Cyclobutyl methyl and phenyl substituted curcumin derivative as well as preparation method and application thereof

Abstract

The invention relates to the technical field of biological medicine, in particular to a cyclobutyl methyl and phenyl substituted curcumin derivative as well as a synthesis method and application thereof. According to the invention, a polycyclic ring is introduced into a beta-diketone structure of curcumin, and benzene ring structures at two ends of the polycyclic ring are changed, so that the cyclobutyl methyl and phenyl substituted curcumin derivative is prepared. An in-vitro tumor suppression research shows that the killing effect of the newly synthesized curcumin derivative on tumor cells is stronger than that of curcumin derivatives ASC-J9 and ASC-JM17.

Description

Technical Field

[0001] The present invention relates to the technical field of biomedicine, and in particular to a cyclobutylmethyl and phenyl substituted curcumin derivative, and a preparation method and application thereof. Background Art

[0002] Dimethoxycurcumin (ASC-J9) is a curcumin derivative with multiple biological activities. It can enhance the degradation of androgen receptors and can play a therapeutic role in androgen receptor-related tumors, but its anti-tumor activity is still difficult to meet clinical needs. It is reported that a new ASC-J9 derivative ASC-JM17 was prepared by introducing a cyclobutyl methyl group between the β-diketone structure of ASC-J9. Compared with ASC-J9, ASC-JM17 has a stronger ability to target androgen receptors for degradation and also exhibits strong antioxidant capacity.

[0003] Currently, research related to ASC-JM17 mainly focuses on the treatment of neurodegenerative diseases such as spinocerebellar ataxia and Huntington's disease, as well as prostate cancer. Summary of the invention

[0004] The purpose of the present invention is to synthesize a new curcumin derivative having an anti-liver cancer effect by changing the β-diketone structure of curcumin or the substituents on the benzene ring. The curcumin derivative designed and synthesized by the present invention has the general chemical formula:

[0005]

[0006] Among them, R1 is cyclobutylmethyl or phenyl.

[0007] R2 is o-, m-, or p-fluorine, acetylamino, or methanesulfonylamino.

[0008] The chemical names and chemical structural formulas of the newly synthesized curcumin derivatives are as follows:

[0009] A1: N,N'-(((1E,6E)-4-(cyclobutylmethyl)-3,5-dioxa-1,6-diene-1,7-diyl)bis(4,1-phenyl))diacetylamino

[0010]

[0011] A2: N,N'-(((1E,6E)-4-(cyclobutylmethyl)-3,5-dioxa-1,6-diene-1,7-diyl)bis(3,1-phenyl))bismethanesulfonamide

[0012]

[0013] A3: N,N'-(((1E,6E)-4-(cyclobutylmethyl)-3,5-dioxa-1,6-diene-1,7-diyl)bis(4,1-phenyl))bismethanesulfonamide

[0014]

[0015] A4: (1E, 6E)-4-(cyclobutylmethyl)-1,7-bis(2-fluorophenyl)hepta-1,6-diene-3,5-dione

[0016]

[0017] A5: (1E, 6E)-4-(cyclobutylmethyl)-1,7-bis(3-fluorophenyl)hepta-1,6-diene-3,5-dione

[0018]

[0019] A6: (1E, 6E)-4-(cyclobutylmethyl)-1,7-bis(4-fluorophenyl)hepta-1,6-diene-3,5-dione

[0020]

[0021] A7: (1E, 6E)-4-(cyclobutylmethyl)-1,7-bis(2,4-difluorophenyl)hepta-1,6-diene-3,5-dione

[0022]

[0023] A8: (1E, 6E)-4-(cyclobutylmethyl)-1,7-bis(3,4-difluorophenyl)hepta-1,6-diene-3,5-dione

[0024]

[0025] B1: N,N'-(((1E,6E)-4-phenyl-3,5-dioxa-1,6-diene-1,7-diyl)bis(4,1-phenyl))diacetylamino

[0026]

[0027] B2: N,N'-(((1E,6E)-4-phenyl-3,5-dioxadiene-1,6-diene-1,7-diyl)bis(3,1-phenyl))bismethanesulfonamide

[0028]

[0029] B3: N,N'-(((1E,6E)-4-phenyl-3,5-dioxadiene-1,6-diene-1,7-diyl)bis(4,1-phenyl))bismethanesulfonamide

[0030]

[0031] B4: (1E, 6E)-4-phenyl-1,7-bis(2-fluorophenyl)hepta-1,6-diene-3,5-dione

[0032]

[0033] B5: (1E, 6E)-4-phenyl-1,7-bis(4-fluorophenyl)hepta-1,6-diene-3,5-dione

[0034]

[0035] B6: (1E, 6E)-4-phenyl-1,7-bis(2,4-difluorophenyl)hepta-1,6-diene-3,5-dione

[0036]

[0037] The preparation method and synthetic route of the novel curcumin derivatives are as follows:

[0038]

[0039] (1) Preparation of acetylacetone derivatives: acetylacetone, bromide and base are added to a solvent, heated at 25-60°C in the dark and stirred for reaction for 8-12 hours; after the reaction, the solvent is removed by rotary evaporation, and the acetylacetone derivative is separated and purified by vacuum distillation to obtain the acetylacetone derivative.

[0040] The solvents are DMF and isopropanol; the bases are potassium carbonate and cesium carbonate; and the brominated substances are bromomethylcyclobutyl and bromobenzene.

