CN102241604A - Amino acid modified curcumin, synthesis method thereof, and application thereof - Google Patents
Amino acid modified curcumin, synthesis method thereof, and application thereof Download PDFInfo
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Abstract
The invention discloses a type of amino acid modified curcumin, a synthesis method thereof, and an application thereof. According to the invention, structural modification is carried out upon curcumin by using natural amino acid, such that 1-(4-hydroxy-3-methoxyphenyl)-7-(4-oxyacetyl amino carbobenzoxy-3-methoxyphenyl)-1,6-heptadiene-3,5-diketone which is represented by a general formula (I) is obtained. With an MTT method, evaluation is carried out upon the compound represented by the general formula (I) in the inhabitance of proliferation activities of four cells which are K562, H22, HL60 and S180. IC50 values of the compound represented by the general formula (I) in inhibiting the proliferations of the four tumor cells are calculated. As a result of experiments, with the compound represented by the general formula (I), proliferations of tumor cells can be substantially inhibited. The compound has excellent anti-tumor activity, and can be prepared into anti-tumor medicines.
Description
Technical field
The present invention relates to amino acid modified curcumine, relate in particular to 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetylamino acid carbobenzoxy-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone and synthetic method thereof, the invention further relates to 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetylamino acid carbobenzoxy-3-p-methoxy-phenyl)-1,6-heptadiene-3, the 5-diketone the invention belongs to the derivative field of curcumine as the clinical application of antitumor drug.
Background technology
Curcumine [(1,7-two-(4-hydroxy 3-methoxybenzene base)-1,6-heptadiene-3,5-diketone] be the active ingredient of Chinese medicine turmeric, have pharmacological properties widely, the Kuttan of India in 1985 etc. proposes turmeric first and curcumine has the possibility of antitumor action.After this, numerous scholars study the antitumor action and the mechanism of curcumine, think that curcumine can suppress the tumor cell line growth.Curcumine because of anticancer spectrum extensively reach toxic side effect little by the state-run tumour of the U.S. classify as the 3rd generation the cancer chemoprevention medicine enter clinical trial.Yet discovering that curcumine anti-tumor activity in vivo is on the low side, absorb less in the body recently, tachytrophism, application are restricted.The contriver understands, and natural amino acid is widely used in improving the absorption and the metabolism of medicine.So, the contriver carries out structural modification with natural amino acid to curcumine, prepare novel 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetylamino acid carbobenzoxy-3-p-methoxy-phenyl)-1,6-heptadiene-3, the 5-diketone is in the hope of obtaining ideal water solubility, absorbent properties and metabolisming property.
Summary of the invention
One of the object of the invention provides 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetylamino acid carbobenzoxy-3-p-methoxy-phenyl)-1 that a class has anti-tumor activity, 6-heptadiene-3,5-diketone;
Two of the object of the invention provides a kind of synthetic above-mentioned 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetylamino acid carbobenzoxy-3-p-methoxy-phenyl)-1 with anti-tumor activity, 6-heptadiene-3, the method for 5-diketone;
Above-mentioned purpose of the present invention is achieved through the following technical solutions:
1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetylamino acid carbobenzoxy-3-p-methoxy-phenyl)-1 with anti-tumor activity, 6-heptadiene-3,5-diketone, its structural formula are shown in the general formula I:
Wherein, AA be selected from that L-alanyl, L-phenylalanyl, L-are valyl, L-seryl, L-Threonyl, L-tyrosyl, L-prolyl, L-methionyl, L-glutamyl, L-asparagyl, L-tryptophyl, L-nitro arginyl, glycyl, L-lysyl, L-glutaminate acyl group, altheine acyl group, L-leucyl or the different bright acyl group of L-.
Two of purpose of the present invention provides a kind of synthetic above-mentioned 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetylamino acid carbobenzoxy-3-p-methoxy-phenyl)-1 with anti-tumor activity, 6-heptadiene-3, and the method for 5-diketone comprises:
(1) preparation 3-methoxyl group-4-(2-butyryl acyloxy) phenyl aldehyde;
(2) preparation 6-(4-hydroxyl-3-methoxyphenyl)-5,6-hexene-2,4-diketone;
(3) product with step (1) and step (2) is that raw material reacts, and prepares 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone;
(4) with 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1,6-heptadiene-3, the 5-diketone carries out saponification, obtains 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetoacetyl-3-p-methoxy-phenyl)-1,6-heptadiene-3, the 5-diketone;
(5) with 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetoacetyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone and hydrochloric acid L-amino-acid benzyl ester or tosic acid amino-acid benzyl ester carry out coupling, promptly.
Wherein, the hydrochloric acid L-amino acid acid benzyl ester described in the step (5) is preferably from hydrochloric acid L-Serine benzyl ester, hydrochloric acid L-threonine benzyl ester or hydrochloric acid L-proline(Pro) benzyl ester; Described tosic acid amino-acid benzyl ester is preferably from tosic acid L-alanine benzyl ester, toluenesulphonic acids L-phenylalanine benzyl ester, tosic acid L-Xie Ansuan benzyl ester, tosic acid L-tyrosine benzyl ester, L-methionine(Met) benzyl ester, tosic acid L-benzyl glutamate, tosic acid L-aspartic acid benzyl ester, tosic acid L-tryptophan benzyl ester, tosic acid L-NG-nitroarginine benzyl ester, tosic acid L-glycine benzyl ester, tosic acid L-Methionin benzyl ester, tosic acid L-leucine benzyl ester or tosic acid L-Isoleucine benzyl ester, tosic acid L-glutaminate benzyl ester or tosic acid L-asparagine benzyl ester.
The present invention adopts mtt assay to estimate The compounds of this invention inhibition K562, H22, HL60 and S180 four strain cell proliferation activities, calculates the IC that The compounds of this invention suppresses these four kinds of tumor cell proliferations
50Value.Test-results shows that The compounds of this invention can significantly suppress the propagation of tumour cell, has excellent anti-tumor activity, can be prepared into antitumor drug.
