CN101700995B - Polyvinylarene substituted beta-diketones with anti-tumor effects - Google Patents
Polyvinylarene substituted beta-diketones with anti-tumor effects Download PDFInfo
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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 one of main lethal disease of modern society, and pathogenesis is complicated, and result for the treatment of is poor, and cancer cells easily produces resistance to chemotherapeutics.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 because of about 500 improper regulation and control of gene, this just need to seek can to a plurality of gene expression products all activated compound prevent and treat tumour.Curcumine is a kind of yellow compound in edible spices, show after deliberation curcumine can with protein-interacting widely, thereby expression and the protein-active of regulation and control genes involved.Wherein, these albumen comprise transcription factor, and the albumen relevant to cell survival, increment, invasion and attack and new vessel.Research finds that curcumine can suppress the propagation of kinds of tumors, can prevent the tumour that caused by carcinogens, separately use 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 for the treatment of.
But clinical experiment finds that the curcumine activity is lower, and reach result for the treatment of 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 is also 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 for 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 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, nitro at least.
Preferably, R in 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 (3,4-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 α-tolylene)-1,6-diene-3,5-heptadione;
(1E, 6E)-1,7-two (3,4-Dimethoxyphenyl)-4-(3,4,5-trimethoxy α-tolylene)-1,6-diene-3,5-heptadione;
(1E, 6E)-1,7-two (3,4,5-trimethoxyphenyl)-4-(3,4-dimethoxy α-tolylene)-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 for the treatment of 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 the medicine for the treatment of mammary cancer and lung cancer.
Correspondingly, the present invention also provides the preparation method of compound shown in formula (I), is specially according to following reaction formula 1～3 preparation:
Reaction formula 1:
This reaction formula is applicable to the synthetic identical Isosorbide-5-Nitrae of 1,7 bit substituent, and 7 three replace 1,6-diene-3,5-heptadione.
The chemical reaction concrete steps that represent in this formula are:
1eq methyl ethyl diketone and 0.6eq boric anhydride in adding the reflux of drying tube take ethyl acetate as solvent 70 degree heated and stirred 2h.Add again the 4eq tributyl borate, 0.05eq n-Butyl Amine 99 and 2eq R
1Aldehyde 70 degree that replace reflux and spend the night.Add 1N HCl to transfer PH to acid, 60 degree stir 1h again.Collected organic layer washes with water to water layer PH as neutral.The dried over sodium sulfate organic layer is spin-dried for and gets thick product, is that the eluent column chromatography gets 1,7-R through re-crystallizing in ethyl acetate or ethyl acetate, sherwood oil mixed solvent
1Replace-1,6-diene-3,5-heptadione (intermediate 1).Equivalent intermediate 1 and R
2The aldehyde that replaces adds the 0.1eq piperidines, 0.12eq acetic acid, reflux is spent the night in the reflux of water trap is housed take toluene as solvent, reaction solution is spin-dried for and gets thick product, take ethyl acetate, sherwood oil mixed solvent pure as the eluent column chromatography gets 1,7-R
1Replacement-4-R
2Methylene radical replaces-1,6-diene-3,5-heptadione.
Reaction formula 2:
This reaction formula is applicable to synthetic 1,7 bit substituent difference 4, the 7 identical Isosorbide-5-Nitraes of bit substituent raw material, and 7 three replace-1,6-diene-3,5-heptadione.
In reaction formula 2, the chemical reaction concrete steps of expression are:
The 5eq methyl ethyl diketone, 4eq tributyl borate and 2.6eq boric anhydride, take ethyl acetate as solvent in adding the reflux of drying tube 70 degree heated and stirred 2h.0.05eq n-Butyl Amine 99,1eq R
1The aldehyde that replaces is dissolved in and slowly drops to flask in ethyl acetate, and 0.5h drips, and 70 degree reflux and spend the night.Add 1N HCl to transfer PH to acid, 60 degree stir 1h again.Collected organic layer washes with water to water layer PH as neutral.The dried over sodium sulfate organic layer is spin-dried for to get thick product, is that the eluent column chromatography gets 1-R through ethyl acetate, sherwood oil mixed solvent
1Replacement-1-alkene-3,5-diacetylmethane (intermediate 2).1eq intermediate 2 and 2eq R
2The aldehyde that replaces adds the 0.1eq piperidines, 0.12eq acetic acid, and reflux is spent the night in the reflux of water trap is housed take toluene as solvent, and reaction solution is spin-dried for and gets thick product, gets pure 1-R take ethyl acetate, sherwood oil mixed solvent as the eluent column chromatography
1Replacement-7-R
2Replacement-4-R
2Methylene radical replaces-1,6-diene-3,5-heptadione.
