CN109134596B - Theanyl amino acid modified curcumin, and synthesis, activity and application thereof - Google Patents
Theanyl amino acid modified curcumin, and synthesis, activity and application thereof Download PDFInfo
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- CN109134596B CN109134596B CN201710458272.XA CN201710458272A CN109134596B CN 109134596 B CN109134596 B CN 109134596B CN 201710458272 A CN201710458272 A CN 201710458272A CN 109134596 B CN109134596 B CN 109134596B
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- methoxyphenyl
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- heptadiene
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
- C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Genetics & Genomics (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxyacetyltheanyl-AA-3-methoxyphenyl) -1, 6-heptadiene-3, 5-diketone (AA is selected from L-Lys residue, L-Leu residue, L-Asn residue, L-Pro residue, L-Gln residue, L-Ser residue, L-Val residue and L-Tyr residue) with the following formula, a preparation method thereof, and the anti-tumor growth activity thereof, thus the invention discloses the application thereof in preparing anti-tumor drugs.
Description
Technical Field
The invention relates to 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxyacetyltheanyl-AA-3-methoxyphenyl) -1, 6-heptadiene-3, 5-diketone, a preparation method thereof, and antitumor growth activity thereof, and thus the invention relates to application thereof in preparing antitumor drugs. The invention belongs to the field of biological medicine.
Background
Malignant tumors are a global problem that seriously jeopardizes human health. Most of patients with tumors are in the middle and late clinical stage, and the treatment method mainly comprises radiotherapy and chemotherapy, which are main treatment means when malignant tumors are in the middle and late stage. The invention discloses an anti-tumor medicament which is an urgent clinical need. The inventors previously disclosed that 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxyacetamidobenzyl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione has significant activity in inhibiting tumor cell proliferation. Later, the inventors further disclosed that anti-adhesion peptide modified curcumin inhibited tumor growth in S180 mice at a dose of 1 μmol/kg. However, the lowest effective dose is still 1. mu. mol/kg. In order to reduce the lowest effective dose, the inventors have made various modifications to the phenolic hydroxyl group of curcumin. After 3 years of exploration, it was found that curcumin modified with theanyl-AA (AA selected from the group consisting of L-Lys residues, L-Leu residues, L-Asn residues, L-Pro residues, L-Gln residues, L-Ser residues, L-Val residues and L-Tyr residues) can reduce the minimum effective dose for anti-tumor growth to 0.1. mu. mol/kg. The effective dose is reduced by 10 times, which shows that the structure modification has outstanding technical effect. Based on these findings, the inventors have proposed the present invention.
Disclosure of Invention
The first aspect of the present invention is to provide 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-AA-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione having the formula (wherein AA is selected from the group consisting of an L-Lys residue, an L-Leu residue, an L-Asn residue, an L-Pro residue, an L-Gln residue, an L-Ser residue, an L-Val residue and an L-Tyr residue).
In a second aspect of the present invention, there is provided a method for synthesizing 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-AA-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (wherein AA is selected from the group consisting of an L-Lys residue, an L-Leu residue, an L-Asn residue, an L-Pro residue, an L-Gln residue, an L-Ser residue, an L-Val residue and an L-Tyr residue), which comprises:
(1) preparing 6- (4-hydroxy-3-methoxyphenyl) -5, 6-hexene-2, 4-dione (1);
(2) preparation of benzyl 2- (4-formyl-2-methoxyphenoxy) -acetate (2);
(3) preparing 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxyacetobenzoyl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-diketone (3) by taking the products obtained in the step (1) and the step (2) as reaction raw materials;
(4) saponifying 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetoacetylbenzyl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione to obtain 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetoacetoxy-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (4);
(5) coupling the compound 4 and L-benzyl theanine to obtain 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxyacetylbenzyl theanine-3-methoxyphenyl) -1, 6-heptadiene-3, 5-diketone (5);
(6) saponifying the compound 5 to obtain 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxyacetophytamic acid-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (6);
(7) coupling of compound 6 with benzyl L-amino acid to give 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-AA-OBzl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (7) according to claim 1;
(8) the compound 7 was saponified to give 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-AA-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (AA selected from the group consisting of L-Lys residue, L-Leu residue, L-Asn residue, L-Pro residue, L-Gln residue, L-Ser residue, L-Val residue and L-Tyr residue).
The third aspect of the present invention is to evaluate the tumor growth activity of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-AA-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione on S180 mice.
Drawings
FIG. 11 is a synthetic route for- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-AA-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione.7 a AA is the L-Lys residue; AA in 7b is L-Leu residue; 7c AA is L-Asn residue; 7d wherein AA is a L-Pro residue; AA in 7e is L-Gln residue; AA in 7f is L-Ser residue; AA in 7g is L-Val residue; AA in 7h is L-Tyr residue; i) boron trioxide (B)2O3) Acetylacetone, tri-n-butyl borate, n-butylamine, aqueous hydrogen chloride (1M); ii) potassium carbonate, benzyl bromoacetate; iii) boron trioxide (B)2O3) Tri-n-butyl borate, n-butylamine, 10% aqueous acetic acid; iv) aqueous sodium hydroxide (2M), acetone; v) Dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), Tetrahydrofuran (THF).
Detailed Description
To further illustrate the invention, a series of examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention.