[0041] The molar ratio of acetylacetone, bromide and base is 1:1-1.2:2-3.

[0042] (2) Preparation of curcumin derivatives: The acetylacetone derivative prepared in step (1), boric acid, tributyl borate, n-butylamine and benzaldehyde with different substituents are added to DMF, heated at 25-80° C. in the dark and stirred for reaction for 2-5 hours; after the reaction is completed, 20% acetic acid aqueous solution is added and stirred for 8 hours, filtered and the residue is collected, and the product is recrystallized from methanol to obtain a curcumin derivative.

[0043] Among them, the benzaldehydes with different substituents are: p-acetamidobenzaldehyde, 3-methanesulfonylaminobenzaldehyde, p-methanesulfonylaminobenzaldehyde, 2-fluorobenzaldehyde, 3-fluorobenzaldehyde, 4-fluorobenzaldehyde, 2,4-difluorobenzaldehyde, and 3,4-difluorobenzaldehyde.

[0044] The molar ratio of acetylacetone derivatives, benzaldehyde with different substituents, boric acid, tributyl borate and n-butylamine is 1:2-2.5:0.5-1:2-2.5:1-1.5.

[0045] Beneficial effects of the present invention:

[0046] (1) The present invention uses acetylacetone, bromide and benzaldehyde with different substituents as raw materials to synthesize curcumin derivatives at a lower cost.

[0047] (2) The biological activity of curcumin can be enhanced by introducing a polycyclic ring at the 3-position of acetylacetone, and the modification of the substituents on the benzene ring can also achieve a similar effect. Both of them were applied to the modification of curcumin, and a new curcumin derivative with high antitumor activity was obtained.

[0048] (3) The novel curcumin derivative provided by the present invention has a stronger killing effect on tumor cells than the curcumin derivatives ASC-JM17 and ASC-J9. DETAILED DESCRIPTION

[0049] The following examples are used to further describe the specific embodiments of the present invention. The following examples are used to illustrate the present invention, but are not intended to limit the scope of the present invention.

[0050] Example 1

[0051] (1) Preparation of 3-(cyclobutylmethyl)pentane-2,4-dione

[0052] 2g (20.0mmol) of acetylacetone and 5.52g (40.0mmol) of potassium carbonate were dissolved in 15mL of DMF, 3.55g (24.0mmol) of bromomethylcyclobutyl was added, and the mixture was stirred at 60°C for 5 hours. After the reaction solution A was cooled, 150ml of distilled water was added to dissolve it, and ethyl acetate (EA) was used for extraction. The organic phase was collected and dried over anhydrous sodium sulfate, and the solid was removed by filtration. The solution was evaporated to remove the solvent and then purified by vacuum distillation to obtain a yellow liquid.

[0053] (2) Preparation of N,N'-(((1E,6E)-4-(cyclobutylmethyl)-3,5-dioxa-1,6-diene-1,7-diyl)bis(4,1-phenyl))diacetylamino

[0054] Dissolve 500 mg (2.97 mmol) of 3-(cyclobutylmethyl)pentane-2,4-dione in 3 mL of DMF, add 969.9 mg (5.95 mmol) of p-acetaminobenzaldehyde, 91.9 mg (1.49 mmol) of boric acid, 1.37 g (5.95 mmol) of tributyl borate and 108.8 mg (1.49 mmol) of n-butylamine, stir at 80 ° C for 3 hours, add 30 mL of 20% acetic acid aqueous solution, stir for 3 hours, filter and collect the residue. Recrystallize with methanol and dry to obtain 933.5 mg of orange-yellow solid powder with a yield of 68.5%. 1 H NMR (400MHz, DMSO-d6) δ10.19(s,2H),7.73(d,J=8.5Hz,2H),7.69-7.56(m,9H),7.26(d,J=15.5Hz,1H),6.92(d, J=16.1Hz,1H),2.06(d,J=4.8Hz,7H),1.93(dd,J=13.6,6.1Hz,4H),1.73(d,J=5.9Hz,3H),1.62(t,J=9.2Hz,1H). 13 C NMR(101MHz,DMSO-d6)δ195.28,183.02,168.69,168.62,143.06,141.71,141.18,140.64,139.93,129.68,129.65,129.39,129 .22,128.65,123.65,119.34,118.91,118.85,110.31,37.90,35.15,33.73,29.92,27.79,26.98,24.11,17.91,17.80.HRMS:m / z of[M+Na] + caculated for C 28 H 30 N2O4 481.2155, found 481.2155.

[0055] Example 2

[0056] (1) The preparation method of 3-(cyclobutylmethyl)pentane-2,4-dione is the same as step (1) in Example 1.

[0057] (2) Preparation of N,N'-(((1E,6E)-4-(cyclobutylmethyl)-3,5-dioxa-1,6-diene-1,7-diyl)bis(3,1-phenyl))dimethylsulfonamide

