CN102050759A - Resveratrol amide derivative and preparation method thereof - Google Patents
Resveratrol amide derivative and preparation method thereof Download PDFInfo
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- CN102050759A CN102050759A CN2010105795242A CN201010579524A CN102050759A CN 102050759 A CN102050759 A CN 102050759A CN 2010105795242 A CN2010105795242 A CN 2010105795242A CN 201010579524 A CN201010579524 A CN 201010579524A CN 102050759 A CN102050759 A CN 102050759A
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- VDYYXWSUGHDGKZ-RMKNXTFCSA-N CCCNC(c(c(/C=C/c(cc1)ccc1OC)cc(OC)c1)c1OC)=O Chemical compound CCCNC(c(c(/C=C/c(cc1)ccc1OC)cc(OC)c1)c1OC)=O VDYYXWSUGHDGKZ-RMKNXTFCSA-N 0.000 description 1
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Abstract
The invention provides a novel resveratrol amide derivative for stopping tumor cells from multiplication. A general formula is shown in the specification, wherein the R refers to the novel resveratrol amide derivative has obvious restraining effect to epidermal cancel cell strains (KB) of the oral cavity of a human body and cell strains (K562) of human leukemia, thereby being capable of being used for preparing antineoplastic drug. The invention also discloses the preparation method of the novel resveratrol amide derivative.
Description
Technical field
The present invention relates to novel trans-resveratrol amide derivatives of a class and preparation method thereof, with and as the purposes of antitumor drug, belong to the field of medicaments category.
Background technology
Trans-resveratrol (resveratrol) is a kind of non-flavones Polyphenols natural product, belongs to a kind of of phytoalexin, is a kind of self-protection material that higher plant is subjected to pathogenic agent infringement and externally produces under the severe environment.Trans-resveratrol has multiple physiologically active, such as anticancer, the cardiovascular and reducing blood lipid of protection, anti-oxidant anti-radical action, protection liver and anti-microbial effect.Antitumous effect is the most noticeable physiologically active of trans-resveratrol.The various trans-resveratrols that studies confirm that all have significant inhibitory effect to kinds of tumors such as nasopharyngeal carcinoma, lung cancer, liver cancer, intestinal cancer, cancer of the stomach, mammary cancer and leukemia.Trans-resveratrol mainly suppresses the propagation of tumour cell by the activity that suppresses cyclo-oxygenase (COX), because cyclo-oxygenase can impel arachidonic acid to be transformed into the precursor of some carcinogenic substances such as prostaglandin(PG), the precursor of these carcinogenic substances can stimulate the propagation of tumour cell, and can suppress immunity system and play a role.Trans-resveratrol mainly suppresses COX-1 as chemopreventive agent, and COX-2 is had tissue specificity, it cancer initial, promote and the development three phases all has restraining effect: by anti-oxidant, anti-mutation with induce second phase medicine to bring into play anti-initiation for the effect of enzyme; Play restraining effect by anti-inflammatory, inhibition cyclo-oxygenase and Peroxidase activity in the promotion stage of cancer; Can induce the differentiation of human promyelocytic leukemia cell and suppress the development of cancer.Trans-resveratrol can induce kinds of tumor cells to comprise the apoptosis of lung carcinoma cell, stomach cancer cell, colon cancer cell, epithelial cancer cells, leukemia cell and prostate cancer cell etc., and different with effect to the used dosage effect of different cancer cells.
Though trans-resveratrol has good antitumour activity, it also exists many shortcomings simultaneously, causes some side effects such as action target spot; Metabolism cycle weak point can not be brought into play medicinal function lastingly effectively in vivo; Antitumour activity is relatively low etc.Therefore, the derivative of synthesizing resveratrol and it is carried out screening active ingredients is an effective means that overcomes the above-mentioned shortcoming of trans-resveratrol, it is furtherd investigate have certain theory and actual value, especially on the basis of the novel trans-resveratrol amide derivatives of synthesizing series, their biological activity is carried out systematic research and have crucial meaning.
Summary of the invention
The object of the present invention is to provide novel white hellebore amide derivatives of a class and preparation method thereof and purposes.
Technical scheme of the present invention is as follows:
The resveratrol amide derivatives, it has following general formula:
R is in the formula:
A kind of method for preparing above-mentioned trans-resveratrol amide derivatives, it comprises the steps:
Step 1. adds trans-resveratrol three methyl ether list aldehyde in DMSO, fully after the dissolving, dropwise add NaH
2PO
4The aqueous solution after dropwising, stirs 0.5h, dropwise adds NaClO then
2The aqueous solution at room temperature reacts 24h after dropwising.After reacting completely, reaction solution is poured a large amount of 5% NaHCO into
3In the solution, water is used the dilute hydrochloric acid acidifying after with ethyl acetate extraction, filters, and the gained solid is used the saturated common salt water washing with methylene dichloride dissolving back, drying, and recrystallization obtains target compound;
Described NaH
2PO
4Consumption be every mmole trans-resveratrol three methyl ether list aldehyde with 50 milligrams of NaH
2PO
4Be dissolved in the 0.5mL water;
Described NaClO
2Consumption be every mmole trans-resveratrol three methyl ether list aldehyde with 180 milligrams of NaClO
2Be dissolved in the 2mL water.
The solid that step 2. obtains the first step and the amine (R-NH of equimolar amount
2) join successively in the methylene dichloride, add EDC.HCl and HOBt again, react 12h under the room temperature, column chromatography gets target product after the solvent evaporated.