EXAMPLE 1 preparation of 6- (4-hydroxy-3-methoxyphenyl) -5, 6-hexene-2, 4-dione (1)
45.0mL (437.7mmol) of acetylacetone, 21.0g (301.6mmol) of boron oxide and 150.0mL of anhydrous ethyl acetate were refluxed at 60 ℃ for 1 h. Then, 22.5g (148.0mmol) of vanillin and 41mL (293.0mmol) of tributylborate were added thereto. The reaction mixture was stirred for 30min at 70 ℃. A solution of 15mL (205.1mmol) of n-butylamine in 135mL of ethyl acetate is added further during 30 min. The mixture was stirred at 100 ℃ for 3h, then cooled to room temperature, and 150mL of hydrochloric acid (1M) was added dropwise thereto. The mixture was stirred at 50 ℃ for 30min, allowed to stand, and the aqueous layer was extracted 3 times with ethyl acetate. The combined ethyl acetate layers were washed with saturated NaCl solution to neutrality, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate ═ 4/1) to give 10.05g (29%) of the title compound as a yellow solid. ESI-MS (m/e): 235[ M + H ]]+；1H NMR(300MHz,DMSO-d6):δ/ppm＝15.74(s,1H),9.64(s,1H),7.50(d,J＝15.9Hz,1H),7.30(s,1H),7.12(d,J＝8.1Hz,1H),6.82(d,J＝8.1Hz,1H),6.64(d,J＝15.9Hz,1H),5.84(s,1H),5.14(s,2H),3.83(s,3H),2.12(s,3H)。
EXAMPLE 2 preparation of 3-methoxy-4- (oxy-2-acetylcarbobenzoxy) benzaldehyde (2)
10g (65.8mmol) of vanillin are dissolved in 100mL of anhydrous tetrahydrofuran. To the solution was added 10.9g (79.0mmol) of potassium carbonate in portions and stirred for 3 h. Then, 9.3mL of benzyl bromoacetate was added dropwise to the solution, and the mixture was stirred at room temperature for 48 hours, followed by TLC (petroleum ether/ethyl acetate: 3/1) to show that the reaction was completed. The reaction mixture is filtered, the filtrate is concentrated under reduced pressure, the residue is triturated with 100mL of diethyl ether and left to stand for 12h before the diethyl ether is decanted off, 10mL of diethyl ether are triturated 3 times and the diethyl ether is removed to give 15.4g (78%) of the title compound as a colorless solid. ESI-MS (m/e): 301[ M + H]+；1H NMR(300MHz,DMSO-d6):δ/ppm＝9.86(s,1H),7.50(dd,J1＝8.4Hz,J2＝1.8Hz,1H),7.44(d,J＝1.8Hz,1H),7.39(s,5H),7.11(d,J＝8.4Hz,1H),5.21(s,2H),5.03(s,2H),3.84(s,3H)。
EXAMPLE 3 preparation of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetylbenzyloxy-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (3)
A suspension of 5.55g (23.7mmol)6- (4-hydroxy-3-methoxyphenyl) -5, 6-hexene-2, 4-dione (1),0.83g (11.9mmol) boron oxide and 100mL ethyl acetate was refluxed at 70 ℃ for 1 h. Then, the mixture was concentrated under reduced pressure. The residue was dissolved in 100mL of anhydrous DMF. To the resulting solution were added 10.67g (35.6mmol) of 3-methoxy-4- (oxy-2-acetylcarbobenzoxy) benzaldehyde (2) and 11.15mL (41.0mmol) of tributyl borate. The resulting solution was stirred at 80 ℃ for 30 min. Thereafter, 0.98mL (6.4mmol) of n-butylamine was added dropwise thereto in 4 portions over 1 hour, and the resulting solution was stirred at 80 ℃ for 3 hours. Thereafter, 200mL of a 10% aqueous acetic acid solution preheated to 60 ℃ was added thereto. The resulting solution was stirred at 80 ℃ for a further 1 h. The reaction mixture was cooled to room temperature, filtered and the filter cake was purified by column chromatography (petroleum ether/ethyl acetate 3/1) to give 6.63g (53%) of the title compound as a yellow solid. ESI-MS (m/e): 517[ M + H]+；1H NMR(300MHz,DMSO-d6):δ/ppm＝9.69(s,1H),8.51(d,J＝7.5Hz,1H),7.80(t,J＝5.7Hz,1H),7.59(d,J＝3.0Hz,1H),7.54(d,J＝3.0Hz,1H),7.37(m,7H),7.16(m,1H),6.89(m,4H),6.09(s,1H),5.14(s,2H),4.62(s,2H),4.37(m,1H),3.87(s,3H),3.84(s,3H),3.04(qd,J1＝7.2Hz,J2＝5.7Hz,2H),2.15(m,2H),2.05(m,1H),1.90(m,1H),0.98(t,J＝7.2Hz,3H)。
EXAMPLE 4 preparation of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetoxy-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (4)