[0058] Dissolve 500 mg (2.97 mmol) of 3-(cyclobutylmethyl)pentane-2,4-dione in 3 mL of DMF, add 1.19 g (5.95 mmol) of 3-methanesulfonamidobenzaldehyde, 91.9 mg (1.49 mmol) of boric acid, 1.37 g (5.95 mmol) of tributyl borate and 108.8 mg (1.49 mmol) of n-butylamine, stir at 80 ° C for 3 hours, add 30 mL of 20% acetic acid aqueous solution, stir for 3 hours, filter and collect the residue. Recrystallize with methanol and dry to obtain 1138.4 mg of orange-yellow solid powder with a yield of 72.3%. 1 H NMR (400MHz, DMSO-d6) δ10.13(s,2H),7.77(d,J=8.6Hz,2H),7.70(d,J=8.6Hz,2H),7.62(d,J=15.7Hz,2H),7.23(dd,J=11.8,8.2Hz,5H), 6.93(d,J=16.1Hz,1H),3.06(d,J=5.1Hz,6H),2.79(d,J=7.4Hz,1H),2.33(s,1H),1.93(dd,J=13.2,6.2Hz,4H),1.73(s,3H),1.62(s,1H). 13 C NMR(101MHz,DMSO-d6)δ195.57,182.95,142.98,140.65,139.02,135.98,135.16,129.97,125.95,123.88,123.64, 122.02,121.66,121.27,119.56,119.38,110.92,59.61,37.81,35.06,33.71,27.81,27.02,17.96,17.78.HRMS:m / z of[M+Na] + caculated for C 26 H 30 N2O6S2 553.1444,found553.1444.

[0059] Example 3

[0060] (1) The preparation method of 3-(cyclobutylmethyl)pentane-2,4-dione is the same as step (1) in Example 1.

[0061] (2) Preparation of N,N'-(((1E,6E)-4-(cyclobutylmethyl)-3,5-dioxa-1,6-diene-1,7-diyl)bis(4,1-phenyl))dimethylsulfonamide

[0062] Dissolve 500 mg (2.97 mmol) of 3-(cyclobutylmethyl)pentane-2,4-dione in 3 mL of DMF, add 1.19 g (5.95 mmol) of p-methylsulfonylaminobenzaldehyde, 91.9 mg (1.49 mmol) of boric acid, 1.37 g (5.95 mmol) of tributyl borate and 108.8 mg (1.49 mmol) of n-butylamine, stir at 80 ° C for 3 hours, add 30 mL of 20% acetic acid aqueous solution, stir for 3 hours, filter and collect the residue. Recrystallize with methanol and dry to obtain 877.0 mg of orange-yellow solid powder with a yield of 55.7%. 1 H NMR (400MHz, DMSO-d6) δ9.90 (s, 2H), 7.70-7.56 (m, 3H), 7.52-7.36 (m, 5H), 7.34-7.22 (m, 3H), 6.91 (dd, J = 32.4, 16.1Hz, 1H), 3.0 3(d,J=13.2Hz,6H),2.79(d,J=7.0Hz,1H),2.42-2.30(m,1H),2.26-2.16(m,1H),1.94(dd,J=15.5,8.5Hz,3H),1.82-1.59(m,4H). 13 C NMR(101MHz,DMSO-d6)δ195.30,183.02,140.41,140.29,130.15,129.86,129.7 1,119.82,118.86,118.64,110.46,37.90,29.91,27.80,26.97,17.91.HRMS:m / z of[M+Na] + caculated forC 26 H 30 N2O6S2 553.1444,found553.1444.

[0063] Example 4

[0064] (1) The preparation method of 3-(cyclobutylmethyl)pentane-2,4-dione is the same as step (1) in Example 1.

[0065] (2) Preparation of (1E, 6E)-4-(cyclobutylmethyl)-1,7-bis(2-fluorophenyl)hept-1,6-diene-3,5-dione

[0066] Dissolve 500 mg (2.97 mmol) of 3-(cyclobutylmethyl)pentane-2,4-dione in 3 mL of DMF, add 738.2 mg (5.95 mmol) of 2-fluorobenzaldehyde, 91.9 mg (1.49 mmol) of boric acid, 1.37 g (5.95 mmol) of tributyl borate and 108.8 mg (1.49 mmol) of n-butylamine, stir at 80 ° C for 3 hours, add 30 mL of 20% acetic acid aqueous solution, stir for 3 hours, filter and collect the residue. Recrystallize with methanol and dry to obtain 464.0 mg of orange-yellow solid powder with a yield of 41.1%. 1 H NMR (400MHz, DMSO-d6) δ8.05-7.98(m,1H),7.89(t,J=7.7Hz,1H),7.74(dd,J=24.9,15.9Hz,2H),7.55-7.42(m,3H),7.31(dq,J=1 1.9,8.1,7.7Hz,4H),7.12(d,J=16.2Hz,1H),4.54(t,J=6.9Hz,1H),2.81(d,J=7.2Hz,1H),2.44-2.17(m,1H),2.02-1.57(m,7H). 13 C NMR(101MHz,Chloroform-d)δ182.24,161.76,159.24,133.28,133.26,130.24,130.16,128.72,128.69 ,123.47,123.43,122.79,122.71,122.60,122.49,115.35,115.13,110.06,37.10,30.60,26.82,17.40. 19 F NMR(282MHz,DMSO-d6)δ-115.33,-116.13.HRMS:m / z of[M+Na] + caculated for C 24 H 22 F2O2 403.1491, found 403.1491.

[0067] Example 5

[0068] (1) The preparation method of 3-(cyclobutylmethyl)pentane-2,4-dione is the same as step (1) in Example 1.