The consumption of described EDC.HCl is every mmole reactant with 1.5 mmole EDC.HCl;
The consumption of described HOBt is every mmole reactant with 0.5 mmole HOBt.
Above-mentioned method for making, in the step 1, described DMSO consumption is every mmole trans-resveratrol 2ml DMSO.
Above-mentioned method for making, in the step 2, described methylene dichloride consumption is every mmole reactant 10ml methylene dichloride.
Experimental result shows that trans-resveratrol amide derivatives of the present invention has obvious suppression growth effect to human oral cavity upper epidermis JEG-3 (KB) and human leukemia cell line (K562), therefore can be used to prepare the lead compound of antitumor drug.
Embodiment
Further describe the present invention by following examples, but should notice that scope of the present invention is not subjected to any restriction of these embodiment.
Embodiment one: 3,5, the preparation of 4 '-trimethoxy-2-carboxyl trans-resveratrol (compound 1)
Add 20ml DMSO in the 50ml single necked round bottom flask, (2.98g 10mmol), dropwise adds NaH to add 3,5,4 '-trimethoxy-2-formyl radical trans-resveratrol under stirring
2PO
4Solution (0.5g NaH
2PO
4Be dissolved in the 5ml water), dropwise the back and stir 0.5h, dropwise add NaClO
2Solution (1.8g NaClO
2Be dissolved in the 20ml water), react 24h under the room temperature, reaction solution is poured 5%NaHCO into
3In the solution, water is used the dilute hydrochloric acid acidifying after with ethyl acetate extraction, filters, and the gained solid is used the saturated common salt water washing with methylene dichloride dissolving back, drying, and recrystallization obtains target compound 3,5,4 '-trimethoxy-2-carboxyl trans-resveratrol.Productive rate 72%, mp:178-179 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 3.78 (s, 6H), 3.85 (s, 3H), 6.54 (s, 1H), 6.91 (s, 1H), 6.92 (d, J=16.4,1H), 6.97 (d, J=8.0,2H), 7.25 (d, J=16.4,1H), 7.445 (d, J=8.0,2H) .MS (ESI): 315.12 (C
18H
18NO
5, [M+H]
+) .Anal.Calcd for C
18H
18NO
5: C, 68.78; H, 5.77%; Found:C, 69.00; H, 5.76%.
Embodiment two: (instead)-2, the preparation of 4-dimethoxy-6-(4-methoxyl-styrene)-phenylbenzamide (compound 2)
Add the 10ml methylene dichloride in the 50ml single necked round bottom flask, (0.102g is 1.1mmol) with 3 to add aniline successively, 5, and 4 '-trimethoxy-2-carboxyl trans-resveratrol (0.314g, 1.0mmol), EDC.HCl (0.287g, 1.5mmol), HOBt (0.068g, 0.5mmol), after reacting 12h under the room temperature, decompression steams solvent, and gained paste solid is dissolved in ethyl acetate, obtains target product compound 1 with saturated common salt water washing back to be dried column chromatography.Productive rate 77%, mp:119-120 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 3.83 (s, 6H), 3.87 (s, 3H), 3.92 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.26 (d, J=16.4,1H), 7.43-7.48 (dd, 3H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 390.16 (C
24H
23NO
4, [M+H]
+) .Anal.Calcd for C
24H
23NO
4: C, 74.02; H, 5.95; N, 3.60%; Found:C, 73.80; H, 5.94; N, 3.61%.
Embodiment three: (instead)-2, the preparation of 4-dimethoxy-N-(4-p-methoxy-phenyl)-6-(4-methoxyl-styrene) benzamide (compound 3)
The preparation method is with embodiment 2.Replace aniline with P-nethoxyaniline, obtain (instead)-2,4-dimethoxy-N-(4-p-methoxy-phenyl)-6-(4-methoxyl-styrene) benzamide.Productive rate 79%, mp:76-97 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 3.83 (s, 6H), 3.87 (s, 3H), 3.92 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 420.17 (C
25H
25NO
5, [M+H]
+) .Anal.Calcd for C
25H
25NO
5: C, 71.58; H, 6.01; N, 3.34%; Found:C, 71.79; H, 6.00; N, 3.33%.
Embodiment four: (instead) N-(4-ethoxyl phenenyl)-2, the preparation of 4-dimethoxy-6-(4-methoxyl-styrene) benzamide (compound 4)
The preparation method is with embodiment 1.Replace aniline with p-ethoxyaniline, obtain (instead)-N-(4-ethoxyl phenenyl)-2,4-methoxyl group-6-(4-methoxyl-styrene) benzamide.Productive rate 74%, mp:109-111 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm):
1H NMR (400MHz, CDCl
3) δ (ppm): 3.83 (s, 6H), 3.87 (s, 3H), 3.92 (s, 3H), 4.11 (q, J1=14.0, J2=7.2,2H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 434.19 (C
26H
27NO
5, [M+H]
+) .Anal.Calcd for C
26H
27NO
5: C, 72.04; H, 6.28; N, 3.23%; Found:C, 72.18; H, 6.27; N, 3.22%.
Embodiment five: (instead)-2, the preparation of 4-dimethoxy-N-(3-p-methoxy-phenyl)-6-(4-methoxyl-styrene) benzamide (compound 5)
The preparation method is with embodiment 1.Replace aniline with m-anisidine, obtain (instead)-2,4-dimethoxy-N-(3-p-methoxy-phenyl)-6-(4-methoxyl-styrene) benzamide.Productive rate 73%, mp:76-78 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 3.83 (s, 6H), 3.87 (s, 3H), 3.92 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,1H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.14 (s, 1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 420.17 (C
25H
25NO
5, [M+H]
+) .Anal.Calcd for C
25H
25NO
5: C, 71.58; H, 6.01; N, 3.34%; Found:C, 71.49; H, 6.02; N, 3.33%.