5g (9.7mmol) of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetylbenzyloxycarbonyl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (3) were dissolved in acetone. Aqueous NaOH (2M) was added thereto at room temperature, and the reaction solution was adjusted to pH 13 and stirred for 6 hours. TLC (petroleum ether/ethyl acetate 3/1) showed the reaction was complete. The reaction mixture was saturated with KHSO4Adjusting pH to 7 with water solution, concentrating under reduced pressure, and adding saturated KHSO to the residue4The aqueous solution was adjusted to pH 2. After that, it was extracted 3 times with ethyl acetate. The ethyl acetate layers were combined, washed with a saturated NaCl solution to neutrality, and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate under reduced pressure and trituration of the residue with dry ether gave 2.64g (64%) of the title compound as a red solid. ESI-MS (m/e): 425[ M-H]-；1H NMR(300MHz,DMSO-d6):δ/ppm＝9.55(s,1H),7.57(m,2H),7.37(m,2H),7.20(m,2H),6.79(m,4H),6.06(s,1H),4.74(s,2H),3.85(s,6H)。
EXAMPLE 5 preparation of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxyacetyltheanine-benzyl ester group-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (5)
2g (4.7mmol) of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetoxy-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (4),1.69g (5.6mmol) of benzyl theanine hydrochloride and 0.761g (5.64mmol) of N-hydroxybenzotriazole (HOBt) are dissolved in 50mL of anhydrous tetrahydrofuran under ice bath. To the solution was added dropwise a solution composed of 1.16g (5.63mmol) of Dicyclohexylcarbodiimide (DCC) and 10mL of anhydrous tetrahydrofuran. The reaction solution was adjusted to pH 8 with N-methylmorpholine and stirred at room temperature for 12 h. TLC (petroleum ether/ethyl acetate 3/1) showed the reaction was complete. The reaction mixture was concentrated to dryness under reduced pressure, and the residue was dissolved in 150mL of ethyl acetate. Filtering, washing the filtrate with saturated sodium bicarbonate water solution for 3 times, saturated sodium chloride water solution for 3 times, saturated potassium bisulfate water solution for 3 times, saturated sodium chloride water solution for 3 times, saturated sodium bicarbonate water solution for 3 times, and saturated sodium chloride water solution for 3 times. The combined ethyl acetate layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol ═ 80/1) to give 2.24g (71%) of the title compound as a yellow solid. ESI-MS (m/e): 673[ M + H]+；1HNMR(300MHz,DMSO-d6):δ/ppm＝9.69(s,1H),8.51(d,J＝7.5Hz,1H),7.80(t,J＝5.7Hz,1H),7.59(d,J＝3.0Hz,1H),7.54(d,J＝3.0Hz,1H),7.37(m,7H),7.16(m,1H),6.89(m,4H),6.09(s,1H),5.14(s,2H),4.62(s,2H),4.37(m,1H),3.87(s,3H),3.84(s,3H),3.04(qd,J1＝7.2Hz,J2＝5.7Hz,2H),2.15(m,2H),2.05(m,1H),1.90(m,1H),0.98(t,J＝7.2Hz,3H)。
EXAMPLE 6 preparation of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanine-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (6)
2.24g (3.3mmol) of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxyacetophtalotin carbobenzoxy-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (5) were dissolved in acetone, and the solution was added dropwise at room temperatureAqueous NaOH (2M) was added to bring the reaction to pH 13, stirred for 6h and TLC (petroleum ether/ethyl acetate 3/1) indicated completion of the reaction. With saturated KHSO4Adjusting pH of the reaction solution to 7 with water solution, concentrating under reduced pressure, and adding saturated KHSO to the residue4The aqueous solution was adjusted to pH 2. Thereafter, extraction was carried out 3 times with ethyl acetate, and the combined ethyl acetate layers were washed with a saturated aqueous NaCl solution to neutrality, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 1.07g (55%) of the title compound as a red syrup. ESI-MS (m/e): 581[ M-H]-；1H NMR(300MHz,DMSO-d6):δ/ppm＝9.42(s,1H),8.1(m,1H),7.77(m,1H),7.57(m,1H),7.37(m,1H),7.24(m,2H),7.10(m,2H),6.96(d,J＝5.1Hz,1H),6.79(m,3H),6.06(s,1H),4.57(s,2H),4.20(m,1H),3.82(s,6H),3.01(m,2H),2.09(m,3H),1.77(m,1H),0.95(t,J＝4.5Hz,3H)。
EXAMPLE 7 preparation of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxyacetyltheanyl-Lys-OBzl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (7a)