Reaction formula 3:
This reaction formula is applicable to synthetic Isosorbide-5-Nitrae, and 7 raw materials are not identical Isosorbide-5-Nitrae, and 7 three replace-1,6-diene-3,5-heptadione.
In reaction formula 3, the chemical reaction concrete steps of expression are:
1eq intermediate 2,0.6eq boric anhydride take ethyl acetate as solvent in adding the reflux of drying tube 70 degree heated and stirred 2h.Add again the 4eq tributyl borate, 0.05eq n-Butyl Amine 99 and 1eq R
1The aldehyde that replaces, 70 degree reflux and spend the night.Add 1N HCl to transfer PH to acid, 60 degree stir 1h again.Collected organic layer washes with water to water layer PH as neutral.The dried over sodium sulfate organic layer is spin-dried for to get thick product, is that the eluent column chromatography gets 1-R through ethyl acetate, sherwood oil mixed solvent
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, 0.12eq acetic acid, and reflux is spent the night in the reflux of water trap is housed take toluene as solvent, and reaction solution is spin-dried for and gets thick product, gets pure 1-R take ethyl acetate, sherwood oil mixed solvent as the eluent column chromatography
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 suppresses 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, this regulation and control imbalance, make NF-κ B path sustained activation in multiple cancer cells, causes the expression of downstream gene.And NF-κ B path can promote growth, the transfer of tumour, 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, the GI of T68 to 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).
In another external tumour increment suppresses experiment, choose compound T68 and T66 to people's lung cancer A549 cell strain of anti-cis-platinum inhibition test of rising in value, result shows that both are to the GI of A549 mdr cell
50Be respectively 0.8 μ M and 1.2 μ M, the GI of cis-platinum to the A549 mdr cell
50＞100 μ M, the GI of curcumine to the 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 the several drug resistance tumor cell line, NF-κ B path sustained activation.The downstream gene of NF-κ B path comprises BC12, 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, the expression of these genes can promote the increment of tumour, suppresses the apoptosis of tumor cells that radiotherapy, chemotherapy etc. cause and promotes metastases.Have resistance as the Humanmachine tumour over 90%, chemotherapeutic treatment is efficient less than 10%, and observes NF-κ B path sustained activation in melanoma.And polyvinylarene substituted beta-diketones of the present invention can suppress NF-κ B from Chromosome migration to nuclear process, and NF-κ B path can't be activated; NF-κ B downstream gene expression is lowered, and makes tumour cell lose 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 effects in the treatment of other tumours, 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 Example
Embodiment one
(1E, 6E)-1,7-two (3,4-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 again the 3.66g Veratraldehyde, 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, and gets intermediate product (1E, 6E)-1,7-two (3,4-Dimethoxyphenyl)-1,6-diene-3,5-heptadione 2.61g, yield 66%.(1E, 6E)-1,7-two (3,4-Dimethoxyphenyl)-1,6-diene-3,5-heptadione 1.98g, 3-methoxy-4-hydroxybenzaldehyde 1.52g, piperidines 0.213g and acetic acid 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, get product (1E, 6E)-1,7-two (3, the 4-Dimethoxyphenyl)-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 again the 2.72g 4-methoxybenzaldehyde, 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, and gets 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, 3-methoxy-4-hydroxybenzaldehyde 1.52g, piperidines 0.213g and acetic acid 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 gets thick product, and ethyl acetate, sherwood oil are made eluent, column chromatography for separation, get 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 α-tolylene)-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 again 2.20g 5-methoxyl group furans-2-aldehyde, 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, and gets 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 acetic acid 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 gets thick product, and ethyl acetate, sherwood oil are made eluent, column chromatography for separation, get product (1E, 6E)-1,7-two (5-methoxyl group furans-2-yl)-4-(4-dimethylin α-tolylene)-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 (3,4-Dimethoxyphenyl)-4-(3,4,5-trimethoxy α-tolylene)-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 again the 3.66g Veratraldehyde, 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, and gets intermediate product (1E, 6E)-1,7-two (3,4-Dimethoxyphenyl)-1,6-diene-3,5-heptadione 2.61g, yield 66%.