Embodiment six: (instead)-2, the preparation of 4-dimethoxy-N-(2-p-methoxy-phenyl)-6-(4-methoxyl-styrene) benzamide (compound 6)
The preparation method is with embodiment 1.Replace aniline with ORTHO ANISIDINE, obtain (instead)-2,4-dimethoxy-N-(2-p-methoxy-phenyl)-6-(4-methoxyl-styrene) benzamide.Productive rate 69%, mp:99-101 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 3.83 (s, 6H), 3.87 (s, 3H), 3.92 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 420.17 (C
25H
25NO
5, [M+H]
+) .Anal.Calcd for C
25H
25NO
5: C, 71.58; H, 6.01; N, 3.34%; Found:C, 71.69; H, 6.03; N, 3.35%.
Embodiment seven: (instead)-N-(2, the 5-Dimethoxyphenyl)-2, the preparation of 4-dimethoxy-6-(4-methoxyl-styrene) benzamide (compound 7)
The preparation method is with embodiment 1.With 2, the 5-dimethoxyaniline replaces aniline, obtains (instead)-N-(2, the 5-Dimethoxyphenyl)-2,4-dimethoxy-6-(4-methoxyl-styrene) benzamide.Productive rate 82%, mp:124-136 ℃.
1H?NMR(400MHz，CDCl
3)δ(ppm)：3.83(s，6H)，3.87(s，6H)，3.92(s，3H)，6.44(s，1H)，6.83(s，1H)，6.87(d，J＝8.8，2H)，6.92(d，J＝8.4，2H)，7.05(d，J＝16.4，1H)，7.26(d，J＝16.4，1H)，7.43(d，J＝8.8，2H)，7.51(s，1H)，7.57(d，J＝8.8，1H).MS(ESI)：450.18(C
26H
27NO
6，[M+H]
+).Anal.Calcd?for?C
26H
27NO
6：C，69.47；H，6.05；N，3.12％；Found：C，69.35；H，6.03；N，3.13％.
Embodiment eight: (instead)-N-(3, the 5-Dimethoxyphenyl)-2, the preparation of 4-dimethoxy-6-(4-methoxyl-styrene) benzamide (compound 8)
The preparation method is with embodiment 1.With 3, the 5-dimethoxyaniline replaces aniline, obtains (instead)-N-(3, the 5-Dimethoxyphenyl)-2,4-dimethoxy-6-(4-methoxyl-styrene) benzamide.Productive rate 76%, mp:112-114 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 3.83 (s, 6H), 3.87 (s, 6H), 3.92 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.26 (d, J=16.4,1H), 7.33 (s, 1H), 7.43 (d, J=8.8,1H), 7.51 (s, 1H), 7.57 (d, J=8.8, H) .MS (ESI): 450.18 (C
26H
27NO
6, [M+H]
+) .Anal.Calcd forC
26H
27NO
6: C, 69.47; H, 6.05; N, 3.12%; Found:C, 69.55; H, 6.03; N, 3.13%.
Embodiment nine: the preparation of anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-(3,4, the 5-trimethoxyphenyl) benzamides (compound 9)
The preparation method is with embodiment 1.With 3,4, the 5-trimethoxy-aniline replaces aniline, obtains anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-(3,4, the 5-trimethoxyphenyl) benzamide.Productive rate 84%, mp:126-128 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 3.83 (s, 12H), 3.87 (s, 3H), 3.92 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (s, 1H), 6.92 (s, 1H), 7.05 (d, J=16.4,1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 480.19 (C
27H
29NO
7, [M+H]
+) .Anal.Calcd for C
27H
29NO
7: C, 67.63; H, 6.10; N, 2.92%; Found:C, 67.59; H, 6.08; N, 2.93%.
Embodiment ten: the preparation of anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-(p-methylphenyl) benzamide (compound 10)
The preparation method is with embodiment 1.So that monomethylaniline is replaced aniline, obtain anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-(p-methylphenyl) benzamide.Productive rate 75%, mp:159-161 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 2.43 (s, 3H), 3.83 (s, 6H), 3.87 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 404.18 (C
25H
25NO
4, [M+H]
+) .Anal.Calcd for C
25H
25NO
4: C, 74.42; H, 6.25; N, 3.47%; Found:C, 74.57; H, 6.23; N, 3.48%.
Embodiment 11: the preparation of anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-(o-tolyl) benzamide (compound 11)
The preparation method is with embodiment 1.Replace aniline with o-toluidine, obtain: be anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-(o-tolyl) benzamide.Productive rate 73%, mp:150-152 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 2.43 (s, 3H), 3.83 (s, 6H), 3.87 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 404.18 (C
25H
25NO
4, [M+H]
+) .Anal.Calcd for C
25H
25NO
4: C, 74.42; H, 6.25; N, 3.47%; Found:C, 74.35; H, 6.26; N, 3.46%.