1.3g (2.23mmol) of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanylamino-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (6),1g (2.68mmol) of HCl. Lys (Boc) -OBzl and 0.36g (2.68mmol) were dissolved in 20mL of anhydrous tetrahydrofuran under ice bath. Thereafter, a solution of 0.55g (2.68mmol) of Dicyclohexylcarbodiimide (DCC) and 5mL of anhydrous tetrahydrofuran was added dropwise thereto. The reaction solution was adjusted to pH 8 with N-methylmorpholine (NMM), stirred at room temperature for 12h, and TLC (dichloromethane/methanol-50/1) indicated completion of the reaction. The reaction solution was concentrated to dryness under reduced pressure, the residue was dissolved in 150mL of dichloromethane, filtered, and the filtrate was washed with a saturated aqueous sodium bicarbonate solution 3 times, a saturated aqueous sodium chloride solution 3 times, a saturated aqueous potassium bisulfate solution 3 times, a saturated aqueous sodium chloride solution 3 times, a saturated aqueous sodium bicarbonate solution 3 times, and a saturated aqueous sodium chloride solution 3 times in this order. The combined dichloromethane layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure. The residue was purified by column chromatography (dichloromethane/methanol-50/1) to give 925mg of a yellow solid. Dissolving the yellow solid in 10mL of hydrogen chloride in ethyl acetate under ice bath (4M), stirring the solution for 4h, monitoring by TLC, draining after the reaction is finished, adding dry EA, draining, repeating for three times, adding anhydrous ether, draining, repeating for three times3 times, a yellow solid was obtained which was purified by C18 column to give 306mg (35.6%) of the title compound as a yellow solid in 16.4% overall yield over the two steps. Mp 191-193 ℃;
(c ═ 0.1, methanol); ESI/MS (m/e): 801[ M + H ]]+1；1HNMR(300MHz,DMSO-d6):δ/ppm＝9.72(s,1H),8.59(d,J＝7.8Hz,1H),8.11(d,J＝8.1Hz,1H),7.80(m,3H),7.57(d,J＝14.7Hz,2H),7.37(m,7H),7.23(d,J＝8.4Hz,1H),7.18(d,J＝8.1Hz,1H),6.96(d,J＝8.4Hz,1H),6.83(m,3H),6.10(s,1H),5.14(s,2H),4.61(s,2H),4.41(m,1H),4.28(m,1H),3.87(s,3H),3.84(s,3H),3.04(dq,J1＝6.0Hz,J2＝7.2Hz,2H),2.72(m,2H),2.29-1.24(m,10H),0.99(t,J＝7.2Hz,3H)。
EXAMPLE 8 preparation of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-Leu-OBzl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (7b)
Under cooling in ice bath, 3.04g (5.22mmol) of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanylamino-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (6), 1.61g (6.26mmol) of Leu-OBzl HCl and 0.85g (6.26mmol) of N-hydroxybenzotriazole (HOBt) were dissolved in dry THF, and a solution prepared by dissolving 1.29g (6.26mmol) of Dicyclohexylcarbodiimide (DCC) in dry THF was added dropwise to the solution. N-methylmorpholine (NMM) was added dropwise to the reaction mixture, and the pH was adjusted to 8. The reaction mixture was stirred at room temperature for 12h and monitored by TLC. After the reaction is finished, concentrating the reaction solution under reduced pressure to be dry, dissolving the obtained residue with 150mL dichloromethane, leaching, washing the filtrate with saturated sodium bicarbonate aqueous solution for 3 times, saturated sodium chloride aqueous solution for 3 times, saturated potassium bisulfate aqueous solution for 3 times, saturated sodium chloride aqueous solution for 3 times, saturated sodium bicarbonate aqueous solution for 3 times and saturated sodium chloride aqueous solution for 3 times in sequence; the combined dichloromethane layers are dried by anhydrous sodium sulfate, filtered, and the filtrate is decompressed and concentrated to be dry; purification by column chromatography (dichloromethane/methanol-60/1) gave 0.93g (22.7%) of the title compound as a yellow solid. Mp is 135.2-136.2 ℃;
(c ═ 0.1, methanol); ESI-MS (m/e): 786[ M + H]+；IR(cm-1):3282,3068,2958,2934,2872,1738,1629,1585,1541,1507,1449,1370,1339,1252,1215,1125,1030,963,844,696；1HNMR(300MHz,DMSO-d6):δ/ppm＝9.71(s,1H),8.50(d,J＝6.6Hz,1H),8.09(d,J＝5.2Hz,1H),7.78(t,J＝6.0Hz,1H),7.57(m,2H),7.36(m,7H),7.22(d,J＝7.80Hz,1H),7.17(d,J＝8.1Hz,1H),6.96(d,J＝8.4Hz,1H),6.81(m,3H),6.09(s,1H),5.13(s,2H),4.61(s,2H),4.37(m,2H),3.87(s,3H),3.84(s,3H),3.04(qd,J1＝6.9Hz,J2＝6.0Hz,2H),2.28(m,1H),2.08(m,2H),1.92(m,1H),1.77(m,1H),1.58(m,2H),0.99(t,J＝6.9Hz,3H),0.87(d,J＝5.7Hz,3H),0.82(d,J＝5.4Hz,3H)。
EXAMPLE 9 preparation of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-Asn-OBzl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (7c)
From 4.12g (7.08mmol) of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-acetoacetylphenyltheanyl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (6) and 2.20g (8.50mmol) of HCl. Asn-OBzl, 1.18g (21.2%) of the title compound are obtained as a yellow solid by the method of example 8. Mp 186-187 deg.C;
