acid, 60 degree stir 1h.Collected organic layer, it is neutral washing with water to water layer PH.The dried over sodium sulfate organic layer, be spin-dried for thick product, get 1-R through ethyl acetate, sherwood oil mixed solvent for the eluent column chromatography
1Replacement-7-R
2Replace-1,6-diene-3,5-heptadione (intermediate 3).1eq intermediate 3 and 1eq R
3The aldehyde that replaces adds the 0.1eq piperidines, and 0.12eq acetate is that solvent reflux in the reflux of water trap is housed is spent the night with toluene, reaction solution be spin-dried for thick product, be that the eluent column chromatography gets pure 1-R with ethyl acetate, sherwood oil mixed solvent
1Replacement-7-R
2Replacement-4-R
3Methylene radical replaces-1,6-diene-3,5-heptadione.
From the mechanism of action of cytobiology, polyvinylarene substituted beta-diketones of the present invention can suppress NF-κ B (nuclear factor-κ B) from tenuigenin to nuclear transfer, thereby suppress the expression of NF-κ B downstream gene.NF-κ B is subjected to the regulation and control of I κ B (inhibitor of nuclear factor-κ B) at normal cell, and this regulation and control imbalance makes NF-κ B path sustained activation in multiple cancer cells, causes the expression of downstream gene.And NF-κ B path can promote growth of tumor, transfer, and makes cancer cells produce resistant function to chemotherapy, radiotherapy.Polyvinylarene substituted beta-diketones of the present invention can suppress the activation of NF-κ B path, thereby causes the apoptosis of tumour cell.
Compare with curcumine, polyvinylarene substituted beta-diketones of the present invention has improved the anti-tumor activity of medicine greatly, and the specific activity curcumine of lung cancer and mammary cancer has been improved 48-100 doubly.
External tumour increment suppresses experiment and shows that T68 is to the GI of human breast cancer cell strain MCF-7
50Be 0.3 μ M, to the GI of human lung carcinoma cell line NCI-H460
50Be 0.71 μ M, improved 100 times of (GI than curcumine respectively
50Be 30 μ M) and 48 times of (GI
50Be 34 μ M).
Suppress in the experiment in another external tumour increment, choose compound T68 and T66 to people's lung cancer A549 cell strain of anti-cis-platinum inhibition test of rising in value, the result shows both GI to the A549 mdr cell
50Be respectively 0.8 μ M and 1.2 μ M, cis-platinum is to the GI of A549 mdr cell
50＞100 μ M, curcumine is to the GI of A549 mdr cell
50Be 68 μ M.
Above statement of facts polyvinylarene substituted beta-diketones of the present invention has have great improvement to the specific activity turmeric of lung cancer and mammary cancer, simultaneously, mechanism in conjunction with the inhibition cancer of polyvinylarene substituted beta-diketones of the present invention, in multiple drug-resistant tumor cell strain, NF-κ B path sustained activation.The downstream gene of NF-κ B path comprises BCl2, LAP, MDR1, cytokine (IL1/2/6/8, TNFa), somatomedin (VEGF, GM-CSF), COX2, cell cycle control gene (MYC, cyclinD1), MMP2, MMP9, adhesion molecule (ICAM1, VCAM1) etc. surpass 200 kinds of genes, these expression of gene can promote the increment of tumour, suppress the apoptosis of tumor cells that radiotherapy, chemotherapy etc. cause and promote metastases.Have resistance as the Humanmachine tumour above 90%, chemotherapeutic treatment is efficient less than 10%, and observes NF-κ B path sustained activation in melanoma.Transfer to nuclear process and polyvinylarene substituted beta-diketones of the present invention can suppress NF-κ B from tenuigenin, NF-κ B path can't be activated; The downward modulation of NF-κ B downstream gene expression makes tumour cell forfeiture resistance.Therefore in conjunction with the above-mentioned mechanism of action, can show that polyvinylarene substituted beta-diketones of the present invention also has similar effect in other tumor treatment, other tumours include but are not limited to cancer of the stomach, esophagus cancer, colorectal carcinoma, ovarian cancer, cervical cancer, prostate cancer, carcinoma of the pancreas, uterus carcinoma.