Embodiment 12: (instead)-N-(2, the 4-3,5-dimethylphenyl)-2, the preparation of 4-dimethoxy-6-(4-methoxyl-styrene) benzamide (compound 12)
The preparation method is with embodiment 1.With 2, the 4-xylidine replaces aniline, obtains anti-)-N-(2, the 4-3,5-dimethylphenyl)-2,4-dimethoxy-6-(4-methoxyl-styrene) benzamide.Productive rate 70%, mp:111-113 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 2.43 (s, 6H), 3.83 (s, 6H), 3.87 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (s, 1H), 7.05 (d, J=16.4,1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 418.19 (C
26H
27NO
4, [M+H]
+) .Anal.Calcd for C
26H
27NO
4: C, 74.80; H, 6.52; N, 3.35%; Found:C, 74.79; H, 6.53; N, 3.36%.
Embodiment 13: (instead)-N-(3, the 4-3,5-dimethylphenyl)-2, the preparation of 4-dimethoxy-6-(4-methoxyl-styrene) benzamide (compound 13)
The preparation method is with embodiment 1.With 3, the 4-xylidine replaces aniline, obtains (instead)-N-(3, the 4-3,5-dimethylphenyl)-2,4-dimethoxy-6-(4-methoxyl-styrene) benzamide.Productive rate 68%, mp:84-85 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 2.43 (s, 6H), 3.83 (s, 6H), 3.87 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (s, 1H), 7.05 (d, J=16.4,1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 418.19 (C
26H
27NO
4, [M+H]
+) .Anal.Calcd for C
26H
27NO
4: C, 74.80; H, 6.52; N, 3.35%; Found:C, 74.86; H, 6.48; N, 3.36%.
Embodiment 14: (instead)-N-(to fluorophenyl)-2, the preparation of 4-dimethoxy-6-(4-methoxyl-styrene) benzamide (compound 14)
The preparation method is with embodiment 1.Replace aniline with para-fluoroaniline, obtain (instead)-N-(to fluorophenyl)-2,4-dimethoxy-6-(4-methoxyl-styrene) benzamide.Productive rate 62%, mp:118-120 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 3.83 (s, 6H), 3.87 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 408.15 (C
24H
22FNO
4, [M+H]
+) .Anal.Calcd for (C
24H
22FNO
4: C, 70.75; H, 5.44; N, 4.66%; Found:C, 70.69; H, 5.44; N, 4.65%.
Embodiment 15: (instead)-N-(to bromophenyl)-2, the preparation of 4-dimethoxy-6-(4-methoxyl-styrene) benzamide (compound 15)
The preparation method is with embodiment 1.Replace aniline with para-bromoaniline, obtain (instead)-N-(to bromophenyl)-2,4-dimethoxy-6-(4-methoxyl-styrene) benzamide.Productive rate 64%, mp:148-150 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 3.83 (s, 6H), 3.87 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 468.07 (C
24H
22BrNO
4, [M+H]
+) .Anal.Calcd for C
24H
22BrNO
4: C, 61.55; H, 4.73; N, 2.99%; Found:C, 61.48; H, 4.72; N, 2.98%.
Embodiment 16: (instead)-N-(rubigan)-2, the preparation of 4-dimethoxy-6-(4-methoxyl-styrene) benzamide (compound 16)
The preparation method is with embodiment 1.Replace aniline with p-Chlorobenzoic acid amide, obtain (instead)-N-(rubigan)-2,4-dimethoxy-6-(4-methoxyl-styrene) benzamide.Productive rate 80%, mp:128-130 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 3.83 (s, 6H), 3.87 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 424.12 (C
24H
22ClNO
4, [M+H]
+) .Anal.Calcd for C
24H
22ClNO
4: C, 68.00; H, 5.23 N, 3.30%; Found:C, 68.10; H, 5.22; N, 3.31%.
Embodiment 17: the preparation of anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-(p-trifluoromethyl phenyl) benzamide (compound 17)
The preparation method is with embodiment 1.Replace aniline with p-trifluoromethylaniline, obtain anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-(p-trifluoromethyl phenyl) benzamide.Productive rate 78%, mp:106-108 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 3.83 (s, 6H), 3.87 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 458.15 (C
25H
22F
3NO
4, [M+H]
+) .Anal.Calcd for C
25H
22F
3NO
4: C, 65.64; H, 4.85; N, 3.06%; Found:C, 65.77; H, 4.84N, 3.05%.
Embodiment 18: (instead)-N-(bromophenyl)-2, the preparation of 4-dimethoxy-6-(4-methoxyl-styrene) benzamide (compound 18)
The preparation method is with embodiment 1.Replace aniline with m-bromoaniline, obtain (instead)-N-(bromophenyl)-2,4-dimethoxy-6-(4-methoxyl-styrene) benzamide.Productive rate 74%, mp:125-127 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 3.83 (s, 6H), 3.87 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.13 (s, 1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,1H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 468.07 (C
24H
22BrNO
4, [M+H]
+) .Anal.Calcd for C
24H
22BrNO
4: C, 61.55; H, 4.73; N, 2.99%; Found:C, 61.49; H, 4.74; N, 2.98%.
Embodiment 19: (instead)-N-(chloro-phenyl-)-2, the preparation of 4-dimethoxy-6-(4-methoxyl-styrene) benzamide (compound 19)
The preparation method is with embodiment 1.Replace aniline with m-chloro aniline, obtain (instead)-N-(chloro-phenyl-)-2,4-dimethoxy-6-(4-methoxyl-styrene) benzamide.Productive rate 62%, mp:91-92 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 3.83 (s, 6H), 3.87 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.13 (s, 1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,1H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 424.12 (C
24H
22ClNO
4, [M+H]
+) .Anal.Calcd for C
24H
22ClNO
4: C, 68.00; H, 5.23; N, 3.30%; Found:C, 68.11; H, 5.23; N, 3.31%.