(c ═ 0.1, methanol); ESI-MS (m/e): 787[ M + H]+；IR(cm-1):3417,3281,3077,2936,1735,1664,1641,1586,1548,1509,1450,1421,1269,1139,1031,964；1HNMR(300MHz,DMSO-d6):δ/ppm＝8.55(d,J＝6.9Hz,1H),8.09(d,J＝8.1Hz,1H),7.75(t,J＝6.3Hz,1H),7.55(m,2H),7.39(m,8H),7.23(d,J＝7.8Hz,1H),7.18(d,J＝7.8Hz,1H),6.98(m,2H),6.82(m,3H),6.10(s,1H),5.11(s,2H),4.72(m,1H),4.62(s,2H),4.40(m,1H),3.87(s,3H),3.85(s,3H),3.05(qd,J1＝7.2Hz,J2＝6.3Hz,2H),2.58(m,2H),2.08(m,2H),1.95(m,1H),1.74(m,1H),0.99(t,J＝7.2Hz,3H)。
EXAMPLE 10 preparation of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-Pro-OBzl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (7d)
From 4.04g (6.94mmol) of 1- (4-hydroxy-3-methoxy-2-hydroxy-ethyl-p-toluenesulfonate using the method of example 8Phenyl) -7- (4-oxoacetyltheanine-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (6) and 2.01g (8.33mmol) HCl. Pro-OBzl gave 1.84g (34.5%) of the title compound as a yellow solid. Mp 112-113 ℃;
(c ═ 0.1, methanol); ESI-MS (m/e): 770[ M + H ]]+；IR(cm-1):3322,3070,2936,1740,1626,1583,1507,1446,1381,1214,1165,1126,1029,965；1HNMR(300MHz,DMSO-d6):δ/ppm＝9.70(s,1H),8.22(d,J＝8.1Hz,1H),7.74(t,J＝5.7Hz,1H),7.57(m,2H),7.37(m,7H),7.20(dd,J＝13.5Hz,J＝1.2Hz,1H),7.14(dd,J＝13.5Hz,J＝1.2Hz,1H),6.96(d,J＝9.6Hz,1H),6.82(m,3H),6.09(s,1H),5.14(s,2H),4.61(m,3H),4.41(m,1H),3.87(s,3H),3.84(s,3H),3.67(m,2H),3.04(qd,J1＝7.2Hz,J2＝5.7Hz,2H),2.19(m,3H),1.92(m,4H),1.89(m,1H),0.99(t,J＝7.2Hz,3H)。
EXAMPLE 11 preparation of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxyacetyltheanyl-Gln-OBzl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (7e)
From 4.11g (7.07mmol) of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-acetoacetylphenyltheanyl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (6) and 2.31g (8.48mmol) of HCl. Gln-OBzl, 532mg (9.4%) of the title compound are obtained as a yellow solid by the method of example 8. Mp 217-219 ℃;
(c ═ 0.1, methanol); ESI-MS (m/e): 801[ M + H ]]+；IR(cm-1):3449,3278,3086,2970,2936,1733,1641,1582,1552,1510,1446,1374,1339,1244,1218,1171,1137,1029,967,696；1HNMR(300MHz,DMSO-d6):δ/ppm＝8.61(d,J＝6.9Hz,1H),8.13(d,J＝8.1Hz,1H),7.80(t,J＝6.3Hz,1H),7.55(m,2H),7.37(m,8H),7.23(d,J＝7.8Hz,1H),7.15(d,J＝7.8Hz,1H),6.98(d,J＝8.4Hz,1H),6.86(m,4H),6.06(s,1H),5.13(s,2H),4.62(s,2H),4.42(m,1H),4.40(m,1H),3.87(s,3H),3.84(s,3H),3.05(qd,J1＝7.2Hz,J2＝6.3Hz,2H),2.00(m,8H),0.99(t,J＝7.2Hz,3H)。
EXAMPLE 12 preparation of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-Ser-OBzl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (7f)
From 2.38g (4.09mmol) of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanylamino-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (6) and 0.95g (4.10mmol) of HCl Ser-OBzl, 742mg (23.9%) of the title compound are obtained as yellow solid by the method of example 8. Mp 185-186 ℃;
(c ═ 0.1, methanol); ESI-MS (m/e): 759[ M + H ]]+；IR(cm-1):3280,3071,2967,2932,1628,1587,1544,1508,1451,1421,1377,1268,1248,1209,1161,1133,1028,963；1HNMR(300MHz,DMSO-d6):δ/ppm＝9.67(s,1H),8.50(d,J＝7.5Hz,1H),8.07(d,J＝8.1Hz,1H),7.74(t,J＝5.7Hz,1H),7.57(m,2H),7.37(m,7H),7.24(d,J＝7.8Hz,1H),7.17(d,J＝8.1Hz,1H),6.97(d,J＝8.4Hz,1H),6.89(m,3H),6.10(s,1H),5.15(s,2H),4.60(s,2H),4.49(m,2H),3.87(s,3H),3.84(s,3H),3.69(m,2H),3.40(m,2H),3.04(qd,J1＝7.2Hz,J2＝5.7Hz,2H),2.10(m,2H),1.94(m,1H),1.77(m,1H),0.99(t,J＝7.2Hz,3H)。
EXAMPLE 13 preparation of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-Val-OBzl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (7g)
From 2.67g (4.59mmol) of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanylamino-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (6) and 1.34g (5.51mmol) of HCl. Val-OBzl, 902mg (26%) of the title compound are obtained as a yellow solid by the method of example 7. Mp 205-;
(c ═ 0.1, methanol); ESI-MS (m/e): 772[ M + H]+；IR(cm-1):3290,3068,2965,2935,1736,1626,1583,1507,1450,1375,1336,1253,1212,1128,1030,964,696；1HNMR(300MHz,DMSO-d6):δ/ppm＝9.67(s,1H),8.37(d,J＝7.8Hz,1H),8.06(d,J＝8.1Hz,1H),7.77(t,J＝6.0Hz,1H),7.57(m,2H),7.37(m,7H),7.23(d,J＝8.1Hz,1H),7.17(d,J＝8.1Hz,1H),6.97(d,J＝8.1Hz,1H),6.89(m,3H),6.10(s,1H),5.15(d,J＝2.7Hz,2H),4.61(s,2H),4.51(m,1H),4.24(t,J＝6.6Hz,1H),3.87(s,3H),3.84(s,3H),3.04(qd,J1＝7.2Hz,J2＝6.0Hz,2H),2.09(m,2H),1.95(m,1H),1.77(m,1H),0.99(t,J＝7.2Hz,3H),0.86(d,J＝6.9Hz,6H)。
EXAMPLE 14 preparation of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-Tyr-OBzl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (7h)