Another purpose of the present invention provides a kind of medicinal compositions for the treatment of tumour, this medicinal compositions is gone up effective dose by treatment The compounds of this invention is with pharmaceutically acceptable excipient or assist and add agent and form, the The compounds of this invention that is about to significant quantity is with after pharmaceutically acceptable carrier or thinner cooperate, and by the formulation method of this area routine it is prepared into any one appropriate drug composition.Usually said composition is suitable for oral administration and drug administration by injection, also is fit to other medication.Said composition can be liquid preparation forms such as tablet, capsule, pulvis, granule, lozenge, suppository, or oral liquid.According to different medications, pharmaceutical composition of the present invention can contain 0.1%-99% weight, the The compounds of this invention of preferred 10-60% weight.
Description of drawings
Fig. 1 1-of the present invention (4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetylamino acid carbobenzoxy-3-p-methoxy-phenyl)-1,6-heptadiene-3, the structural formula of 5-diketone.
Fig. 2 the present invention-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetylamino acid carbobenzoxy-3-p-methoxy-phenyl)-1,6-heptadiene-3, the synthetic route chart of 5-diketone (5a-r); I) anhydrous K
2CO
3, BrCH
2COOC
2H
5Ii) B
2O
3, methyl ethyl diketone, (nBuo)
3B, nBu-NH
2, 1NHCl; Iii) B
2O
3, methyl ethyl diketone, (nBuo)
3B, nBu-NH
2, 1NHCl; Iv) DCC, HOBt, NMM., amino-acid benzyl ester.AA=L-alanyl among the 5a; AA=L-phenylalanyl among the 5b; AA=L-is valyl among the 5c; AA=L-seryl among the 5d; AA=L-Threonyl among the 5e; AA=L-tyrosyl among the 5f; AA=L-prolyl among the 5g; AA=L-methionyl among the 5h; A=L-glutamyl among the 5i; AA=L-asparagyl among the 5j; AA=L-tryptophyl among the 5k; AA=L-nitro arginyl among the 5l; AA=glycyl among the 5m; AA=L-lysyl among the 5n; AA=L-glutaminyl among the 5o; AA=L-asparagyl among the 5p; AA=L-leucyl among the 5q; the different bright acyl group of AA=L-among the 5r.
Embodiment
In order further to set forth the present invention, provide a series of embodiment below.These embodiment are illustrative fully, and they only are used for the present invention is specifically described, and not should be understood to limitation of the present invention.
Embodiment 1 preparation 3-methoxyl group-4-(2-butyryl acyloxy) phenyl aldehyde (1)
10g (65.7mmol) Vanillin is dissolved in the anhydrous THF of 200ml.In the solution that obtains, add 11.8g (85.6mmol) salt of wormwood in batches and stir 2h.Drip the 7.68ml ethyl bromoacetate then inwards, room temperature vigorous stirring 48h, TLC plate monitoring (sherwood oil: ethyl acetate=3: 1) show that reaction finishes.The reaction mixture suction filtration, filtrate decompression is concentrated into dried.The resistates that obtains with the 150mL acetic acid ethyl dissolution, place the 250ml separating funnel, successively with 5% aqueous potassium hydrogen sulfate wash (30mL * 3), saturated sodium-chloride water solution is washed (30mL * 3).Ethyl acetate layer is concentrated into dried with anhydrous sodium sulfate drying, filtration, filtrate decompression, obtain 10.9g (70%) target compound, is colorless solid.
Add 10.58ml (102.9mmol) methyl ethyl diketone, 5.0g (72.1mmol) boron oxide and 50.0mL ethyl acetate in the 150mL three-necked bottle, load onto reflux condensate device, oil bath constant temperature stirs 1h down for 70 ℃.Add 5.2g (34.3mmol) Vanillin and 4.8ml (34.3mmol) tributyl borate then.Reaction mixture stirs 30min for 85 ℃.Slowly drip 1.8mL (41.1mmol) triethylamine that is diluted in the 10mL ethyl acetate in 30min in three-necked bottle, 100 ℃ of reaction 1h are cooled to room temperature then.Drip 36mL hydrochloric acid (1N) in reaction flask, 50 ℃ are stirred 30min, leave standstill fully layering.Water layer with ethyl acetate extraction 3 times, combined ethyl acetate layer, be washed to neutrality, anhydrous sodium sulfate drying, filtration, filtrate decompression and be concentrated into dried, residue with purification by silica gel column chromatography (sherwood oil: acetone=5: 1), obtain 3.66g (47.6%) target compound, be yellow solid.
In the 150mL three-necked bottle, add 5.0g (21.4mmol) 6-(4-hydroxyl-3-methoxyphenyl)-5,6-hexene-2,4-diketone (2), 1.0g (14.9mmol) boron oxide and 50.0mL ethyl acetate.Load onto reflux condensate device.Reaction mixture stirs 1h for 70 ℃.Add 4.3g (18.1mmol) 3-methoxyl group-4-(2-butyryl acyloxy) phenyl aldehyde (1) and 3.7ml (21.4mmol) tributyl borate then.Reaction mixture stirs 30min for 85 ℃.0.98mL (21.4mmol) n-Butyl Amine 99 that is diluted in the 10mL ethyl acetate slowly is added drop-wise in the three-necked bottle in 30min.Reaction mixture continues to react 1h in 100 ℃, is cooled to room temperature then.In reaction mixture, add 19.6mL hydrochloric acid (1N), 50 ℃ of stirring reaction 30min, leave standstill, fully layering, water layer be with ethyl acetate extraction 3 times.The ethyl acetate layer that merges washes with water to neutrality, anhydrous sodium sulfate drying, filtration, filtrate decompression and is concentrated into dried.Residue column chromatography purification (sherwood oil: acetone=3: 1), obtain 2.88g (35.2%) target compound, be yellow solid.
Embodiment 4 preparation 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetoacetyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (4)
With 1g (2.2mmol) 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1,6-heptadiene-3, the 5-diketone dissolves with THF.Under the room temperature, dripping 1NNaOH solution to reacting liquid pH value inward is 9, stirs 2h, the TLC monitoring, and raw material disappears.With 1N HCl solution reacting liquid pH value is transferred to 7, concentrating under reduced pressure, the resistates that obtains adds ethyl acetate with 1N HCl solution adjust pH to 3, places the 100ml separating funnel, extracts 3 times.The ethyl acetate layer that merges concentrates with anhydrous sodium sulfate drying, filtration, filtrate decompression, obtains 937.9mg (90%) target compound, is the orange pressed powder.