Embodiment 20: (instead)-N-(3, the 4-dichlorophenyl)-2, the preparation of 4-dimethoxy-6-(4-methoxyl-styrene) benzamide (compound 20)
The preparation method is with embodiment 1.With 3, the 4-dichlorphenamide bulk powder replaces aniline, obtains (instead)-N-(3, the 4-dichlorophenyl)-2,4-dimethoxy-6-(4-methoxyl-styrene) benzamide.Productive rate 79%, mp:94-95 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 3.83 (s, 6H), 3.87 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,1H), 7.05 (d, J=16.4,1H), 7.13 (s, 1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,1H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 458.08 (C
24H
21Cl
2NO
4, [M+H]
+) .Anal.Calcd for C
24H
21Cl
2NO
4: C, 62.89; H, 4.62; N, 3.06%; Found:C, 62.93; H, 4.63; N, 3.05%.
Embodiment 21: (instead)-N-(to the acetyl phenyl)-2, the preparation of 4-dimethoxy-6-(4-methoxyl-styrene) benzamide (compound 21)
The preparation method is with embodiment 1.So that Acetanilide is replaced aniline, obtain (instead)-N-(to the acetyl phenyl)-2,4-dimethoxy-6-(4-methoxyl-styrene) benzamide.Productive rate 77%, mp:92-93 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 2.83 (s, 3H), 3.83 (s, 6H), 3.87 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.26 (d, J=16.4,1H), 7.43-7.48 (dd, 3H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 432.17 (C
26H
25NO
5, [M+H]
+) .Anal.Calcd for C
26H
25NO
5: C, 72.37; H, 5.84; N, 3.25%; Found:C, 72.38; H, 5.85; N, 3.25%.
Embodiment 22: the preparation of anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-(p-nitrophenyl) benzamide (compound 22)
The preparation method is with embodiment 1.Replace aniline with p-Nitroaniline, obtain anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-(p-nitrophenyl) benzamide.Productive rate 74%, mp:111-113 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 3.83 (s, 6H), 3.87 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 435.15 (C
24H
22N
2O
6, [M+H]
+) .Anal.Calcd for C
24H
22N
2O
6: C, 66.35; H, 5.10; N, 6.45%; Found:C, 66.32; H, 5.11; N, 6.43%.
Embodiment 23: the preparation of anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-(m-nitro base) benzamide (compound 23)
The preparation method is with embodiment 1.Replace aniline with m-nitraniline, obtain anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-(m-nitro base) benzamide.Productive rate 61%, mp:140-142 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 3.83 (s, 6H), 3.87 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.13 (s, 1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,1H) .MS (ESI): 435.15 (C
24H
22N
2O
6, [M+H]
+) .Anal.Calcd for C
24H
22N
2O
6: C, 66.35; H, 5.10; N, 6.45%; Found:C, 66.29; H, 5.11; N, 6.44%.
Embodiment 24: the preparation of anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-(ortho-nitrophenyl base) benzamide (compound 24)
The preparation method is with embodiment 1.Replace aniline with o-Nitraniline, obtain anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-(ortho-nitrophenyl base) benzamide.Productive rate 65%, mp:133-135 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 3.83 (s, 6H), 3.87 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.13 (s, 1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,1H) .MS (ESI): 435.15 (C
24H
22N
2O
6, [M+H]
+) .Anal.Calcd for C
24H
22N
2O
6: C, 66.35; H, 5.10; N, 6.45%; Found:C, 66.41; H, 5.11; N, 6.44%.
Embodiment 25: the preparation of anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-(to Trifluoromethoxyphen-l) benzamide (compound 25)
The preparation method is with embodiment 1.So that trifluoro-methoxyaniline is replaced aniline, obtain anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-(to Trifluoromethoxyphen-l) benzamide.Productive rate 77%, mp:127-129 ℃.
1H NMR (400MHzCDCl
3) δ (ppm): 3.83 (s, 6H), 3.87 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 474.15 (C
25H
22F
3NO
5, [M+H]
+) .Anal.Calcd for C
25H
22F
3NO
5: C, 63.42; H, 4.68; N, 2.96%; Found:C, 63.35; H, 4.675; N, 2.97%.
Embodiment 26: the preparation of anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-(Trifluoromethoxyphen-l) benzamide (compound 26)
The preparation method is with embodiment 1.Replace aniline with a trifluoro-methoxyaniline, obtain anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-(Trifluoromethoxyphen-l) benzamide.Productive rate 72%, mp:121-123 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 3.83 (s, 6H), 3.87 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.13 (s, 1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,1H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 474.15 (C
25H
22F
3NO
5, [M+H]
+) .Anal.Calcd forC
25H
22F
3NO
5: C, 63.42; H, 4.68; N, 2.96%; Found:C, 63.44; H, 4.70; N, 2.97%.
Embodiment 27: the preparation of anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-(adjacent Trifluoromethoxyphen-l) benzamide (compound 27)
The preparation method is with embodiment 1.Replace aniline with ortho-trifluoro-methoxyaniline, obtain anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-(adjacent Trifluoromethoxyphen-l) benzamide.Productive rate 77%, mp:124-16 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 3.83 (s, 6H), 3.87 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.13 (s, 1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,1H) .MS (ESI): 474.15 (C
25H
22F
3NO
5, [M+H]
+) .Anal.Calcd forC
25H
22F
3NO
5: C, 63.42; H, 4.68; N, 2.96%; Found:C, 63.43; H, 4.69; N, 2.97%.