[0069] (2) Preparation of (1E, 6E)-4-(cyclobutylmethyl)-1,7-bis(3-fluorophenyl)hept-1,6-diene-3,5-dione

[0070] Dissolve 500 mg (2.97 mmol) of 3-(cyclobutylmethyl)pentane-2,4-dione in 3 mL of DMF, add 738.2 mg (5.95 mmol) of 3-fluorobenzaldehyde, 91.9 mg (1.49 mmol) of boric acid, 1.37 g (5.95 mmol) of tributyl borate and 108.8 mg (1.49 mmol) of n-butylamine, stir at 80 ° C for 3 hours, add 30 mL of 20% acetic acid aqueous solution, stir for 3 hours, filter and collect the residue. Recrystallize with methanol and dry to obtain 591.6 mg of orange-yellow solid powder with a yield of 52.4%. 1 H NMR (400MHz, DMSO-d6) δ7.82-7.75(m,1H),7.66(dt,J=15.1,7.1Hz,4H),7.58(d,J=7.8Hz,1H),7.52-7.43(m,3H),7.28(qd,J=8.2,2.4Hz,2 H),7.15(d,J=16.1Hz,1H),4.47(t,J=6.9Hz,1H),2.87(d,J=7.3Hz,1H),2.39-2.16(m,1H),2.03-1.84(m,3H),1.69(dq,J=35.2,8.7Hz,4H). 13 C NMR(101MHz,Chloroform-d)δ183.01,164.30,161.85,140.10,140.07,137.76,137.68,130.54,130 .45,124.30,124.28,122.12,116.96,116.75,114.26,114.05,110.97,38.11,31.61,27.87,18.47. 19 F NMR(282MHz,DMSO-d6)δ-112.72,-112.86.HRMS:m / z of[M+Na] + caculated for C 24 H 22 F2O2403.1491, found 403.1491.

[0071] Example 6

[0072] (1) The preparation method of 3-(cyclobutylmethyl)pentane-2,4-dione is the same as step (1) in Example 1.

[0073] (2) Preparation of (1E, 6E)-4-(cyclobutylmethyl)-1,7-bis(4-fluorophenyl)hept-1,6-diene-3,5-dione

[0074] Dissolve 500 mg (2.97 mmol) of 3-(cyclobutylmethyl)pentane-2,4-dione in 3 mL of DMF, add 738.2 mg (5.95 mmol) of 4-fluorobenzaldehyde, 91.9 mg (1.49 mmol) of boric acid, 1.37 g (5.95 mmol) of tributyl borate and 108.8 mg (1.49 mmol) of n-butylamine, stir at 80 ° C for 3 hours, add 30 mL of 20% acetic acid aqueous solution, stir for 3 hours, filter and collect the residue. Recrystallize with methanol and dry to obtain 742.9 mg of orange-yellow solid powder with a yield of 65.8%. 1 H NMR (400MHz, DMSO-d6) δ7.89(dd,J=8.5,5.7Hz,2H),7.85-7.80(m,2H),7.67(dd,J=15.9,10.0Hz,2H),7.34-7.25(m,5H),6.99(dd,J =34.8,16.0Hz,1H),4.48(t,J=7.0Hz,1H),2.83(d,J=7.3Hz,1H),2.39-2.16(m,1H),1.93(dt,J=24.0,8.0Hz,3H),1.81-1.56(m,4H). 13 C NMR(101MHz,Chloroform-d)δ183.15,164.98,162.49,140.08,139.41,131.76,131.72,130.01 ,129.92,123.68,120.65,120.62,116.21,115.99,110.47,110.45,38.11,31.63,27.90,18.48. 19 F NMR(282MHz,DMSO-d6)δ-109.28,-110.17.HRMS:m / z of[M+Na] + caculated for C 24 H 22 F2O2 403.1491, found403.1491.

[0075] Example 7

[0076] (1) The preparation method of 3-(cyclobutylmethyl)pentane-2,4-dione is the same as step (1) in Example 1.

[0077] (2) Preparation of (1E, 6E)-4-(cyclobutylmethyl)-1,7-bis(2,4-difluorophenyl)heptyl-1,6-diene-3,5-dione

[0078] Dissolve 500 mg (2.97 mmol) of 3-(cyclobutylmethyl)pentane-2,4-dione in 3 mL of DMF, add 845.5 mg (5.95 mmol) of 2,4-difluorobenzaldehyde, 91.9 mg (1.49 mmol) of boric acid, 1.37 g (5.95 mmol) of tributyl borate and 108.8 mg (1.49 mmol) of n-butylamine, stir at 80°C for 3 hours, add 30 mL of 20% acetic acid aqueous solution, stir for 3 hours, filter and collect the residue. Recrystallize with methanol and dry to obtain 446.2 mg of orange-yellow solid powder with a yield of 36.1%. 1 H NMR (400MHz, DMSO-d6) δ8.12(td,J=8.8,6.6Hz,1H),7.98(q,J=8.3Hz,1H),7.76-7.61(m,2H),7.47-7.36(m,4H),7.27-7.17(m,2H),7.06( dd,J=29.2,16.1Hz,1H),4.50(t,J=7.0Hz,1H),2.80(d,J=7.2Hz,1H),2.41-2.10(m,1H),1.93(dt,J=15.0,5.2Hz,2H),1.80-1.59(m,4H). 13 C NMR(101MHz,Chloroform-d)δ183.13,164.88(d,J=12.3Hz),163.05(d,J=12.0Hz),162.36(d ,J=12.4Hz),160.50(d,J=11.9Hz),133.34,132.45,130.85(d,J=4.8Hz),130.75(d,J=4.8Hz) ,123.27,123.20,120.12(d,J=3.9Hz),120.00(d,J=4.0Hz),112.18(d,J=3.7Hz),111.96(d, J=3.8Hz),110.99(d,J=1.8Hz),105.00,104.75,104.49,102.19,38.11,31.59,27.85,18.43. 19 F NMR(282MHz,DMSO-d6)δ-105.31,-106.19,-110.58,-111.52.HRMS:m / z of[M+Na] + caculated for C 24 H 20 F4O2 439.1291, found 439.1291.