Embodiment
One, preparation embodiment
Embodiment one
(1E, 6E)-1,7-two (3, the 4-Dimethoxyphenyl)-4-(4-hydroxy 3-methoxybenzene methylene radical)-1,6-diene-3,5-heptadione synthetic:
1.0g methyl ethyl diketone, 0.4g boric anhydride and 25mL ethyl acetate are put into the 100mL there-necked flask, 70 degree reaction 1h; Add 3.66g 3 again, the 4-dimethoxy benzaldehyde, 2g tributyl borate and 50mg n-Butyl Amine 99,70 degree reactions are spent the night; Add 1N hydrochloric acid 25mL reaction 30min; Collected organic layer, washing, anhydrous sodium sulfate drying; Rotary evaporation gets thick product, and recrystallization is purified, intermediate product (1E, 6E)-1,7-two (3, the 4-Dimethoxyphenyl)-1,6-diene-3,5-heptadione 2.61g, yield 66%.(1E, 6E)-1,7-two (3, the 4-Dimethoxyphenyl)-1,6-diene-3,5-heptadione 1.98g, 4-hydroxy 3-methoxybenzene formaldehyde 1.52g, piperidines 0.213g and acetate 0.24g are dissolved in 25mL toluene and put into there-necked flask, bonus point water device, back flow reaction 5h.Washing, anhydrous sodium sulfate drying, rotary evaporation get thick product, and ethyl acetate, sherwood oil are made eluent, column chromatography for separation, product (1E, 6E)-1,7-two (3, the 4-Dimethoxyphenyl)-and 4-(4-hydroxy 3-methoxybenzene methylene radical)-1,6-diene-3,5-heptadione 1.09g, yield 41%.
Product is analyzed through NMR:
1H-NMR(500MHz)ppm?7.80(s，1H)ppm?7.75(d，1H，J＝15.4Hz)ppm?7.50(d，1H，J＝16.1Hz)ppm?7.18(dd，1H，J＝2.0Hz，J＝8.5Hz)ppm?7.09(dd，1H，J＝2.0Hz，J＝8.5Hz)ppm?7.06(dd，1H，J＝2.0Hz，J＝8.0Hz)ppm?7.06(d，1H，J＝2.0Hz)ppm?7.04(d，1H，J＝2.0Hz)ppm?6.98(d，1H，J＝2.0Hz)ppm?6.97(d，1H，J＝15.4Hz)ppm?6.87(d，1H，J＝8.5Hz)ppm?6.86(d，1H，J＝8.0Hz)ppm?6.82(d，1H，J＝8.5Hz)ppm?6.81(d，1H，J＝16.1Hz)ppm?3.91(m，6H)ppm?3.89(s，3H)ppm?3.87(s，3H)ppm?3.83(s，3H)。
Embodiment two
(1E, 6E)-1,7-two (4-p-methoxy-phenyl)-4-(4-hydroxy 3-methoxybenzene methylene radical)-1,6-diene-3,5-heptadione synthetic:
1.0g methyl ethyl diketone, 0.4g boric anhydride and 25mL ethyl acetate are put into the 100mL there-necked flask, 70 degree reaction 1h; Add 2.72g 4-methoxybenzaldehyde again, 2g tributyl borate and 50mg n-Butyl Amine 99,70 degree reactions are spent the night; Add 1N hydrochloric acid 25mL reaction 30min; Collected organic layer, washing, anhydrous sodium sulfate drying; Rotary evaporation gets thick product, and recrystallization is purified, intermediate product (1E, 6E)-1,7-two (4-p-methoxy-phenyl)-1,6-diene-3,5-heptadione 2.52g, yield 75%.(1E, 6E)-1,7-two (4-p-methoxy-phenyl)-1,6-diene-3,5-heptadione 1.68g, 4-hydroxy 3-methoxybenzene formaldehyde 1.52g, piperidines 0.213g and acetate 0.24g are dissolved in 25mL toluene and put into there-necked flask, bonus point water device, back flow reaction 5h.Washing, anhydrous sodium sulfate drying, rotary evaporation get thick product, and ethyl acetate, sherwood oil are made eluent, column chromatography for separation, product (1E, 6E)-1,7-two (4-p-methoxy-phenyl)-4-(4-hydroxy 3-methoxybenzene methylene radical)-1,6-diene-3,5-heptadione 0.68g, yield 29%.