From 2.5g (5.87mmol) of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanylamino-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (6) and 3.84g (8.80mmol) of HCl. Tyr-OBzl, 1.78g (20%) of the title compound are obtained as yellow solid by the method of example 7. Mp 148-150 ℃;
(c ═ 0.1, methanol); ESI-MS (m/e): 836[ M + H ]]+；IR(cm-1):3281,3077,2928,1629,1586,1543,1508,1448,1375,1340,1252,1221,1165,1134,1029,963,810,695；1HNMR(300MHz,DMSO-d6):δ/ppm＝9.70(s,1H),9.24(s,1H),8.53(d,J＝6.9Hz,1H),8.02(d,J＝8.1Hz,1H),7.74(t,J＝4.8Hz,1H),7.57(m,2H),7.22(m,9H),7.04(m,3H),6.84(m,3H),6.65(d,J＝8.4Hz,2H),6.09(s,1H),5.07(d,J＝1.5Hz,2H),4.59(s,2H),4.44(m,2H),3.87(s,3H),3.85(s,3H),3.04(qd,J1＝7.2Hz,J2＝4.8Hz,2H),2.90(m,2H),2.09(m,2H),1.95(m,1H),1.77(m,1H),0.99(t,J＝7.2Hz,3H)。
EXAMPLE 15 preparation of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-Lys-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (8a)
500mg (0.67mmol) of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-Lys-OBzl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (7a) were dissolved in acetone, and NaOH solution (2M) was added dropwise at room temperature to a reaction solution pH of 13 and stirred for 6 hours, and TLC (petroleum ether/ethyl acetate. RTM. 3/1) showed completion of the reaction. Saturated KHSO is used for reaction liquid4Adjusting pH to 7 with water solution, concentrating under reduced pressure, and adding saturated KHSO to the residue4Adjusting pH of the aqueous solution to 2, extracting with ethyl acetateThe combined ethyl acetate layers were washed 3 times with saturated aqueous NaCl solution to neutrality, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was triturated with anhydrous ether and purified by C18 column chromatography to give 164mg (37%) of the title compound as a yellow solid. Mp191.0-192 ℃;
(c ═ 0.1, methanol); ESI-MS (m/e): 709[ M-H]-；IR(cm-1):2934,1626,1506,1447,1249,1126,1029,964,844,811,729,602；1HNMR(300MHz,DMSO-d6):δ/ppm＝9.68(s,1H),8.23(d,J＝8.1Hz,1H),7.99(t,J＝6.0Hz,1H),7.74(d,J＝7.8Hz,1H),7.57(m,2H),7.35(m,2H),7.23(d,J＝7.8Hz,1H),7.15(d,J＝7.8Hz,1H),6.97(d,J＝7.8Hz,1H),6.83(m,4H),6.08(s,1H),4.62(s,2H),4.33(m,2H),3.86(s,3H),3.83(s,3H),3.17(m,2H),2.71(m,2H),1.99～1.18(m,10H),0.98(t,J＝6.9Hz,3H)。
EXAMPLE 16 preparation of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-Leu-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (8b)
Using the method of example 15, from 600mg (0.76mmol)1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-Leu-OBzl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (7b) 385mg (73%) of the title compound are obtained as a yellow solid. Mp 143-145 ℃;
(c ═ 0.1, methanol); ESI-MS (m/e): 694[ M-H ]]-；IR(cm-1):3287,2935,1626,1586,1509,1425,1260,1134,1031,963,843,809,717,603；1HNMR(300MHz,DMSO-d6):δ/ppm＝12.60(s,1H),9.68(s,1H),8.31(d,J＝7.5Hz,1H),8.05(d,J＝8.1Hz,1H),7.76(t,J＝6.3Hz,1H),7.57(m,2H),7.37(d,J＝18.9Hz,2H),7.23(d,J＝7.5Hz,1H),7.17(d,J＝8.1Hz,1H),6.97(d,J＝8.4Hz,1H),6.82(m,3H),6.10(s,1H),4.61(s,2H),4.41(m,1H),4.22(m,1H),3.88(s,3H),3.85(s,3H),3.04(qd,J1＝7.2Hz,J2＝6.3Hz,2H),2.10(m,2H),1.92(m,1H),1.78(m,2H),1.58(m,3H),0.99(t,J＝7.2Hz,3H),0.89(d,J＝6.3Hz,3H),0.83(d,J＝6.0Hz,3H)。
EXAMPLE 17 preparation of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-Asn-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (8c)
Using the method of example 15, from 500mg (0.64mmol)1- (4-hydroxy-3-methoxyphenyl) -7- (4-acetoacetyltheanyl-Asn-OBzl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (7c) 118mg (27%) of the title compound are obtained as a yellow solid. Mp 146-147 deg.C;
(c ═ 0.1, methanol); ESI-MS (m/e): 695[ M-H]-；IR(cm-1):2932,1625,1584,1507,1423,1252,1128,1029,964,845,812,666；1HNMR(300MHz,DMSO-d6):δ/ppm＝12.70(s,1H),9.69(s,1H),8.40(m,1H),8.08(dd,J＝10.5Hz,J＝6.0Hz,1H),7.75(t,J＝5.7Hz,1H),7.60(s,1H),7.57(d,J＝15.9Hz,2H),7.36(d,J＝18.3Hz,2H),7.24(d,J＝8.1Hz,1H),7.17(d,J＝9.9Hz,1H),6.97(d,J＝8.4Hz,1H),6.83(m,3H),6.09(s,1H),4.61(s,2H),4.55(m,1H),4.39(m,1H),3.88(s,3H),3.85(s,3H),3.05(qd,J1＝6.9Hz,J2＝5.7Hz,2H),2.66(m,2H),2.10(m,2H),1.93(m,1H),1.76(m,1H),0.99(t,J＝6.9Hz,3H)。
EXAMPLE 18 preparation of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-Pro-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (8d)