Embodiment 5 preparation 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetyl-L-alanyl carbobenzoxy-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (5a)
The ice bath cooling is down to the 1g that places 100mL eggplant bottle (2.3mmol) 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetoacetyl-3-p-methoxy-phenyl)-1,6-heptadiene-3, the THF solution of 5-diketone (4), 906mg (2.06mmol) tosic acid L-alanine benzyl ester and 326mg (2.45mmol) N-hydroxybenzotriazole (HOBt) splashes into the THF solution of 568mg (2.76mmol) dicyclohexyl carbonyl diimine (DCC).Drip N methylmorpholine (NMM) adjust pH to 8 to the solution that obtains.Reaction mixture stirring at room 12h, the TLC monitoring.Reaction finishes the back suction filtration, filtrate decompression is concentrated into dried.The resistates that obtains with the 150mL acetic acid ethyl dissolution, place the 250ml separating funnel, wash (30mL * 3), saturated sodium-chloride water solution with saturated sodium bicarbonate aqueous solution successively and wash (30mL * 3), 5% aqueous potassium hydrogen sulfate and wash (30mL * 3), saturated sodium-chloride water solution and wash that (30mL * 3), saturated sodium bicarbonate aqueous solution are washed (30mL * 3), saturated sodium-chloride water solution is washed (30mL * 3).The ethyl acetate layer that merges is concentrated into dried with anhydrous sodium sulfate drying, filtration, filtrate decompression.Residue column chromatography purification (R
f=0.30, sherwood oil: acetone=2: 1), obtain 0.352g (25.9%) target compound, be yellow solid.Mp 109-110 ℃;
(c=0.53, acetone); ESI-MS (m/e) 588[M+H]
+IR (KBr): 3293,2942,1736,1628,1585,512,1453,1272,1212,1137,1032,970,831,565;
1H-NMR (500MHz, and DMSO-d6) 9.71 (s, 1H), 8.61 (d, J=6.0Hz, 1H), 7.61 (d, J=3.0Hz, 1H), 7.56 (d, J=3.0Hz, 1H), 7.38～7.34 (m, 7H), 7.18 (s, 1H), 7.16 (s, 1H), 6.91 (d, J=8.4Hz, 1H), 6.86 (d, J=6.9Hz, 1H), 6.81 (d, J=4.5Hz, 1H), 6.75 (s, 1H), 6.09 (s, 1H), 5.14 (s, 2H), 4.61 (s, 2H), 4.45 (t, J=7.2Hz, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 1.35 (d, J=7.2Hz, 3H);
13C-NMR (125MHz, DMSO-d6) δ/ppm=184.41,182.92,172.54,168.01,149.92,149.84,149.79,148.47,141.54,140.32,136.41,130.87,129.2,128.9,128.49,128.8,126.76,123.67,123.04,122.82,121.59,116.39,116.19,114.47,111.89,111.52,101.50,68.16,66.49,56.17,48.01,17.41.
Embodiment 6 preparation 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetyl-L-phenylalanyl carbobenzoxy-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (5b)
According to the method for embodiment 5 from 642mg (1.50mmol) 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetoacetyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (4) and 704mg (1.65mmol) tosic acid L-phenylalanine benzyl ester obtain 315mg (31.5%) target compound, are yellow solid.Mp 92-93 ℃;
(c=0.52, acetone); ESI-MS (m/e) 664[M+H]
+IR (KBr): 3401,2344,1742,1683,1626,1586,1512,1455,1273,1133,1032,830,721,466;
1H-NMR (500MHz, and DMSO-d6) 9.69 (s, 1H), 8.41 (d, J=7.85Hz, 1H), 7.58 (dd, J=15.75Hz, J=3.55Hz, 1H), 7.37 (m, J=2.15Hz, 1H), 7.37 (m, J=6.90Hz, 2H), 7.33 (m, J=7.20Hz, J=1.50Hz, 4H), 7.25 (m, J=7.35Hz, 3H), 7.17 (m, J=6.45Hz, J=1.65Hz, 3H), 7.13 (d, J=7.20Hz, 1H), 6.85 (d, J=16.95Hz, 1H), 6.84 (d, J=7.95Hz, 1H), 6.79 (d, J=15.95Hz, 1H), 6.84 (d, J=8.35Hz, 1H), 6.11 (s, 1H), 5.13 (d, J=2.50Hz, 2H), 4.67 (m, J=8.35Hz, J=2.60Hz, 1H), 4.56 (s, 2H), 3.85 (s, 3H), 3.83 (s, 3H), 3.12 (dd, J=13.80Hz, J=5.45Hz, 1H), 3.03 (dd, J=13.70Hz, J=8.85Hz, 1H);
13C-NMR (125MHz, DMSO-d6) δ/ppm=184.41,182.94,171.43,168.14,149.92,149.70,148.47,141.55,140.36,137.25,136.16,129.60,129.16,128.90,128.79,128.57,128.38,127.11,126.76,123.69,123.03,122.85,121.59,116.19,114.25,111.87,111.44,101.51,67.96,66.69,56.16,53.67,36.99.
Embodiment 7 preparation 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetyl-L-valyl carbobenzoxy-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (5c)
According to the method for embodiment 5 from 806mg (1.90mmol) 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetoacetyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (4) and 790mg (1.69mmol) tosic acid L-Xie Ansuan benzyl ester obtain 355mg (30.5%) target compound, are yellow solid.Mp 29-30 ℃;
(c=0.55, acetone); ESI-MS (m/e) 616[M+H]
+IR (KBr): 3737,3336,2966,2346,1738,1680,1626,1586,1512,1457,1272,1135,1032,969,835,463;
1H-NMR (500MHz, and DMSO-d6) 9.68 (s, 1H), 8.25 (d, J=8.3Hz, 1H), 7.59 (d, J=2.45Hz, 1H), 7.56 (d, J=2.55Hz, 1H), 7.40～7.34 (m, 7H), 7.20 (dd, J=8.45Hz, J=1.7Hz, 1H), 7.17 (dd, J=8.25Hz, J=1.75Hz, 1H), 6.95 (d, J=8.45Hz, 1H), 6.84 (m, 3H), 6.10 (s, 1H), 5.16 (m, 2H), 4.69 (m, 2H), 4.32 (m, 1H), 3.85 (s, 3H), 3.83 (s, 3H), 2.12 (m, 1H), 0.87 (m, 6H);
13C-NMR (125MHz, DMSO-d6) δ/ppm=184.41,182.93,171.49,168.32,149.92,149.80,149.70,148.47,141.54,140.33,136.26,129.13,128,92,128.63,128.55,126.76,123.68,123.04,122.87,121.59,116.18,114.21,111.89,111.52,101.47,67.86,66.58,57.50,56.24,56.18,30.52,19.35,18,35,14.55.