[0079] Example 8

[0080] (1) The preparation method of 3-(cyclobutylmethyl)pentane-2,4-dione is the same as step (1) in Example 1.

[0081] (2) Preparation of (1E, 6E)-4-(cyclobutylmethyl)-1,7-bis(3,4-difluorophenyl)heptyl-1,6-diene-3,5-dione

[0082] Dissolve 500 mg (2.97 mmol) of 3-(cyclobutylmethyl)pentane-2,4-dione in 3 mL of DMF, add 845.5 mg (5.95 mmol) of 3,4-difluorobenzaldehyde, 91.9 mg (1.49 mmol) of boric acid, 1.37 g (5.95 mmol) of tributyl borate and 108.8 mg (1.49 mmol) of n-butylamine, stir at 80°C for 3 hours, add 30 mL of 20% acetic acid aqueous solution, stir for 3 hours, filter and collect the residue. Recrystallize with methanol and dry to obtain 530.2 mg of orange-yellow solid powder with a yield of 42.9%. 1 H NMR (400MHz, DMSO-d6) δ8.08(ddd,J=12.3,7.9,2.0Hz,1H),7.96(ddd,J=10.1,7.8,2.0Hz,1H),7.71-7.57(m,4H),7.52(dt,J=10.7,8.5Hz,2H),7. 43(d,J=15.5Hz,1H),7.11(d,J=16.1Hz,1H),4.41(t,J=6.9Hz,1H),2.86( d,J=7.3Hz,1H),2.37-2.15(m,1H),2.02-1.83(m,3H),1.81-1.58(m,4H). 13 C NMR(101MHz,Chloroform-d)δ182.85,152.57(d,J=12.9Hz),151.90(d,J=13.2Hz),150.05(d,J=12.5Hz),149.42(d,J=13.1Hz),139.18(d,J=2.3Hz),132 .73,132.69,132.67,132.63,125.00,124.97,124.94,124.90,121.76(d,J=2 .5Hz),117.97,117.79,116.23,116.05,110.83,38.09,31.57,27.86,18.47. 19 F NMR(282MHz,DMSO-d6)δ-134.89,-135.79,-137.85,-138.07.HRMS:m / z of[M+Na] +caculated forC 24 H 20 F4O2 439.1291, found 439.1291.

[0083] Example 9

[0084] (1) Preparation of 3-phenylpentane-2,4-dione

[0085] 2 g (20.0 mmol) of acetylacetone and 5.52 g (40.0 mmol) of potassium carbonate were dissolved in 15 mL of DMF, 3.74 g (24.0 mmol) of benzene bromide were added, and the mixture was stirred at 60°C for 5 hours. After the reaction solution A was cooled, 150 ml of distilled water was added to dissolve it, and ethyl acetate (EA) was used for extraction. The organic phase was collected and dried over anhydrous sodium sulfate, and the solid was removed by filtration. The solution was evaporated to remove the solvent and then purified by vacuum distillation to obtain a yellow liquid.

[0086] (2) N, N'-(((1E, 6E)-4-phenyl-3,5-dioxa-1,6-diene-1,7-diyl)bis(4,1-phenyl)) diacetylamino

[0087] Dissolve 200 mg (1.14 mmol) of 3-phenylpentane-2,4-dione in 3 mL of DMF, add 370.7 mg (2.27 mmol) of p-acetaminobenzaldehyde, 35.1 mg (0.57 mmol) of boric acid, 522.8 mg (2.27 mmol) of tributyl borate and 41.5 mg (0.57 mmol) of n-butylamine, stir at 80°C for 3 hours, add 30 mL of 20% acetic acid aqueous solution, stir for 3 hours, filter and collect the residue. Recrystallize with methanol and dry to obtain 417.7 mg of orange-yellow solid powder with a yield of 78.6%. 1 H NMR (400MHz, DMSO-d6) δ10.15(s,2H),7.65-7.49(m,10H),7.34(dt,J=7.5,1.5Hz,6H),6.35(d,J=15.7Hz,2H),2.04(s,6H). 13 C NMR(101MHz,DMSO-d6)δ182.31,169.10,141.87,141.20,135.04,132.45,129 .55,129.50,129.23,128.46,120.07,119.47,116.27,49.06,24.54.HRMS:m / z of[M+Na] + caculated for C 29 H 26 N2O4 489.1788, found 489.1788.

[0088] Example 10

[0089] (1) The preparation of 3-phenylpentane-2,4-dione was carried out in the same manner as step (1) in Example 9.