Product is analyzed through NMR:
1H-NMR(400MHz，CD
3Cl)ppm?7.81(s，1H)ppm?7.77(d，1H，J＝15.4Hz)，7.53(d，1H，J＝16.1Hz)，7.52(d，2H，J＝8.9Hz)，ppm?7.42(d，2H，J＝8.8Hz)ppm?7.08(dd，1H，J＝2.0Hz，J＝8.3Hz)ppm?7.03(d，1H，J＝2.0Hz)ppm?6.99(d，1H，J＝15.4Hz)，ppm6.89(d，2H，J＝8.8Hz)ppm?6.86(d，1H，J＝8.3Hz)ppm?6.86(d，2H，J＝8.9Hz)ppm6.81(d，1H，J＝16.1Hz)ppm?3.83(s，3H)ppm?3.81(m，6H)。
13C-NMR(100MHz，CD
3Cl)198.6，186.8，162.2，161.8，148.1，146.6，146.5，144.5，140.8，138.7，130.5，130.4，127.6，126.9，126.0，125.8，125.4，120.1，114.8，114.5，114.4，112.5，77.3，76.7，55.9，55.4。
Embodiment three
(1E, 6E)-1,7-two (5-methoxyl group furans-2-yl)-4-(4-dimethylin Ben Yajiaji)-1,6-diene-3,5-heptadione synthetic:
1.0g methyl ethyl diketone, 0.4g boric anhydride and 25mL ethyl acetate are put into the 100mL there-necked flask, 70 degree reaction 1h; Add 2.20g 5-methoxyl group furans-2-aldehyde again, 2g tributyl borate and 50mg n-Butyl Amine 99,70 degree reactions are spent the night; Add 1N hydrochloric acid 25mL reaction 30min; Collected organic layer, washing, anhydrous sodium sulfate drying; Rotary evaporation gets thick product, and recrystallization is purified, intermediate product (1E, 6E)-1,7-two (5-methoxyl group furans-2-yl)-1,6-diene-3,5-heptadione 2.34g, yield 82%.(1E, 6E)-1,7-two (5-methoxyl group furans-2-yl)-1,6-diene-3,5-heptadione 1.42g, 4-dimethylin phenyl aldehyde 1.49g; Piperidines 0.213g and acetate 0.24g are dissolved in 25mL toluene and put into there-necked flask, bonus point water device, back flow reaction 5h.Washing, anhydrous sodium sulfate drying, rotary evaporation get thick product, and ethyl acetate, sherwood oil are made eluent, column chromatography for separation, product (1E, 6E)-1,7-two (5-methoxyl group furans-2-yl)-4-(4-dimethylin Ben Yajiaji)-1,6-diene-3,5-heptadione 0.81g, yield 39%.
Product is analyzed through NMR:
1H-NMR(500MHz)ppm?7.79(s，1H)ppm?7.46(d，1H，J＝15.1Hz)ppm?7.41(d，2H，J＝8.8Hz)ppm?7.24(d，1H，J＝15.8Hz)ppm?6.89(d，1H，J＝15.1Hz)ppm?6.76(d，1H，J＝15.8Hz)ppm?6.61(d，2H，J＝8.8Hz)ppm?6.56(d，1H，J＝3.3Hz)ppm?6.52(d，1H，J＝3.3Hz)ppm6.07(dd，1H，J＝0.9Hz，J＝3.3Hz)ppm?6.06(dd，1H，J＝0.9Hz，J＝3.3Hz)ppm?3.00(s，6H)ppm?2.35(s，3H)ppm?2.32(s，3H)。
Embodiment four
(1E, 6E)-1,7-two (3, the 4-Dimethoxyphenyl)-4-(3,4,5-trimethoxy Ben Yajiaji)-1,6-diene-3,5-heptadione synthetic:
1.0g methyl ethyl diketone, 0.4g boric anhydride and 25mL ethyl acetate are put into the 100mL there-necked flask, 70 degree reaction 1h; Add 3.66g 3 again, the 4-dimethoxy benzaldehyde, 2g tributyl borate and 50mg n-Butyl Amine 99,70 degree reactions are spent the night; Add 1N hydrochloric acid 25mL reaction 30min; Collected organic layer, washing, anhydrous sodium sulfate drying; Rotary evaporation gets thick product, and recrystallization is purified, intermediate product (1E, 6E)-1,7-two (3, the 4-Dimethoxyphenyl)-1,6-diene-3,5-heptadione 2.61g, yield 66%.(1E, 6E)-1,7-two (3, the 4-Dimethoxyphenyl)-1,6-diene-3,5-heptadione 1.98g, 3,4,5-TMB 1.96g, piperidines 0.213g and acetate 0.24g are dissolved in 25mL toluene and put into there-necked flask, bonus point water device, back flow reaction 5h.Washing, anhydrous sodium sulfate drying, rotary evaporation get thick product, and ethyl acetate, sherwood oil are made eluent, column chromatography for separation, product (1E, 6E)-1,7-two (3, the 4-Dimethoxyphenyl)-4-(3,4,5-trimethoxy Ben Yajiaji)-1,6-diene-3,5-heptadione 1.21g, yield 42%.