Embodiment 8 preparation 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetyl-L-seryl carbobenzoxy-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (5d)
According to the method for embodiment 5 from 400mg (0.94mmol) 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetoacetyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (4) and 240mg (1.04mmol) hydrochloric acid L-Serine benzyl ester obtain 181mg (31.6%) target compound, are yellow solid.68 ℃ of Mp;
(c=0.55, acetone); ESI-MS (m/e) 604[M+H]+; IR (KBr): 3744,3407,2935,2320,1741,1628,1583,1512,1456,1273,1135,1032,971,475;
1HNMR (500MHz, DMSO-d6) 9.69 (s, 1H), 8.30 (d, J=7.8Hz, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.37 (m, 7H), 7.20～7.15 (m, 2H), 6.97 (d, J=8.4Hz, 2H), 6.88～6.75 (m, 3H), 6.09 (s, 1H), 5.24 (t, J=5.4Hz, 1H), 5.16 (s, 2H), 4.65 (s, 2H), 4.50 (m, 1H), 3.85 (s, 3H), 3.84 (s, 3H);
13C-NMR (125MHz, DMSO-d6) δ/ppm=184.42,182.89,170.57,168.26,149.93,149.85,149.73,148.49,141.54,140.30,136.38,129.35,128.87,128.45,128.09,126.78,123.67,123.12,122.83,121.62,116.21,114.75,111.96,111.60,101.45,68.33,66.55,61.63,56.27,56.21,54.84,47.99,33.81,25.80,24.92.
Embodiment 9 preparation 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetyl-L-threonyl carbobenzoxy-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (5e)
According to the method for embodiment 5 from 587mg (1.38mmol) 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetoacetyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (4) and 373mg (1.52mmol) hydrochloric acid L-threonine benzyl ester obtain 200mg (23.5%) target compound, are yellow solid.48 ℃ of Mp;
(c=0.55, acetone); ESI-MS (m/e) 618[M+H]
+IR (KBr): 3395,1741,1627,1585,1512,1457,1275,1135,1032,970,834,465;
1HNMR (500MHz, DMSO-d6) 9.71 (s, 1H), 8.07 (d, J=8.7Hz, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.31 (m, 7H), 7.18 (m, 2H), 6.99 (d, J=8.4Hz, 2H), 6.88 (s, 1H), 6.83 (m, 2H), 6.76 (s, 1H), 6.09 (s, 1H), 5.25 (d, J=4.8Hz, 1H), 5.15 (s, 2H), 4.47 (s, 2H), 4.42 (dd, J=6.0Hz, J=2.7Hz, 1H), 4.23 (m, 3H), 3.85 (s, 3H), 3.842 (s, 3H), 1.07 (m, 3H);
13C-NMR (125MHz, DMSO-d6) δ/ppm=184.44,182.88,170.68,168.68,149.91,149.80,149.65,148.46,141.55,140.30,136.38,129.33,128.86,128.45,128.14,126.74,123.69,123.12,122.83,121.59,116.17,114.62,111.87,111.54,101.49,68.23,66.64,66.57., 56.28,56.17,20.70.
Embodiment 10 preparation 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetyl-L-tyrosyl carbobenzoxy-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (5f)
According to the method for embodiment 5 from 784mg (1.84mmol) 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetoacetyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (4) and 897mg (2.02mmol) tosic acid L-tyrosine benzyl ester obtain 320mg (25.6%) target compound, are yellow solid.118 ℃ of Mp;
(c=0.53, acetone); ESI-MS (m/e) 680[M+H]
+IR (KBr): 3415,1739,1626,1588,1512,1451,1272,1134,1033,970,830,731,470;
1H-NMR (500MHz, DMSO-d6) 9.66 (s, 1H), 9.28 (s, 1H), 8.30 (d, J=7.90Hz, 1H), 7.59 (d, J=4.85Hz, 1H), 7.56 (d, J=4.95Hz, 1H), 7.40-7.31 (m, 7H), 7.17 (dd, J=8.25Hz, J=1.65Hz, 1H), 7.14 (dd, J=8.5Hz, J=1.45Hz, 1H), 6.98 (s, 1H), 6.96 (s, 1H), 6.86-6.75 (m, 4H), 6.67 (s, 1H), 6.65 (s, 1H), 6.10 (s, 1H), 5.13 (m, 2H), 4.62-4.53 (m, 3H), 3.85 (s, 3H), 3.84 (s, 3H)) 3.00 (dd, J=13.86Hz, J=5.45Hz, 1H), 2.91 (m, 1H);
13C-NMR (125MHz, DMSO-d6) δ/ppm=156.60,149.93,149.70,148.49,141.54,140.35,136.20,130.57,129.15,128.88,128.55,128,37,127.12,126.78,123.68,123.05,122.79,121.61,116.21,115.62,114.27,111.93,111.52,101.49,67.93,66.62,65.37,56.20,53.89,36.38.