[0090] (2) Preparation of N,N'-(((1E,6E)-4-phenyl-3,5-dioxadiene-1,6-diene-1,7-diyl)bis(3,1-phenyl))bismethanesulfonamide

[0091] Dissolve 200 mg (1.14 mmol) of 3-phenylpentane-2,4-dione in 3 mL of DMF, add 452.6 mg (2.27 mmol) of 3-methanesulfonamidobenzaldehyde, 35.1 mg (0.57 mmol) of boric acid, 484.3 mg (2.27 mmol) of tributyl borate and 41.5 mg (0.57 mmol) of n-butylamine, stir at 80°C for 3 hours, add 30 mL of 20% acetic acid aqueous solution, stir for 3 hours, filter and collect the residue. Recrystallize with methanol and dry to obtain 298.7 mg of orange-yellow solid powder with a yield of 48.7%. 1 H NMR (400MHz, DMSO-d6) δ9.86 (s, 2H), 7.65 (d, J = 15.7Hz, 2H), 7.54 (dd, J = 5.2, 1.9Hz, 3H), 7.4 3(d,J=2.8Hz,1H),7.41-7.29(m,4H),7.25-7.11(m,6H),6.44(d,J=15.7Hz,2H),2.98(s,6H). 13 CNMR(101MHz,DMSO-d6)δ182.26,141.24,139.56,135.98,134.53,132.38,130. 57,129.30,128.68,124.25,122.44,121.67,118.63,116.91.HRMS:m / zof[M+Na] + caculated forC 27 H 26 N2O6S2 561.1126, found 561.1126.

[0092] Embodiment 11

[0093] (1) The preparation of 3-phenylpentane-2,4-dione was carried out in the same manner as step (1) in Example 9.

[0094] (2) Preparation of N,N'-(((1E,6E)-4-phenyl-3,5-dioxadiene-1,6-diene-1,7-diyl)bis(4,1-phenyl))bismethanesulfonamide

[0095] Dissolve 200 mg (1.14 mmol) of 3-phenylpentane-2,4-dione in 3 mL of DMF, add 452.6 mg (2.27 mmol) of p-methylsulfonylaminobenzaldehyde, 35.1 mg (0.57 mmol) of boric acid, 484.3 mg (2.27 mmol) of tributyl borate and 41.5 mg (0.57 mmol) of n-butylamine, stir at 80°C for 3 hours, add 30 mL of 20% acetic acid aqueous solution, stir for 3 hours, filter and collect the residue. Recrystallize with methanol and dry to obtain 426.9 mg of orange-yellow solid powder with a yield of 69.8%. 1 H NMR (400MHz, DMSO-d6) δ10.09(s,2H),7.63(d,J=15.7Hz,2H),7.52(d,J=6.7Hz,3H),7.36(dd,J=1 8.1,7.6Hz,6H),7.17(d,J=8.2Hz,4H),6.36(d,J=15.7Hz,2H),3.16(d,J=4.7Hz,1H),3.03(s,6H). 13 C NMR(101MHz,DMSO-d6)δ182.29,141.01,140.98,134.93,132.43,129.97,129.94,129.24,128.48,120.58,119.29,116.39.HRMS:m / z of[M+Na] + caculated forC 27 H 26 N2O6S2 561.1126, found 561.1126.

[0096] Example 12

[0097] (1) The preparation of 3-phenylpentane-2,4-dione was carried out in the same manner as step (1) in Example 9.

[0098] (2) Preparation of (1E, 6E)-4-phenyl-1,7-bis(2-fluorophenyl)hept-1,6-diene-3,5-dione

[0099] Dissolve 200 mg (1.14 mmol) of 3-phenylpentane-2,4-dione in 3 mL of DMF, add 281.9 mg (2.27 mmol) of 2-fluorobenzaldehyde, 35.1 mg (0.57 mmol) of boric acid, 484.3 mg (2.27 mmol) of tributyl borate and 41.5 mg (0.57 mmol) of n-butylamine, stir at 80°C for 3 hours, add 30 mL of 20% acetic acid aqueous solution, stir for 3 hours, filter and collect the residue. Recrystallize with methanol and dry to obtain 235.1 mg of orange-yellow solid powder with a yield of 53.3%. 1 H NMR(400MHz,Chloroform-d)δ7.84(d,J=15.9Hz,1H),7.49-7.42(m,2H),7.37(q,J=3.2Hz,1H),7.33 -7.20(m,6H),7.16-6.88(m,5H),6.61(d,J=15.9Hz,1H),6.31(d,J=15.9Hz,1H),4.12-3.77(m,1H). 13 CNMR(101MHz,DMSO-d6)δ200.38,182.29,162.41,159.90,134.80,134.18,132.84,132.75,132.33,131.92,130.45, 130.42,130.09,129.25,129.21,128.63,128.43,125.60,124.90,122.75,122.64,117.26,116.80,116.59,116.52. 19 FNMR(282MHz,DMSO-d6)δ-114.81(dt,J=11.7,6.8Hz),-115.32(dq,J=11.9,6.5,6.1Hz).HRMS:m / z of[M+Na] + caculated forC 25 H 18 F2O2 411.1171, found411.1171.

[0100] Embodiment 13

[0101] (1) The preparation of 3-phenylpentane-2,4-dione was carried out in the same manner as step (1) in Example 9.

[0102] (2) Preparation of (1E, 6E)-4-phenyl-1,7-bis(4-fluorophenyl)hept-1,6-diene-3,5-dione

[0103] Dissolve 200 mg (1.14 mmol) of 3-phenylpentane-2,4-dione in 3 mL of DMF, add 281.9 mg (2.27 mmol) of p-fluorobenzaldehyde, 35.1 mg (0.57 mmol) of boric acid, 484.3 mg (2.27 mmol) of tributyl borate and 41.5 mg (0.57 mmol) of n-butylamine, stir at 80°C for 3 hours, add 30 mL of 20% acetic acid aqueous solution, stir for 3 hours, filter and collect the residue. Recrystallize with methanol and dry to obtain 238.6 mg of orange-yellow solid powder with a yield of 54.1%. 1 H NMR (400MHz, Chloroform-d) δ7.66 (d, J = 15.7Hz, 2H), 7.52-7.42 (m, 3H), 7.35-7. 28(m,6H),7.04-6.94(m,4H),6.41(d,J=15.7Hz,2H),2.45(dd,J=7.4,1.8Hz,1H). 13 C NMR(101MHz,DMSO-d6)δ182.31,164.90,162.42,140.37,134.70,132.41,132.03, 131.61,131.58,130.88,130.79,129.29,128.60,121.74,116.72,116.62,116.51. 19 F NMR(282MHz, DMSO-d6)δ-109.66(tt,J=8.7,5.5Hz),-110.14.HRMS:m / z of[M+Na] + caculated for C 25 H 18 F2O2 411.1171, found411.1171.