Using the method of example 15, from 800mg (0.91mmol)1- (4-hydroxy-3-methoxyphenyl) -7- (4-acetoacetyltheanyl-Pro-OBzl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (7d) there are obtained 435mg (61%) of the title compound as a yellow solid. Mp 113-114 ℃;
(c ═ 0.1, methanol); ESI-MS (m/e): 678[ M-H]-；IR(cm-1):3297,2971,1624,1583,1507,1446,1250,1126,1029,965,846,813,666；1HNMR(300MHz,DMSO-d6):δ/ppm＝12.60(s,1H),9.68(s,1H),8.18(d,J＝7.8Hz,1H),7.74(t,J＝5.7Hz,1H),7.57(m,2H),7.37(m,2H),7.24(d,J＝7.5Hz,1H),7.17(d,J＝8.1Hz,1H),6.97(d,J＝8.1Hz,1H),6.89(m,3H),6.10(s,1H),4.61(m,3H),4.28(m,1H),4.21(m,1H),3.87(s,3H),3.85(s,3H),3.06(qd,J1＝7.2Hz,J2＝5.7Hz,2H),2.20(m,4H),1.93(m,3H),1.76(m,1H),1.00(t,J＝7.2Hz,3H)。
EXAMPLE 19 preparation of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-Gln-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (8e)
Using the method of example 15, from 500mg (0.63mmol)1- (4-hydroxy-3-methoxyphenyl) -7- (4-acetoacet-theanyl-Gln-OBzl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (7e) 31mg (7%) of the title compound are obtained as a yellow solid. Mp 135-;
(c ═ 0.1, methanol); ESI-MS (m/e): 709[ M-H]-；IR(cm-1):3306,2935,1625,1583,1507,1446,1239,1126,1029,963,849,811,605；1HNMR(300MHz,DMSO-d6):δ/ppm＝12.60(s,1H),9.71(s,1H),8.40(d,J＝6.3Hz,1H),8.09(d,J＝6.9Hz,1H),7.78(t,J＝6.3Hz,1H),7.57(m,2H),7.37(m,5H),6.97(d,J＝7.8Hz,1H),6.89(m,4H),6.09(s,1H),4.61(s,2H),4.40(m,1H),4.16(m,1H),3.88(s,3H),3.85(s,3H),3.04(qd,J1＝7.2Hz,J2＝6.3Hz,2H),2.10(m,4H),1.93(m,2H),1.76(m,2H),0.98(t,J＝7.2Hz,3H)。
EXAMPLE 20 preparation of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-Ser-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (8f)
Using the method of example 15, from 500mg (0.66mmol)1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-Ser-OBzl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (7f) there are obtained 70mg (16%) of the title compound as yellow solid. Mp 169-170 deg.C;
(c ═ 0.1, methanol); ESI-MS (m/e): 668[ M-H ]]-；IR(cm-1):3293,2937,1626,1585,1508,1425,1256,1133,1058,1032,963,843,810,721,597；1HNMR(300MHz,DMSO-d6):δ/ppm＝16.5(s,1H),9.68(s,1H),8.29(d,J＝7.5Hz,1H),8.06(d,J＝8.1Hz,1H),7.76(t,J＝6.3Hz,1H),7.57(m,2H),7.37(m,2H),7.24(d,J＝8.1Hz,1H),7.17(d,J＝7.5Hz,1H),6.98(d,J＝5.4Hz,1H),6.89(m,3H),6.10(s,1H),4.61(s,2H),4.49(m,1H),4.23(m,1H),3.88(s,3H),3.85(s,3H),3.65(m,2H),3.33(m,2H),3.04(qd,J1＝7.2Hz,J2＝6.3Hz,2H),2.10(m,2H),1.93(m,1H),1.76(m,1H),0.99(t,J＝7.2Hz,3H)。
EXAMPLE 21 preparation of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-Val-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (8g)
From 500mg (0.67mmol) of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-acetoacetyltheanyl-Val-OBzl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (7g) by the method of example 15 were obtained 327mg (75%) of the title compound as a yellow solid. Mp 140-141 ℃;
(c ═ 0.1, methanol); ESI-MS (m/e): 680[ M-H ]]-；IR(cm-1):3289,2931,1625,1507,1423,1264,1132,1029,964,845,811,666；1HNMR(300MHz,DMSO-d6):δ/ppm＝12.65(s,1H),9.69(s,1H),8.18(d,J＝8.4Hz,1H),8.07(d,J＝7.5Hz,1H),7.77(t,J＝6.3Hz,1H),7.57(m,2H),7.37(m,2H),7.23(d,J＝7.8Hz,1H),7.17(d,J＝8.1Hz,1H),6.97(d,J＝8.4Hz,1H),6.89(m,3H),6.10(s,1H),4.61(s,2H),4.50(m,1H),4.15(m,1H),3.87(s,3H),3.85(s,3H),3.04(qd,J1＝7.2Hz,J2＝6.3Hz,2H),2.10(m,3H),1.93(m,1H),1.76(m,1H),0.99(t,J＝7.2Hz,3H),0.88(d,J＝6.6Hz,6H)。
EXAMPLE 22 preparation of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-Tyr-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (8h)
From 600mg (0.72mmol) of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-Tyr-OBzl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (7h) by the method of example 15, 354mg (66%) of the title compound are obtained as a yellow solid. Mp 146-147 deg.C;
(c ═ 0.1, methanol); ESI-MS (m/e): 744[M-H]-；IR(cm-1):3280,1646,1626,1585,1540,1509,1424,1251,1130,1030,963,813,667；1HNMR(300MHz,DMSO-d6):δ/ppm＝12.68(s,1H),9.70(s,1H),9.21(s,1H),8.29(d,J＝7.2Hz,1H),8.00(d,J＝8.4Hz,1H),7.75(t,J＝6.0Hz,1H),7.57(m,2H),7.37(m,2H),7.23(d,J＝8.1Hz,1H),7.17(d,J＝7.8Hz,1H),7.00(m,3H),6.89(m,3H),6.65(d,J＝8.4Hz,2H),6.10(s,1H),4.59(s,2H),4.37(m,2H),3.87(s,3H),3.85(s,3H),3.04(qd,J1＝6.9Hz,J2＝6.0Hz,2H),2.10(m,2H),1.93(m,1H),1.76(m,1H),0.99(t,J＝6.9Hz,3H)。
EXAMPLE 23 determination of the anti-tumor growth Activity of Compounds 8a-h