Embodiment 11 preparation 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetyl-L-prolyl carbobenzoxy-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (5g)
According to the method for embodiment 5 from 541mg (1.27mmol) 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetoacetyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (4) and 338mg (1.40mmol) hydrochloric acid L-proline(Pro) benzyl ester obtain 215mg (28.2%) target compound, are yellow solid.76 ℃ of Mp;
(c=0.55, acetone); ESI-MS (m/e) 600[M+H]
+IR (KBr): 3742,2953,2360,1741,1627,1587,1511,1456,1267,1135,1031,967,845,740,550,470;
1HNMR (500MHz, DMSO-d6) 9.69 (s, 1H), 7.59 (s, 1H), 7.539 (s, 1H), 7.40-7.33 (m, 7H), 7.17-7.12 (m, 2H), 6.87～6.75 (m, 4H), 6.09 (s, 1H), 5.15-5.07 (m, 2H), 4.43-4.39 (m, 1H), 3.83 (m, 6H), 3.61 (m, 2H), 1.97-1.83 (m, 4H);
13CNMR (125MHz, DMSO-d6) δ/ppm=184.42,182.89,170.57,168.26,149.93,149.85,149.73,148.49,141.54,140.30,136.38,129.35,128.87,128.45,128.09,126.78,123.67,123.12,122.83,121.62,116.21,114.75,111.96,111.60,101.45,68.33,66.55,61.63,56.27,56.21,54.84,47.99,33.81,25.80,24.92.
Embodiment 12 preparation 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetyl-L-methionyl carbobenzoxy-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (5h)
According to the method for embodiment 5 from 660mg (1.50mmol) 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetoacetyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (4) and 678mg (1.65mmol) L-methionine(Met) benzyl ester obtain 350mg (35.0%) target compound, are yellow solid.94 ℃ of Mp;
(c=0.55, acetone); ESI-MS (m/e) 650[M+H]
+IR (KBr): 3741,411,2360,1736,1627,1587,1512,1458,1428,1275,1135,1031,968,814,700,447;
1H-NMR (500MHz, DMSO-d6) 9.68 (s, 1H), 8.51 (d, J=6.9Hz, 1H), 7.59 (s, 1H), 7.54 (s, 1H), 7.37-7.34 (m, 7H), 7.18 (s, 1H), 7.15 (s, 1H), 6.93 (d, J=8.4Hz, 1H), 6.85 (d, J=6.9Hz, 1H), 6.81 (s, 1H), 6.75 (s, 1H), 6.09 (s, 1H), 5.15 (s, 2H), 4.69-4.54 (m, 3H), 3.85 (s, 6H), 2.00 (s, 5H);
13C-NMR (125MHz, DMSO-d6) δ/ppm=184.39,182.92,171.75,168.44,149.91,149.83,149.76,148.46,141.54,140.33,136.33,129.16,128.92,128.57,128.33,126.75,123.68,123.02,122.79,121.58,116.18,114.31,111.87,111.51,101.49,68.08,66.65,56.17,51.27,30.75,29.89,14.98.
Embodiment 13 preparation 1-(4-hydroxy 3-methoxybenzene base)-7-(the two carbobenzoxys of 4-oxygen acetyl-L-glutamy-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (5i)
According to the method for embodiment 5 from 627mg (1.47mmol) 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetoacetyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (4) and 810mg (1.62mmol) tosic acid L-benzyl glutamate obtain 390mg (36.0%) target compound, are yellow solid.Mp 111-112 ℃;
(c=0.55, acetone); ESI-MS (m/e) 736[M+H]
+IR (KBr): 3739,3407,2936,2360,1736,1676,1627,1587,1512,1455,1271,1210,1166,1134,1031,969,814,746,698,546,455;
1H-NMR (500MHz, DMSO-d6) 9.70 (s, 1H), 9.28 (d, J=7.75Hz, 1H), 7.60～7.55 (m, 2H), 7.38-7.34 (m, 12H), 7.24 (d, J=11.95Hz, 1H), 7.17 (d, J=7.1Hz, 1H), 6.92-6.77 (m, 5H), 6.10 (s, 1H), 5.14 (s, 2H), 5.08 (s, 2H), 4.62 (m, 2H), 4.47 (m, 1H), 3.85 (s, 6H), 2.47 (m, 2H), 2.12 (m, 2H);
13CNMR (125MHz, DMSO-d6) δ/ppm=184.42,182.92,172.45,171.61,168.47,149.93,149.85,149.79,148,48,141.55,140.33,136.56,136.31,130.88,129.19,128.90,128.55,128.48,128.38,128.29,127.16,126.77,126.40,123,69,123.02,122.79,121.59,116.40,116.19,114.40,111.89,111.52,101.51,68.14,66.66,66.04,56.17,51.50,40.49,40.33,40.16,39.99,39.83,39.66,39.49,30.22,26.42,20.83,20.55.
Embodiment 14 preparation 1-(4-hydroxy 3-methoxybenzene base)-7-(the two carbobenzoxys of 4-oxygen acetyl-L-aspartoyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (5j)
According to the method for embodiment 5 from 656mg (1.54mmol) 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetoacetyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (4) and 822mg (1.70mmol) tosic acid L-aspartic acid benzyl ester obtain 400mg (36.0%) target compound, are yellow solid.Mp 79-80 ℃;
(c=0.51, acetone); ESI-MS (m/e) 722[M+H]
+IR (KBr): 3740,3406,2928,2360,1738,1678,1626,1586,1511,1456,1274,1208,1134,1033,969,848,746,698,547,469;
1H-NMR (500MHz, DMSO-d6) 9.66 (s, 1H), 9.28 (s, 1H), 8.30 (d, J=7.9Hz, 1H), 7.59 (d, J=4.85Hz, 1H), 7.56 (d, J=4.95Hz, 1H), 7.40-7.31 (m, 7H), 7.17 (dd, J=8.25Hz, J=1.65Hz, 1H), 7.14 (dd, J=8.5Hz, J=1.45Hz, 1H), 6.98 (s, 1H), 6.96 (s, 1H), 6.86-6.75 (m, 4H), 6.67 (s, 1H), 6.65 (s, 1H), 6.10 (s, 1H), 5.13 (m, 2H), 4.62～4.53 (m, 3H), 3.85 (s, 3H), 3.84 (s, 3H)) 3.00 (dd, J=13.86Hz, J=5.45Hz, 1H), 2.91 (m, 1H);
13C-NMR (125MHz, DMSO-d6) δ/ppm=184.44,182.89,170.61,170.43,168.22,160.36,149.93,149.84,149.68,148.48,141.55,40,29,136.26,136.14,130,87,129.35,128.88,128.54,128.42,128.20,126.76,123.68,123.12,122.76,121.60,121.34,116.40,116.20,114.62,111.93,111.61,101.47,68.26,66.92,66.40,65.37,60.21,56.22,48.78,36.12,21.22,15.63,14.55.