[0104] Embodiment 14

[0105] (1) The preparation of 3-phenylpentane-2,4-dione was carried out in the same manner as step (1) in Example 9.

[0106] (2) Preparation of (1E, 6E)-4-phenyl-1,7-bis(2,4-fluorophenyl)hept-1,6-diene-3,5-dione

[0107] Dissolve 200 mg (1.14 mmol) of 3-phenylpentane-2,4-dione in 3 mL of DMF, add 322.6 mg (2.27 mmol) of 2,4-difluorobenzaldehyde, 35.1 mg (0.57 mmol) of boric acid, 484.3 mg (2.27 mmol) of tributyl borate and 41.5 mg (0.57 mmol) of n-butylamine, stir at 80°C for 3 hours, add 30 mL of 20% acetic acid aqueous solution, stir for 3 hours, filter and collect the residue. Recrystallize with methanol and dry to obtain 361.2 mg of orange-yellow solid powder with a yield of 89.4%. 1 H NMR(400MHz,Chloroform-d)δ7.77(d,J=15.9Hz,1H),7.62(d,J=16.0Hz,2H),7.51-7.43(m,2H),7.40-7.35(m,1H),7.32- 7.15(m,4H),7.04(d,J=44.1Hz,1H),6.84-6.71(m,3H),6.53(d,J=15.9Hz,1H),6.28-6.16(m,1H),3.90(t,J=7.3Hz,1H). 13 C NMR (101MHz, DMSO-d6) δ182.23,173.22,160.28,160.15,134.39,133.38,132.31,132.26,132.14,131. 91,129.25,128.63,128.45,124.48,119.63,119.55,117.16,113.19,112.97,105.58,105.32,105.06. 19 F NMR(282MHz, DMSO-d6)δ-105.91(p,J=9.1Hz),-106.42--106.56(m),-110.07(q,J=9.9Hz),-110.51--110.70(m).HRMS:m / z of[M+Na] + caculated for C 25 H 16 F4O2 447.0992, found 447.0992.

[0108] Test Example 1

[0109] The research methods and results of the cell proliferation activity of curcumin derivatives A1-A8 and B1-B6 are as follows:

[0110] 1. Preparation of experimental drugs: The curcumin derivatives prepared in Examples 1-14 of the present invention were dissolved in dimethyl sulfoxide to prepare a solution with a concentration of 4 mmol / L. DMEM medium was then used to dilute the curcumin derivatives of different concentrations to 1.25, 2.5, 5, 10, 20 and 40 μmol / L. ASC-JM17 and ASC-J9 were also diluted to 6 groups of concentrations in the same manner.

[0111] 2. Cell lines: human hepatoma cells (HepG2) and mouse embryonic fibroblasts (3T3).

[0112] 3. Cell activity experiment:

[0113] The killing effect of different concentrations of curcumin derivatives on cells was detected by the MTT method. When the cells grew to logarithmic, they were digested and resuspended with trypsin, the cell solution was diluted to a concentration of 50,000 / mL, and 100 μL was inoculated into a 96-well plate. After incubation for 24 hours, different concentrations of ASC-JM17, ASC-J9 and curcumin derivatives were added, and 4 parallel groups were set for each concentration, and the corresponding blank control group was set, and incubated in a 37°C constant temperature incubator for 24 hours. Without removing the culture medium, MTT (5 mg / mL) 20uL / well was added, cultured for 4 hours, the culture medium was removed, 200uL DMSO was added to each well, the shaker was shaken at low speed for 30 minutes, and the absorbance was detected at 490nm by an enzyme reader.

[0114] The results showed that the IC values ​​of ASC-JM17 and ASC-J9 for HepG2 cells 50 were 29.86 and 33.577 μM, while the IC 50 The values ​​were 6.49, 12.27, and 14.13 μM, respectively, with stronger HepG2 cell inhibition. The cancer cell inhibition activities of ASC-JM17, ASC-J9, and turmeric derivatives are shown in Table 1.

[0115] Table 1. Cancer cell inhibitory activity of ASC-JM17, ASC-J9 and curcumin derivatives

[0116]

[0117] According to the killing effect of curcumin derivatives on cancer cells, curcumin derivatives A1-A3 were selected to perform MTT experiments on 3T3 cells. The results showed that the IC 50 The value was 25.54, which was significantly higher than its IC for HepG2 cells 50 IC values ​​of ASC-JM17 and ASC-J9 for 3T3 cells 50 The values ​​were also higher than the IC values ​​for 22Rv1 cells and HepG2 cells.50 The value was higher than that of A2, but the increase was not as significant as that of A2, indicating that the curcumin derivative A2 can more effectively exert a selective anti-tumor effect than ASC-JM17 and ASC-J9. The 3T3 cell inhibitory activity of curcumin derivatives is shown in Table 2.