Product is analyzed through NMR:
1H-NMR(400MHz，CD
3Cl)ppm?7.75(s，1H)ppm?7.76(d，1H，J＝15.4Hz)ppm7.51(d，1H，J＝16.1Hz)ppm?7.18(dd，1H，J＝2.0Hz，J＝8.4Hz)ppm?7.07(d，1H，J＝2.0Hz)ppm?7.05(dd，1H，J＝8.4Hz，J＝2.0Hz)ppm?6.98(d，1H，J＝2.0Hz)ppm6.98(d，1H，J＝15.4Hz)ppm?6.86(d，1H，J＝8.4Hz)ppm?6.82(d，1H，J＝8.4Hz)ppm6.80(d，1H，J＝16.1Hz)ppm?6.76(s，2H)3.90(s，3H)，3.89(s，3H)，3.88(s，3H)，3.86(s，3H)，3.84(s，3H)，3.78(s，6H)。
Embodiment five
(1E, 6E)-1,7-two (3,4, the 5-trimethoxyphenyl)-4-(3,4-dimethoxy Ben Yajiaji)-1,6-diene-3,5-heptadione synthetic:
1.0g methyl ethyl diketone, 0.4g boric anhydride and 25mL ethyl acetate are put into the 100mL there-necked flask, 70 degree reaction 1h; Add 3.92g 3 again, the 4-dimethoxy benzaldehyde, 2g tributyl borate and 50mg n-Butyl Amine 99,70 degree reactions are spent the night; Add 1N hydrochloric acid 25mL reaction 30min; Collected organic layer, washing, anhydrous sodium sulfate drying; Rotary evaporation gets thick product, and recrystallization is purified, intermediate product (1E, 6E)-1,7-two (3, the 4-Dimethoxyphenyl)-1,6-diene-3,5-heptadione 2.06g, yield 45%.(1E, 6E)-1,7-two (3, the 4-Dimethoxyphenyl)-1,6-diene-3,5-heptadione 2.28g, 3,4-dimethoxy benzaldehyde 1.66g, piperidines 0.213g and acetate 0.24g are dissolved in 25mL toluene and put into there-necked flask, bonus point water device, back flow reaction 5h. washing, anhydrous sodium sulfate drying, rotary evaporation get thick product, ethyl acetate, sherwood oil are made eluent, column chromatography for separation, product (1E, 6E)-1,7-two (3,4, the 5-trimethoxyphenyl)-4-(3,4-dimethoxy Ben Yajiaji)-1,6-diene-3, the 5-heptadione; Yield 57%.
Product is analyzed through NMR:
1H-NMR(400MHz，CD
3Cl)ppm?7.82(s，1H)ppm?7.72(d，1H，J＝15.5Hz)ppm7.47(d，1H，J＝16.1Hz)ppm?7.13(dd，1H，J＝2.0Hz，J＝8.5Hz)ppm?7.04(d，1H，J＝2.0Hz)ppm?7.02(d，1H，J＝15.5Hz)ppm?6.83(d，1H，J＝8.5Hz)ppm?6.83(d，1H，J＝16.1Hz)ppm?6.80(s，2H)ppm?6.70(s，2H)ppm?3.89(s，6H)ppm?3.88(s，3H)ppm?3.87(s，3H)ppm?3.86(s，3H)ppm?3.84(s，6H)ppm?3.82(s，3H)。
13C-NMR(100MHz，CD
3Cl)198.2，186.908，153.4，151.3，149.0，146.8，145.0，141.2，140.9，138.8，130.2，129.5，126.8，126.2，125.0，121.5，113.0，111.2，106.2，106.1，61.0，56.3，56.2，55.9，55.9。
Above embodiment one to embodiment five all is applicable to 1,4,7 three replacements 1 that synthetic 1,7 bit substituent is identical, 6-diene-3,5-heptadione.
Two, cancer cell multiplication suppresses embodiment
Embodiment six
The proliferation inhibition test of human breast cancer cell MCF-7 and lung carcinoma cell NCI-H460:
1, experimental procedure:
Human breast cancer cell MCF-7 is cultivated in containing the DMEM substratum of 10% foetal calf serum, human lung carcinoma cell NCI-H460 cultivates in containing 1640 substratum of 10% foetal calf serum, the rise period cell dissociation of taking the logarithm is seeded in 96 well culture plates, cell density 8 * 10
4/ mL, every hole 0.1mL.At 5%CO
2Cell culture incubator is cultivated 24h.Former substratum is removed in suction, add contain the different concns compound contain the new substratum of 10% serum, each concentration repeats three holes.Every hole adds the PBS damping fluid 0.01mL that contains MTT 2.5% concentration after continuing to cultivate 48h.Put into incubator 4h, inhale and remove substratum, every hole adds DMSO 0.02mL, and fully the vibration back is write down absorbancy with microplate reader at 495nm.