Embodiment 15 preparation 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetyl-L-tryptophyl carbobenzoxy-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (5k)
According to the method for embodiment 5 from 596mg (1.40mmol) 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetoacetyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (4) and 718mg (1.54mmol) tosic acid L-tryptophan benzyl ester obtain 300mg (30.5%) target compound, are yellow solid.Mp 74-76 ℃;
(c=0.57, acetone); ESI-MS (m/e) 703[M+H]
+IR (KBr): 3735,3311,2358,1739,1674,1626,1585,1511,1456,1274,1133,1031,968,834,747;
1H-NMR (500MHz, DMSO-d6) 10.95 (s, 1H), 9.70 (s, 1H), 8.39 (d, J=7.8Hz, 1H), 7.32 (s, 1H), 7.53 (m, 3H), 7.39-7.33 (m, 6H), 7.26-7.06 (m, 7H), 6.97 (t, J=7.5Hz, 3H), 6.82 (m, 4H), 6.10 (s, 1H), 5.08 (d, J=5.4Hz, 2H), 4.69 (m, 1H), 4.57 (s, 2H), 3.84 (s, 3H), 3.81 (s, 3H), 3.23 (m, 2H);
13C-NMR (125MHz, DMSO-d6) δ/ppm=184.40,182.93,171.83,168.06,149.92,149.70,149.67,148.47,141.54,140.35,136.66,136.50,136.18,129.15,129.00,128.86,128.66,128.49,128.24,128.14,127.56,126.76,124.30,123.68,123.02,122.81,121.60,121.51,118.98,118.46,116.19,114.32,111.93,111.47,109.43,101.49,68.01,66.63,56.18,53.26,30.07.
Embodiment 16 preparation 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetyl-L-nitro arginyl carbobenzoxy-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (5l)
According to the method for embodiment 5 from 366mg (0.86mmol) 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetoacetyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (4) and 455mg (0.95mmol) tosic acid L-NG-nitroarginine benzyl ester obtain 126mg (20%) target compound, are yellow solid.89 ℃ of Mp;
(c=0.51, acetone); ESI-MS (m/e) 732[M+H]
+IR (KBr): 3745,3321,2940,1739,1627,1589,1512,1430,1268,1134,1031,968,815,753,551,471;
1H-NMR (500MHz, and DMSO-d6) 9.68 (s, 1H), 8.48 (d, J=6.9Hz, 1H), 7.59 (d, J=3.6Hz, 1H), 7.54 (d, J=3.6Hz, 1H), 7.38-7.33 (m, 7H), 7.18 (s, 1H), 7.15 (s, 1H), 6.91 (d, J=8.4Hz, 1H), 6.85 (d, J=8.4Hz, 1H), 6.81 (d, J=3.9Hz, 1H), 6.75 (s, 1H), 6.09 (s, 1H), 5.14 (s, 2H), 4.63 (s, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.38 (dd, J=14.7Hz, J=7.2Hz, 1H), 3.15 (d, J=6Hz, 2H);
13C-NMR (125MHz, DMSO-d6) δ/ppm=184.40,182.91,171.89,168.34,159.83,149.94,149.86,149.82,148.49,141.52,140.30,136.31,129.26,128.92,128.54,128.28,126.78,123.65,123.09,122.76,121.63,116.22,114.54,111.97,111.66,101.43,79.64,68.19,66.61,65.36,56.23,56.22,52.03,28.50.
Embodiment 17 preparation 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetyl glycyl carbobenzoxy-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (5m)
According to the method for embodiment 5 from 722mg (1.69mmol) 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetoacetyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (4) and 627mg (1.86mmol) tosic acid L-glycine benzyl ester obtain 350mg (36.0%) target compound, are yellow solid.Mp 103-04 ℃;
(c=0.51, acetone); ESI-MS (m/e) 574[M+H]
+IR (KBr): 3732,3385,2941,2358,1728,1625,1588,1513,1472,1269,1136,1165,962;
1HNMR (500MHz, DMSO-d6) 9.67 (s, 1H), 8.39 (m, 1H), 7.61 (s, 1H), 7.56 (s, 1H), 7.37 (m, 7H), 7.18 (m, 2H), 6.83-6.81 (m, 3H), 6.10 (s, 1H), 5.15 (s, 2H), 4.63 (s, 2H), 4.14 (d, J=7.0Hz, 1H), 4.02 (s, 1H), 4.01 (s, 1H), 3.87 (s, 3H), 3.85 (s, 3H);
13CNMR (125MHz, DMSO-d6) δ/ppm=184.48,184.43,169.94,168.69,149.94,149.83,148.48,141.54,140.30,136.33,132.22,131.99,130.85,129.11,128.89,128.55,128.41,126.77,123.66,123.09,122.79,121.59,116.39,116.19,114.53,111.89,111.56,68.29,66.41,56.19,38.57.
Embodiment 18 preparation 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetyl-L-lysyl carbobenzoxy-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (5n)
According to the method for embodiment 5 from 656mg (1.54mmol) 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetoacetyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (4) and 860mg (1.69mmol) tosic acid L-Methionin benzyl ester obtain 85mg (93.4%) target compound, are yellow solid.Mp 92-93 ℃;
(c=0.53, acetone); ESI-MS (m/e) 745[M+H]
+IR (KBr): 3742,3327,2929,2851,1742,1678,1627,1578,1513,1429,1270,1137,1033,966,843,814,646,569,470;
1H-NMR (300MHz, DMSO-d6) 9.82 (s, 1H), 8.53 (d, J=7.2Hz, 1H), 7.86 (s, 3H), 7.59 (s, 1H), 7.54 (s, 1H), 7.37-7.33 (m, 7H), 7.18 (s, 1H), 7.15 (s, 1H), 6.85 (m, 4H), 6.10 (s, 1H), 5.14 (s, 2H), 4.64 (s, 2H), 4.36 (m, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 2.73-2.71 (m, 2H), 1.74 (m, 2H), 1.54 (m, 2H), 1.33 (m, 2H);
13C-NMR (75MHz, DMSO-d6) δ/ppm=184.41,182.90,171.95,168.34,149.97,149.85,149.80,148.49,141.55,140.28,136.34,129.22,128,92,128.56,128.30,126.74,123.66,123.09,122.83,121.59,116.22,114.45,111.97,111.56,101.45,68.12,66.57,63.57,56.25,52.04,30.63,26.85,22.63.