Embodiment 28: the preparation of anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-(2-pyridyl) benzamide (compound 28)
The preparation method is with embodiment 1.Replace aniline with the 2-aminopyridine, obtain anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-(2-pyridyl) benzamide.Productive rate 67%, mp:113-115 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 3.83 (s, 6H), 3.87 (s, 3H), 3.92 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,4H), 7.05 (d, J=16.4,1H), 7.16 (dd, 2H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 391.16 (C
23H
22N
2O
4, [M+H]
+) .Anal.Calcd for C
23H
22N
2O
4: C, 70.75; H, 5.68; N, 7.17%; Found:C, 70.77; H, 5.66; N, 7.16%.
Embodiment 29: the preparation of anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-(3-pyridyl) benzamide (compound 29)
The preparation method is with embodiment 1.Replace aniline with the 3-aminopyridine, obtain anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-(3-pyridyl) benzamide.Productive rate 64%, mp:106-108 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 3.83 (s, 6H), 3.87 (s, 3H), 3.92 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,4H), 7.05 (d, J=16.4,1H), 7.16 (dd, 1H), 7.26 (d, J=16.4,1H), 7.34 (s, 1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 391.16 (C
23H
22N
2O
4, [M+H]
+) .Anal.Calcd forC
23H
22N
2O
4: C, 70.75; H, 5.68; N, 7.17%; Found:C, 70.70; H, 5.67; N, 7.15%.
Embodiment 30: (instead)-N-(3-(dimethylamino) propyl group)-2, the preparation of 4-dimethoxy-6-(4-methoxyl-styrene) benzamide (compound 30)
The preparation method is with embodiment 1.Replace aniline with the 3-dimethylaminopropylamine, obtain (instead)-N-(3-(dimethylamino) propyl group)-2,4-dimethoxy-6-(4-methoxyl-styrene) benzamide.Productive rate 87%, mp:66-67 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 1.83 (q, 2H), 2.16 (s, 6H), 2.46 (t, 2H), 3.46 (m, 2H), 3.83 (s, 6H), 3.87 (s, 3H), 3.92 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.26 (d, J=16.4,1H), 7.43-7.48 (dd, 3H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 385.20 (C
22H
28N
2O
4, [M+H]
+) .Anal.Calcd for C
22H
28N
2O
4: C, 68.73; H, 7.34; N, 7.29%; Found:C, 68.75; H, 7.33; N, 7.28%.
Embodiment hentriaconta-: anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-octyl group) preparation of benzamide (compound 31)
The preparation method is with embodiment 1.Replace aniline with n-octyl amine, obtain anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-octyl group) benzamide.Productive rate 81%, mp:86-87 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 0.83 (t, 3H), 1.31-1.56 (m, 12H), 3.24 (m, 2H), 3.83 (s, 6H), 3.87 (s, 3H), 3.92 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 426.26 (C
26H
35NO
4, [M+H]
+) .Anal.Calcdfor C
26H
35NO
4: C, 73.38; H, 8.29; N, 3.29%; Found:C, 73.45; H, 8.27; N, 3.28%.
Embodiment 32: anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-heptyl) preparation of benzamide (compound 32)
The preparation method is with embodiment 1.Replace aniline with positive heptyl amice, obtain anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-heptyl) benzamide.Productive rate 72%, mp:82-83 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 0.83 (t, 3H), 1.31-1.56 (m, 10H), 3.24 (m, 2H), 3.83 (s, 6H), 3.87 (s, 3H), 3.92 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 412.24 (C
25H
33NO
4, [M+H]
+) .Anal.Calcdfor C
25H
33NO
4: C, 72.96; H, 8.08; N, 3.40%; Found:C, 72.87; H, 8.06; N, 3.41%.
Embodiment 33: anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-hexyl) preparation of benzamide (compound 33)
The preparation method is with embodiment 1.Replace aniline with normal hexyl Amine, obtain anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-hexyl) benzamide.Productive rate 76%, mp:79-80 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 0.83 (t, 3H), 1.31-1.56 (m, 8H), 3.24 (m, 2H), 3.83 (s, 6H), 3.87 (s, 3H), 3.92 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 398.23 (C
24H
31NO
4, [M+H]
+) .Anal.Calcdfor C
24H
31NO
4: C, 72.52; H, 7.86; N, 3.52%; Found:C, 72.63; H, 7.85; N, 3.53%.
Embodiment 34: anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-amyl group) preparation of benzamide (compound 34)
The preparation method is with embodiment 1.Replace aniline with n-amylamine, obtain anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-amyl group) benzamide.Productive rate 71%, mp:76-77 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 0.83 (t, 3H), 1.31-1.56 (m, 6H), 3.24 (m, 2H), 3.83 (s, 6H), 3.87 (s, 3H), 3.92 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 384.21 (C
23H
29NO
4, [M+H]
+) .Anal.Calcdfor C
23H
29NO
4: C, 72.04; H, 7.62; N, 3.65%; Found:C, 72.05; H, 7.63; N, 3.64%.
Embodiment 35: anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-butyl) preparation of benzamide (compound 34)
The preparation method is with embodiment 1.Replace aniline with n-Butyl Amine 99, obtain anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-butyl) benzamide.Productive rate 77%, mp:71-72 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 0.83 (t, 3H), 1.31-1.56 (m, 4H), 3.24 (m, 2H), 3.83 (s, 6H), 3.87 (s, 3H), 3.92 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 370.19 (C
22H
27NO
4, [M+H]
+) .Anal.Calcdfor C
22H
27NO
4: C, 71.52; H, 7.37; N, 3.79%; Found:C, 71.45 H, 7.39; N, 3.79%.