2, experimental result and analysis:
Each hole inhibiting rate=1-(this hole absorbancy-blank group mean light absorbency)/(negative control group mean light absorbency-blank group mean light absorbency)
Wherein, blank is not for adding the hole of MTT, and negative control is not for adding the hole of compound.Logarithmic value with concentration is an X-coordinate, and inhibiting rate is the inhibition curve that ordinate zou draws this compound, is 50% o'clock compound concentration by the curve rate of being inhibited, and is GI
50
Experimental result is as shown in the table:
Interpretation is estimated:
This compounds improves a lot than curcumine to the NCI-H460 cytotoxicity, T63, T86, the GI of T68
50All less than 5 μ M, wherein T68's is active best, GI
50Be 0.71 μ M.Compare curcumine (GI
5034 μ M) 48 times have been improved.This compounds improves greatly to MCF-7 cell increment inhibition specific activity curcumine, and 6 compound GI are arranged in the compound of test
50Less than 1 μ M.Active best compound T68GI
50Be 0.30 μ M, activity is curcumine (GI
5030 μ M) 100 times.
The above is a preferred implementation of the present invention; should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; can also make some improvements and modifications, these improvements and modifications also are considered as protection scope of the present invention.
Claims (6)
1. polyvinylarene substituted beta-diketones, its structure is suc as formula shown in (I):
In the formula (I)
R
1, R
2, R
3For the aromatic series group or contain substituent aromatic series group, described aromatic series group comprises benzene, furans, thiophene, pyridine, thiazole, imidazoles;
Described substituting group comprises a kind of in hydroxyl, methoxyl group, oxyethyl group, methyl, ethyl, trifluoromethyl, fluorine, chlorine, bromine, amino, methylamino, dimethylin, diethylin, the nitro at least.
2. polyvinylarene substituted beta-diketones as claimed in claim 1 is characterized in that R in the formula (I)
1, R
2, R
3Be selected from following substituting group:
3. polyvinylarene substituted beta-diketones as claimed in claim 1, it is selected from following compounds:
(1E, 6E)-1,7-two (3, the 4-Dimethoxyphenyl)-4-(4-hydroxy 3-methoxybenzene methylene radical)-1,6-diene-3,5-heptadione;
(1E, 6E)-1,7-two (4-p-methoxy-phenyl)-4-(4-hydroxy 3-methoxybenzene methylene radical)-1,6-diene-3,5-heptadione;
(1E, 6E)-1,7-two (5-methoxyl group furans-2-yl)-4-(4-dimethylin Ben Yajiaji)-1,6-diene-3,5-heptadione;
(1E, 6E)-1,7-two (3, the 4-Dimethoxyphenyl)-4-(3,4,5-trimethoxy Ben Yajiaji)-1,6-diene-3,5-heptadione;
(1E, 6E)-1,7-two (3,4, the 5-trimethoxyphenyl)-4-(3,4-dimethoxy Ben Yajiaji)-1,6-diene-3,5-heptadione.
4. the application of any described polyvinylarene substituted beta-diketones in the preparation antitumor drug in the claim 1～3.
5. the application of any described polyvinylarene substituted beta-diketones in preparation treatment cancer of the stomach, esophagus cancer, colorectal carcinoma, lung cancer, mammary cancer, ovarian cancer, cervical cancer, prostate cancer, carcinoma of the pancreas, uterus carcinoma medicine in the claim 1～3.
6. the application of any described polyvinylarene substituted beta-diketones in preparation treatment mammary cancer and lung-cancer medicament in the claim 1～3.
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| CN104030904A (en) * | 2014-03-07 | 2014-09-10 | 福建医科大学 | Application of 4-arylmethyl curcumin analogues serving as Hsp90 inhibitor |
| CN114133372A (en) * | 2021-10-26 | 2022-03-04 | 广州中大南沙科技创新产业园有限公司 | Polyarylethene beta-diketone compound or pharmaceutically acceptable salt thereof and application thereof |
| CN114133372B (en) * | 2021-10-26 | 2023-11-07 | 广州中大南沙科技创新产业园有限公司 | Poly (vinylarene) beta-diketone compound or pharmaceutically acceptable salt thereof and application thereof |
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