Embodiment 19 preparation 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetyl-L-glutamine acyl carbobenzoxy-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (5o)
According to the method for embodiment 5 from 560mg (1.30mmol) 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetoacetyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (4) and 390mg (1.43mmol) tosic acid L-glutaminate benzyl ester obtain 212mg (25.2%) target compound, are yellow solid.79 ℃ of Mp;
(c 0.51, acetone); ESI-MS (m/e) 645[M+H]
+IR (KBr): 3352,2933,1738,1666,1627,1586,1512,1455,1274,1133,1031,967,828,573;
1H-NMR (500MHz, and DMSO-d6) 9.68 (s, 1H), 8.51 (d, J=7.5Hz, 1H), 7.59 (d, J=2.7Hz, 1H), 7.54 (d, J=3.0Hz, 1H), 7.38-7.30 (m, 7H), 6.94 (s, 1H), 6.91 (s, 1H), 6.92 (d, J=8.4Hz, 1H), 6.86 (d, J=6.3Hz, 1H), 6.81 (d, J=3.3Hz, 1H), 6.75 (s, 1H), 6.09 (s, 1H), 5.14 (s, 2H), 4.62 (s, 2H), 4.39 (dd, J=8.7Hz, J=8.7Hz, 1H), 3.86 (s, 3H), 3.84 (s, 3H), 2.18～2.05 (m, 4H);
13C-NMR (125MHz, DMSO-d6) δ/ppm=184.40,182.92,173.67,171.91,168.36,149.90,149.88,149.77,148.46,141.54,140.36,136.36,129.15,128.92,128.53,128.27,126.75,123.69,123.00,122.86,121.58,116.17,114.42,111.85,111.50,101.50,68.07,66.54,56.18,56.16,52.00,31.46,26.95.
Embodiment 20 preparation 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetyl-L-asparaginyl carbobenzoxy-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (5p)
According to the method for embodiment 5 from 642mg (1.50mmol) 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetoacetyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (4) and 427mg (1.65mmol) tosic acid L-asparagine benzyl ester obtain 200mg (21.0%) target compound, are yellow solid.113 ℃ of Mp;
(c=0.51, acetone); ESI-MS (m/e) 631[M+H]
+IR (KBr): 3405,1737,1665,1627,1583,1511,1457,1265,1136,1032,964,730,579;
1H-NMR (500MHz, and DMSO-d6) 9.67 (s, 1H), 8.47 (d, J=7.2Hz, 1H), 7.59 (d, J=2.4Hz, 1H), 7.54 (d, J=2.4Hz, 1H), 7.35 (s, 7H), 7.17 (s, 1H), 7.15 (s, 1H), 6.93 (d, J=8.4Hz, 1H), 6.86 (d, J=8.4Hz, 1H), 6.82 (s, 1H), 6.75 (s, 1H), 6.03 (s, 1H), 5.14 (s, 2H), 4.82 (dd, J=5.1Hz, J=7.5Hz, 1H), 4.61 (s, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 2.66 (m, 2H);
13C-NMR (125MHz, DMSO-d6) δ/ppm=184.42,182.88,171.55,171.33,168.03,149.94,149.80,149.66,148.46,141.56,140.31,136.41,129.28,128.85,128.40,128.02,126.72,123.70,123.07,122.84,121.57,116.17,114.60,111.85,111.54,101.51,68.20,66.55,56.23,56.16,48.94,36.83.
Embodiment 21 preparation 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetyl-L-leucyl carbobenzoxy-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (5q)
According to the method for embodiment 5 from 689mg (1.62mmol) 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetoacetyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (4) and 700mg (1.78mmol) tosic acid L-leucine benzyl ester obtain 326mg (32.0%) target compound, are yellow solid.Mp 69-70 ℃;
(c=0.55, acetone); ESI-MS (m/e) 630[M+H]
+IR (KBr): 3499,3348,2937,2864,2359,1734,1687,1627,1585,1512,1456,1365,1270,1169,1134,1032,969,847,814,747,697,601,470;
1H-NMR (500MHz, and DMSO-d6) 9.68 (s, 1H), 8.42 (d, J=7.9Hz, 1H), 7.59 (d, J=3.85Hz, 1H), 7.55 (d, J=3.8Hz, 1H), 7.39-7.33 (m, 7H), 7.18 (s, 1H), 7.16 (s, 1H), 6.92 (d, J=8.4Hz, 1H), 6.83 (m, 2H), 6.7 (s, 1H), 6.10 (s, 1H), 5.14 (s, 2H), 4.63 (m, 2H), 4.42 (m, 1H), 3.86 (s, 3H), 3.85 (s, 3H), 1.60 (m, 3H), 0.88 (d, J=6.05Hz, 3H), 0.84 (d, J=6.00Hz, 3H);
13C-NMR (125MHz, DMSO-d6) δ/ppm=184.41,182.93,172.42,168.27,149.92,149.85,149.78,148.48,141.54,140.33,136.36,130.87,129,20,128.93,128.55,128.28,126.76,123.68,123.04,122.80,121.60,121.33,116.40,116.19,114.41,111.90,111.54,101.47,68.11,66.52,65.37,56.19,50.64,24.70,23.18,21.73,15.63.