Embodiment 36: anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-propyl group) preparation of benzamide (compound 34)
The preparation method is with embodiment 1.Replace aniline with Tri N-Propyl Amine, obtain anti--(2, the 4-dimethoxy)-6-(4-methoxyl-styrene)-N-propyl group) benzamide.Productive rate 80%, mp:68-69 ℃.
1H NMR (400MHz, CDCl
3) δ (ppm): 0.83 (t, 3H), 1.31-1.56 (m, 2H), 3.24 (m, 2H), 3.83 (s, 6H), 3.87 (s, 3H), 3.92 (s, 3H), 6.44 (s, 1H), 6.83 (s, 1H), 6.87 (d, J=8.8,2H), 6.92 (d, J=8.4,2H), 7.05 (d, J=16.4,1H), 7.26 (d, J=16.4,1H), 7.43 (d, J=8.8,2H), 7.51 (s, 1H), 7.57 (d, J=8.8,2H) .MS (ESI): 356.18 (C
21H
25NO
4, [M+H]
+) .Anal.Calcdfor C
21H
25NO
4: C, 70.96; H, 7.09; N, 3.94%; Found:C, 71.08; H, 7.07; N, 3.95%.
Embodiment 37: the anti tumor activity in vitro research of novel trans-resveratrol amide derivatives
Adopt MTT[3-(4,5)-two methyl-2-thiazole-(2,5)-phenyl bromination tetrazole indigo plant] method measure thiourea derivatives to the minimum inhibitory concentration of human oral cavity upper epidermis JEG-3 (KB) and human leukemia cell line (K562) (minimal inhibitoryconcentration, MIC).
(1) preparation of nutrient solution (every liter): 1. suspension cell: RPMI-1640 cultivates one bag in powder (10.4g), new-born calf serum 100ml, penicillin solution (200,000 U/ml) 0.5ml, Streptomycin sulphate solution (200,000 U/ml) 0.5ml, after adding the tri-distilled water dissolving, the NaHCO with 5.6%
3Solution transfers pH value to 7.2-7.4, is settled to 1000ml at last.Filtration sterilization.2. attached cell: the same, add NaHCO again
32.00g, HEPES 2.38g.
(2) preparation of D-Hanks damping fluid (every liter): NaCl 8.00g, KCl 0.40g, Na
2HPO
412H
2O 0.06g, KH
2PO
40.06g, NaHCO
30.35g.Autoclaving.
(3) preparation of trypsin solution: utilizing the D-Hanks damping fluid to be made into concentration is 0.5% trypsin solution.Filtration sterilization.
(4) preparation of experiment soup: specimen is made into storing solution with a spot of tri-distilled water dissolving, general 10 times of preparation storing solutions by the experiment maximum concentration.According to the compound dissolution difference, available tri-distilled water directly dissolves, or with a small amount of DMSO hydrotropy, adds the tri-distilled water dissolving again.The concentration of DMSO in nutrient solution is unsuitable excessive, and the final concentration of DMSO generally is no more than 0.05%-0.1% in the every porocyte suspension after the dosing.Storing solution is stored in-20 ℃ of refrigerators standby.
(5) cultivation of human leukemia cell K562: be the suspension growth cell, routine is incubated in the RPMI-1640 nutrient solution (containing 10% calf serum, 100U/ml Streptomycin sulphate), places 37 ℃, 5% CO
2Cultivate in the incubator, went down to posterity once every 3-4 days.When going down to posterity nutrient solution in the former bottle is transferred in the centrifuge tube, the centrifugal 5min of 1000rpm discards original fluid, add the equivalent fresh medium, piping and druming evenly pipettes in right amount to the fresh culture bottle, and the restock fresh medium is to original volume (nutrient solution volume be about culturing bottle capacity 1/10).
(6) cultivation of human oral cavity upper epidermis cancer cells KB: be the adherent growth cell, routine is incubated in the RPMI-1640 nutrient solution (containing 10% calf serum, 100U/ml Streptomycin sulphate), puts 37 ℃, 5% CO
2Cultivate in the incubator, went down to posterity once every 3-4 days.Discard original fluid when going down to posterity earlier, again with the washing of D-Hanks damping fluid; Use 0.5% tryptic digestion about 30 seconds then, add a small amount of fresh medium and stop digestion; Piping and druming makes attached cell split away off from the culturing bottle wall; Pipette in right amount to the fresh culture bottle, the restock fresh medium is to original volume (nutrient solution volume be about culturing bottle capacity 1/10).
(7) cell is hatched: 2 kinds of tumour cells in the vegetative period of taking the logarithm, the accent concentration of cell suspension is 1-1.5 * 10
5Individual ml
-1Every hole adds cell suspension 100 μ l in 96 well culture plates, puts 37 ℃, 5% CO
2Cultivate 24h in the incubator.After cultivating 24h, add soup by design respectively.
(8) dosing: will test soup and join respectively in each hole according to the concentration gradient of ultimate density, each concentration is established 6 parallel holes.Experiment is divided into drug test group (the test medicine that adds different concns respectively), control group (only add nutrient solution and cell, do not add the test medicine) and blank group (only add nutrient solution, do not add cell and test medicine).96 orifice plates after the dosing are placed 37 ℃, 5%CO
2Cultivate 48h in the incubator.The activity of positive control medicine is measured according to the method for specimen.