(1E, 6E)-1,7-two (3,4-Dimethoxyphenyl)-1,6-diene-3,5-heptadione 1.98g, 3,4,5-TMB 1.96g, piperidines 0.213g and acetic acid 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, and column chromatography for separation gets product (1E, 6E)-1,7-two (3,4-Dimethoxyphenyl)-4-(3,4,5-trimethoxy α-tolylene)-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 (3,4,5-trimethoxyphenyl)-4-(3,4-dimethoxy α-tolylene)-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 again the 3.92g Veratraldehyde, 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, and gets intermediate product (1E, 6E)-1,7-two (3,4-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, Veratraldehyde 1.66g, piperidines 0.213g and acetic acid 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 gets product (1E, 6E)-1,7-two (3,4,5-trimethoxyphenyl)-4-(3,4-dimethoxy α-tolylene)-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 the synthetic identical Isosorbide-5-Nitrae of 1,7 bit substituent, and 7 three replace 1,6-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.Suck former substratum, add the 10% new substratum of serum that contains that contains the different concns compound, each concentration repeats three holes.After continuing to cultivate 48h, every hole adds the PBS damping fluid 0.01mL that contains MTT 2.5% concentration.Put into incubator 4h, suck substratum, every hole adds DMSO 0.02mL, fully records absorbancy with microplate reader at 495nm after vibration.
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.Take the logarithmic value of concentration as X-coordinate, inhibiting rate is the inhibition curve that ordinate zou draws this compound, and compound concentration when being 50% by the curve rate of being inhibited 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 the preferred embodiment 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 (2)
1. polyvinylarene substituted beta-diketones, it is selected from following compounds:
(1
E, 6
E)-1,7-two (3,4-Dimethoxyphenyl)-4-(4-hydroxyl-3 – anisole methylene radical)-1,6-diene-3,5-heptadione;
(1
E, 6
E)-1,7-two (5-methoxyl group furans-2-yl)-4-(4-dimethylin α-tolylene)-1,6-diene-3,5-heptadione;
(1
E, 6
E)-1,7-two (3,4-Dimethoxyphenyl)-4-(3,4,5-trimethoxy α-tolylene)-1,6-diene-3,5-heptadione;
(1
E, 6
E)-1,7-two (3,4,5-trimethoxyphenyl)-4-(3,4-dimethoxy α-tolylene)-1,6-diene-3,5-heptadione.
2. the application of the described polyvinylarene substituted beta-diketones of any one in preparation treatment mammary cancer and lung-cancer medicament in claim 1.
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| CN110183320A (en) * | 2019-04-15 | 2019-08-30 | 四川大学 | A kind of polyenoid diketone anti-tumor compounds |
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| CN104030904B (en) * | 2014-03-07 | 2017-01-18 | 福建医科大学 | Application of 4-arylmethyl curcumin analogues serving as Hsp90 inhibitor |
| 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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|---|---|---|---|---|
| WO2008085984A1 (en) * | 2007-01-08 | 2008-07-17 | Androscience Corporation | Compounds with (substituted phenyl)-propenal moiety, their derivatives, biological activity, and uses thereof |
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| WO2008085984A1 (en) * | 2007-01-08 | 2008-07-17 | Androscience Corporation | Compounds with (substituted phenyl)-propenal moiety, their derivatives, biological activity, and uses thereof |
Non-Patent Citations (1)
| Title |
|---|
| Ajit P. Zambre er al.Copper Conjugates of Knoevenagel Condensates of Curcumin and their Schiff Base Derivatives: Synthesis, Spectroscopy,Magnetism, ESR, and Electrochemistry.《Synthesis and Reactivity in Inorganic, Metal-Organic and Nano-Metal Chemistry》.2007,第37卷(第1期),19-27. * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110183320A (en) * | 2019-04-15 | 2019-08-30 | 四川大学 | A kind of polyenoid diketone anti-tumor compounds |
| CN110183320B (en) * | 2019-04-15 | 2021-06-11 | 四川大学 | Polyene diketone antitumor compound |
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