Embodiment 22 preparation 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetyl-L-isoleucyl-carbobenzoxy-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (5r)
According to the method for embodiment 5 from 580mg (1.36mmol) 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetoacetyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone (4) and 590mg (1.50mmol) tosic acid L-Isoleucine benzyl ester obtain 300mg (35.0%) targeted combination compound, are yellow solid.100 ℃ of Mp;
(c=0.55, acetone); ESI-MS (m/e) 630[M+H]
+IR (KBr): 3736,3403,2962,2359,1736,1680,1627,1587,1512,1458,1277,1136,1032,966,816,671,470;
1H-NMR (500MHz, DMSO-d6) 9.65 (s, 1H), 8.22 (d, J=8.3Hz, 1H), 7.59 (d, J=1.95Hz, 1H), 7.55 (d, J=1.95Hz, 1H), and 7.39-7.33 (m, 7H), 7.20 (dd, J=6.75Hz, J=1.7Hz, 1H), 7.17 (dd, J=6.0Hz, J=1.75Hz, 1H), 6.95 (d, J=8.45Hz, 1H), 6.84 (m, 2H), 6.79 (s, 1H), 6.10 (s, 1H), 5.16 (d, J=3.95Hz, 2H), 4.67 (d, J=3.95Hz, 2H), 4.36 (m, 1H), 3.85 (s, 3H), 3.84 (s, 3H), 1.87 (m, 1H), 1.37 (m, 1H), 1.15 (m, 1H), 0.90 (m, 6H);
13C-NMR (125MHz, DMSO-d6) δ/ppm=184.41,182.93,171.47,168.22,149.92,149.80,149.79,148.48,141.54,140.33,136.24,129.16,128,91,128.63,128.55,126.76,123.68,123.05,122.87,121.60,116.19,114.26,111.91,111.53,101.46,67.88,66.56,56.52,56.25,56.19,36.96,25.11,15.86,11.56.
The inhibition tumor cell proliferation test of test example 1 The compounds of this invention
1, the compound (5a-r) that test compound: embodiment of the invention 5-22 is prepared;
2, test method
Respectively that growth conditions is good, as to be in logarithmic phase S180, HL60, K562, H22 cell are according to 2 * 10
4The density of individual/mL is inoculated in 96 orifice plates, every hole 100 μ l.At 37 ℃, 5%CO
2Cultivate 4h in the incubator, by default concentration gradient 80 μ M, 40 μ M, 20 μ M, 10 μ M and 5 μ M, add the test compound through sterilising treatment, control group adds the equal-volume solvent.After continuing to cultivate 48h, it is the MTT solution of 5mg/mL that every hole adds 25 μ l concentration, place 37 ℃ to hatch 4h, carefully remove every hole, supernatant liquor (suspension cell is removed supernatant liquor after centrifugal) back and add 100 μ l DMSO (dimethyl sulfoxide (DMSO)), about 15min dissolution precipitation vibrates.The 570nm wavelength is measured O.D. (absorbancy) value down on microplate reader immediately.Calculate tumour inhibiting rate and IC
50
3, test-results
Test-results is listed table 1 in.Test-results shows that The compounds of this invention all has the effect of clear and definite inhibition tumor cell proliferation, wherein, compound 5e, 5l and 5n to the cytotoxic activity of four strain cells for the highest.
Table 1 The compounds of this invention 5a-r suppresses the IC of tumor cell proliferation
50(μ M) value
a
a)n＝9，
Claims (6)
1. 1-(4-hydroxy 3-methoxybenzene the base)-7-(4-oxygen acetylamino acid carbobenzoxy-3-p-methoxy-phenyl)-1 that has anti-tumor activity, 6-heptadiene-3, the 5-diketone is characterized in that, its structural formula is shown in the general formula I:
Wherein, AA be selected from that L-alanyl, L-phenylalanyl, L-are valyl, L-seryl, L-Threonyl, L-tyrosyl, L-prolyl, L-methionyl, L-glutamyl, L-asparagyl, L-tryptophyl, L-nitro arginyl, glycyl, L-lysyl, L-glutaminate acyl group, altheine acyl group, L-leucyl or the different bright acyl group of L-.
2. described 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetylamino acid carbobenzoxy-3-p-methoxy-phenyl)-1 of synthetic claim 1 with anti-tumor activity, 6-heptadiene-3, the method for 5-diketone comprises:
(1) preparation 3-methoxyl group-4-(2-butyryl acyloxy) phenyl aldehyde;
(2) preparation 6-(4-hydroxyl-3-methoxyphenyl)-5,6-hexene-2,4-diketone;
(3) product with step (1) and step (2) is that raw material reacts, and prepares 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone;
(4) with 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetyl triethyl base-3-p-methoxy-phenyl)-1,6-heptadiene-3, the 5-diketone carries out saponification, obtains 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetoacetyl-3-p-methoxy-phenyl)-1,6-heptadiene-3, the 5-diketone;
(5) with 1-(4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetoacetyl-3-p-methoxy-phenyl)-1,6-heptadiene-3,5-diketone and hydrochloric acid L-amino-acid benzyl ester or tosic acid amino-acid benzyl ester carry out coupling, promptly.
3. it is characterized in that in accordance with the method for claim 2: the hydrochloric acid L-amino acid acid benzyl ester described in the step (5) is selected from hydrochloric acid L-Serine benzyl ester, hydrochloric acid L-threonine benzyl ester or hydrochloric acid L-proline(Pro) benzyl ester.
4. it is characterized in that in accordance with the method for claim 2: the tosic acid amino-acid benzyl ester described in the step (5) is selected from tosic acid L-alanine benzyl ester, toluenesulphonic acids L-phenylalanine benzyl ester, tosic acid L-Xie Ansuan benzyl ester, tosic acid L-tyrosine benzyl ester, L-methionine(Met) benzyl ester, tosic acid L-benzyl glutamate, tosic acid L-aspartic acid benzyl ester, tosic acid L-tryptophan benzyl ester, tosic acid L-NG-nitroarginine benzyl ester, tosic acid L-glycine benzyl ester, tosic acid L-Methionin benzyl ester, tosic acid L-leucine benzyl ester or tosic acid L-Isoleucine benzyl ester, tosic acid L-glutaminate benzyl ester or tosic acid L-asparagine benzyl ester.
5. pharmaceutical composition for the treatment of tumour, it is characterized in that: the described 1-of claim 1 (4-hydroxy 3-methoxybenzene the base)-7-(4-oxygen acetylamino acid carbobenzoxy-3-p-methoxy-phenyl)-1 that goes up significant quantity by treatment, 6-heptadiene-3,5-diketone and pharmaceutically acceptable carrier or auxiliary material are formed.
6. the described 1-of claim 1 (4-hydroxy 3-methoxybenzene base)-7-(4-oxygen acetylamino acid carbobenzoxy-3-p-methoxy-phenyl)-1,6-heptadiene-3, the purposes of 5-diketone in the preparation antitumor drug.
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