(9) mensuration of survivaling cell: in having cultivated 96 orifice plates behind the 48h, every hole adds MTT 40 μ l (being made into 4mg/ml with the D-Hanks damping fluid).Behind 37 ℃ of placement 4h, remove supernatant liquor.Every hole adds 150 μ l DMSO, and vibration 5min makes formazan crystallization dissolving.At last, utilize automatic microplate reader to detect the optical density(OD) (OD value) in each hole at 570nm wavelength place.
The calculating of inhibiting rate: the inhibiting rate of cell growth calculates according to following formula:
Growth inhibition ratio=(1-survival rate) * 100%=[1-(OD
Experiment-OD
Blank)/(OD
Contrast-OD
Blank)] * 100% (OD
ExperimentThe average optical of expression testing drug group, OD
ContrastThe average optical of expression control group, OD
BlankThe average optical of expression control group).
Half-inhibition concentration (IC
50) be defined as the drug level when the survival of 50% tumour cell.According to the optical density(OD) of measuring (OD value), make the typical curve of inhibitory rate of cell growth, on typical curve, try to achieve its corresponding drug level.
The IC that records
50Be shown in Table 1
The listed trans-resveratrol amide derivatives of table 1 the present invention is to the inhibition IC of tumour cell
50Value (μ M)
Claims (3)
1. resveratrol is looked into amide derivatives, it is characterized in that it has following general formula:
R is in the formula:
2. a method for preparing the described trans-resveratrol amide derivatives of claim 1 is characterized in that it comprises the steps:
Step 1. adds trans-resveratrol three methyl ether list aldehyde in DMSO, fully after the dissolving, dropwise add NaH
2PO
4The aqueous solution after dropwising, stirs 0.5h, dropwise adds NaClO then
2The aqueous solution dropwises and at room temperature reacts 24h.After reacting completely, reaction solution is poured in the big water gaging, uses ethyl acetate extraction, the organic phase anhydrous sodium sulfate drying, and column chromatography gets faint yellow solid;
Described NaH
2PO
4Consumption be every mmole trans-resveratrol three methyl ether list aldehyde with 50 milligrams of NaH
2PO
4Be dissolved in the 0.5mL water;
Described NaClO
2Consumption be every mmole trans-resveratrol three methyl ether list aldehyde with 180 milligrams of NaClO
2Be dissolved in the 2mL water.
The solid that step 2. obtains the first step and the amine (R-NH of equimolar amount
2) join successively in the methylene dichloride, add EDC.HCl and HOBt again, react 12h under the room temperature, column chromatography gets target product after the solvent evaporated, and wherein R is identical with the R definition in the claim 1.
The consumption of described EDC.HCl is every mmole reactant with 1.5 mmole EDC.HCl;
The consumption of described HOBt is every mmole reactant with 0.5 mmole HOBt.
Above-mentioned method for making, in the step 1, described DMSO consumption is every mmole trans-resveratrol 2ml DMSO.
Above-mentioned method for making, in the step 2, described methylene dichloride consumption is every mmole reactant 10ml methylene dichloride.
3. the described trans-resveratrol amide derivatives of claim 1 is at the lead compound of preparation antitumor drug.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102617391A (en) * | 2012-04-13 | 2012-08-01 | 合肥工业大学 | Resveratrol benzene acrylamide derivative, preparing method and application thereof |
| WO2018112545A1 (en) * | 2016-12-23 | 2018-06-28 | The University Of Queensland | Inhibitors of sox18 protein activity for treating angiogenesis- and/or lymphangiogenesis-related diseases |
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| CN101186594A (en) * | 2007-12-13 | 2008-05-28 | 江苏省原子医学研究所 | (Z)-2,4-dimethoxy-6-styryl-5-(Schiff's base or benzoylhydrazone)benzene compounds and preparation method thereof |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102617391A (en) * | 2012-04-13 | 2012-08-01 | 合肥工业大学 | Resveratrol benzene acrylamide derivative, preparing method and application thereof |
| WO2018112545A1 (en) * | 2016-12-23 | 2018-06-28 | The University Of Queensland | Inhibitors of sox18 protein activity for treating angiogenesis- and/or lymphangiogenesis-related diseases |
| KR20190105018A (en) * | 2016-12-23 | 2019-09-11 | 더 유니버서티 어브 퀸슬랜드 | Inhibitors of SOX18 protein activity to treat angiogenesis- and / or lymphangiogenesis-related diseases |
| JP2020506884A (en) * | 2016-12-23 | 2020-03-05 | ザ ユニバーシティー オブ クイーンズランド | Inhibitors of SOX18 protein activity for treatment of diseases associated with angiogenesis and / or lymphangiogenesis |
| US11434190B2 (en) | 2016-12-23 | 2022-09-06 | The University Of Queensland | Inhibitors of SOX18 protein activity for treating angiogenesis-and/or lymphangiogenesis-related diseases |
| AU2017383102B2 (en) * | 2016-12-23 | 2023-05-11 | The University Of Queensland | Inhibitors of SOX18 protein activity for treating angiogenesis- and/or lymphangiogenesis-related diseases |
| KR102572077B1 (en) | 2016-12-23 | 2023-08-29 | 더 유니버서티 어브 퀸슬랜드 | Inhibitors of SOX18 protein activity for the treatment of angiogenesis- and/or lymphangiogenesis-related disorders |
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