Doxorubicin, compound 6 and compounds 8a-h were dissolved in physiological saline prior to assay for administration to S180 mice. Taking S180 ascites tumor liquid which is inoculated in a male ICR mouse and grows vigorously for 10 days in a sterile environment, diluting the S180 ascites tumor liquid into liquid (1:2) by using normal saline, fully mixing the liquid, dyeing the tumor cell suspension by using freshly prepared 0.2% trypan blue, uniformly mixing the liquid and the liquid, counting the liquid according to a white cell counting method, wherein the blue-dyed cell is a dead cell, and the non-dyed cell is a live cell. The cell concentration is 4-large-grid viable cell number/4 × 104The cell density was calculated as x dilution factor ═ cell number/mL, and the cell survival rate was calculated as live cell number/(live cell number + dead cell number) × 100%. Homogenizing tumor solution with survival rate of more than 90% to density of 2.0 × 107Cell suspension per mL. This cell suspension was inoculated subcutaneously (0.2 mL/mouse) in the right axilla of a mouse to prepare S180 tumor-bearing mice. 24h after inoculation, S180 tumor-bearing mice were intraperitoneally injected daily with a normal saline solution of doxorubicin (dose 2. mu. mol/kg/day g), or with a normal saline solution of compound 6 (dose 1. mu. mol/kg/day), or with a normal saline solution of compounds 8a-h (dose 0.1. mu. mol/kg/day), 10 per group. The administration is once daily for 12 days. The next day of the last administration, cervical spine was removed under ether anesthesia, and then the right axillary tumor growth site of the mouse was fixed with forceps, and the skin was excised and the tumor was blunt-stripped and weighed. Efficacy was expressed as tumor weight (mean ± SD g), and data were analyzed by t-test and variance. The results are shown in Table 1. Compounds 8a-h are not only effective at inhibiting tumor growth at a dose of 0.1 μmol/kg,and compound 6, which was 10-fold more active than them at the dose, did not differ significantly. These data indicate that the present invention has significant technical effects.
TABLE 1 Effect of Compounds 8a-h on tumor growth in S180 mice
a) P <0.05 to saline, p >0.05 to compound 6; n is 10.
Claims (3)
1. 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-AA-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione of the formula, wherein AA is selected from the group consisting of an L-Lys residue, an L-Leu residue, an L-Asn residue, an L-Pro residue, an L-Gln residue, an L-Ser residue, an L-Val residue and an L-Tyr residue,
2. a process for the preparation of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxyacethyl-AA-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione according to claim 1, which comprises:
(1) preparing 6- (4-hydroxy-3-methoxyphenyl) -5, 6-hexene-2, 4-dione (1);
(2) preparation of benzyl 2- (4-formyl-2-methoxyphenoxy) -acetate (2);
(3) preparing 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxyacetobenzoyl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-diketone (3) by taking the products obtained in the step (1) and the step (2) as reaction raw materials;
(4) saponifying 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetoacetylbenzyl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione to obtain 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetoacetoxy-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (4);
(5) coupling the compound 4 and L-benzyl theanine to obtain 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxyacetylbenzyl theanine-3-methoxyphenyl) -1, 6-heptadiene-3, 5-diketone (5);
(6) saponifying the compound 5 to obtain 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxyacetophytamic acid-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (6);
(7) coupling of compound 6 with benzyl L-amino acid to give 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-AA-OBzl-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione (7) according to claim 1;
(8) the compound 7 is saponified to obtain 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxyacethyl-AA-3-methoxyphenyl) -1, 6-heptadiene-3, 5-diketone.
3. Use of 1- (4-hydroxy-3-methoxyphenyl) -7- (4-oxoacetyltheanyl-AA-3-methoxyphenyl) -1, 6-heptadiene-3, 5-dione according to claim 1 for preparing a medicament for combating tumour growth.
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