[0118] Table 2. 3T3 cell inhibitory activity of curcumin derivatives

[0119]

[0120] Finally, the method of the present invention is only a preferred embodiment and is not intended to limit the scope of protection of the present invention. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the scope of protection of the present invention.

Claims

1. A cyclobutylmethyl and phenyl substituted curcumin derivative, characterized in that, The structural formula of the curcumin derivative is shown below: Among them, R1 is cyclobutylmethyl or phenyl. R2 is o-, m-, or p-fluorine, acetylamino, or methanesulfonylamino.

2. The curcumin derivative according to claim 1, characterized in that The chemical names and chemical structural formulas of the curcumin derivatives are as follows: A1: N,N'-(((1E,6E)-4-(cyclobutylmethyl)-3,5-dioxa-1,6-diene-1,7-diyl)bis(4,1-phenyl))diacetylamino A2: N,N'-(((1E,6E)-4-(cyclobutylmethyl)-3,5-dioxa-1,6-diene-1,7-diyl)bis(3,1-phenyl))bismethanesulfonamide A3: N,N'-(((1E,6E)-4-(cyclobutylmethyl)-3,5-dioxa-1,6-diene-1,7-diyl)bis(4,1-phenyl))bismethanesulfonamide A4: (1E, 6E)-4-(cyclobutylmethyl)-1,7-bis(2-fluorophenyl)hepta-1,6-diene-3,5-dione A5: (1E, 6E)-4-(cyclobutylmethyl)-1,7-bis(3-fluorophenyl)hepta-1,6-diene-3,5-dione A6: (1E, 6E)-4-(cyclobutylmethyl)-1,7-bis(4-fluorophenyl)hepta-1,6-diene-3,5-dione A7: (1E, 6E)-4-(cyclobutylmethyl)-1,7-bis(2,4-difluorophenyl)hepta-1,6-diene-3,5-dione A8: (1E, 6E)-4-(cyclobutylmethyl)-1,7-bis(3,4-difluorophenyl)hepta-1,6-diene-3,5-dione B1: N,N'-(((1E,6E)-4-phenyl-3,5-dioxa-1,6-diene-1,7-diyl)bis(4,1-phenyl))diacetylamino B2: N,N'-(((1E,6E)-4-phenyl-3,5-dioxadiene-1,6-diene-1,7-diyl)bis(3,1-phenyl))bismethanesulfonamide B3: N,N'-(((1E,6E)-4-phenyl-3,5-dioxadiene-1,6-diene-1,7-diyl)bis(4,1-phenyl))bismethanesulfonamide B4: (1E, 6E)-4-phenyl-1,7-bis(2-fluorophenyl)hepta-1,6-diene-3,5-dione B5: (1E, 6E)-4-phenyl-1,7-bis(4-fluorophenyl)hepta-1,6-diene-3,5-dione B6: (1E, 6E)-4-phenyl-1,7-bis(2,4-difluorophenyl)hepta-1,6-diene-3,5-dione 3. The curcumin derivative according to claim 1, characterized in that The preparation method of the curcumin derivative comprises the following steps: (1) Preparation of acetylacetone derivatives: acetylacetone, bromide and base are added to a solvent, and heated and stirred to react in the dark; after the reaction, the solvent is removed by rotary evaporation, and the acetylacetone derivative is separated and purified by vacuum distillation to obtain the acetylacetone derivative; (2) Preparation of curcumin derivatives: The acetylacetone derivative prepared in step (1), boric acid, tributyl borate, n-butylamine and benzaldehyde with different substituents are added to a solvent, and heated and stirred to react in the dark; after the reaction, 20% acetic acid aqueous solution is added and stirred, and the residue is filtered and collected, and the product is recrystallized to obtain a curcumin derivative.

4. The curcumin derivative according to claim 3, characterized in that In step (1), the brominated compound is: bromomethylcyclobutane, bromobenzene.

5. The curcumin derivative according to claim 3, characterized in that In step (1), the molar ratio of acetylacetone, bromide and base is 1:1-1.2:2-3; and the solvent is N,N-dimethylformamide and isopropanol.

6. The curcumin derivative according to claim 3, characterized in that In step (1), the temperature of the heating and stirring reaction is 25 to 60° C.; and the time of the heating and stirring reaction is 8 to 12 hours.

7. The curcumin derivative according to claim 3, characterized in that In step (2), the benzaldehydes with different substituents are: p-acetamidobenzaldehyde, 3-methanesulfonylaminobenzaldehyde, p-methanesulfonylaminobenzaldehyde, 2-fluorobenzaldehyde, 3-fluorobenzaldehyde, 4-fluorobenzaldehyde, 2,4-difluorobenzaldehyde, and 3,4-difluorobenzaldehyde.

8. The curcumin derivative according to claim 3, characterized in that In step (2), the molar ratio of the acetylacetone derivative, benzaldehyde with different substituents, boric acid, tributyl borate and n-butylamine is 1:2-2.5:0.5-1:2-2.5:1-1.5; and the solvent is N,N-dimethylformamide.

9. The curcumin derivative according to claim 3, characterized in that In step (2), the temperature of the heating and stirring reaction is 25 to 80° C., and the time of the heating and stirring reaction is 2 to 5 hours.

10. A use of the curcumin derivative according to claim 1, characterized in that: The curcumin derivative is used for preparing an anti-tumor medicament.

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