Cinnamic acid Yunnan hedychin A derivative as well as preparation method and application thereof

Abstract

The invention provides a cinnamic acid Yunnan hedychin A derivative which is a derivative of a natural product and has cytotoxic activity on tumor cells.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to a cinnamic acid dianthin A derivative. Background Art

[0002] The mortality rate caused by malignant tumors is the second highest among all diseases, second only to cardiovascular and cerebrovascular diseases. Chemotherapy plays an important role in the three major treatments for malignant tumors, but there are many adverse reactions to the drugs currently used in chemotherapy, and new, effective and safe tumor treatment drugs are urgently needed. Terpene natural compounds extracted from medicinal plants, fruits and vegetables have many biological activities, such as anti-tumor, anti-inflammatory, liver protection, antiviral, anti-diabetic, antibacterial and anti-parasitic, and have become a hot topic of research in recent years.

[0003] Zingiberaceae plants are an important source of diterpenes, sesquiterpenes and monoterpenes. Among them, plants such as Zingiber, Curcuma, Zingiber officinale, Alpinia officinalis, Kaempferia galanga and Cardamom are rich in diterpenes. Domestic and foreign studies have found that this type of diterpenoid compounds have a variety of biological activities, such as antibacterial, anti-inflammatory, cytotoxic and anti-tumor activities, but have defects such as low anti-tumor activity, poor water solubility and low bioavailability. Therefore, it is of great scientific research value and social benefit to modify their chemical structure and develop them into excellent anti-tumor drug candidates. Summary of the invention

[0004] In order to solve the technical problem that natural compounds have low anti-tumor activity, the present invention provides a cinnamic acid dianthin A derivative having high cytotoxic activity against tumor cells.

[0005] In order to achieve the purpose of the present invention, the technical solution adopted by the present invention is:

[0006] A cinnamic acid dianginol A derivative, the structure of which is as follows:

[0007]

[0008] Wherein, R is H, -CH3 or halogen.

[0009] The specific structure of the cinnamic acid dianthin A derivative of the present invention is as follows:

[0010]

[0011] Wherein, R is H, -CH3 or fluorine.

[0012] The invention discloses use of the cinnamic acid dianthin A derivative in the preparation of anti-tumor drugs.

[0013] Preferably, the anti-tumor drug is used to treat human acute promyelocytic leukemia, liver cancer, breast cancer, colon cancer and lung cancer.

[0014] The preparation method of the cinnamic acid dianthin A derivative of the present invention comprises the following steps:

[0015] A. A cinnamic acid chloride compound is reacted with diangingerol A to undergo chlorination reaction. After the reaction is complete, a Na2CO3 solution is added to the reaction solution to remove excess chlorine. The mixture is stirred and extracted. The mixture is dried with anhydrous Na2SO4 and concentrated and recovered. The mixture is separated and eluted by silica gel column chromatography to obtain an intermediate product.

[0016] B. Dissolve the intermediate product in an organic solvent, add rose bengal, introduce oxygen, and stir to react under LED light. After the reaction is complete, recover and concentrate the solvent, separate and elute through silica gel column chromatography to obtain the product.

[0017] Preferably, in the step A, potassium carbonate or cesium carbonate is first added to the cinnamoyl chloride compound to absorb the moisture in the reagent, and then the dianthin A is added after ultrasonic treatment for 10-30 minutes.

[0018] Preferably, the extractant in step A is ethyl acetate, and after drying and concentration, petroleum ether:ethyl acetate is used for secondary elution.

[0019] Preferably, the organic solvent in step B is pyridine or dichloromethane.

[0020] Preferably, the eluent in step B is petroleum ether:ethyl acetate, and the mixture is first separated by chromatography on a neutral alumina column and then by secondary chromatography on a silica gel column. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 is the hydrogen spectrum of compound A3.

[0022] Figure 2 is the carbon spectrum of compound A3. DETAILED DESCRIPTION

[0023] In order to more clearly and in detail illustrate the technical solution of the present invention, the present invention is further described below through relevant embodiments. The following embodiments are only for specific explanation of the implementation method of the present invention, and do not limit the protection scope of the present invention.

[0024] Example 1

[0025] A cinnamic acid dianginol A derivative, the structure of which is as follows:

[0026]

[0027] Wherein, R is H, -CH3 or halogen.

[0028] Example 2

[0029] The present invention synthesized the following compound structure:

[0030]

[0031]

[0032]

[0033] Example 3

[0034] Synthesis of Compound A1

[0035] Take an appropriate amount of phenylpropionyl chloride and a small amount of potassium carbonate to absorb the water in the reagent. After ultrasonication for 30 minutes, add 244.5 mg of Yunnan ginger flower A, heat and stir in an oil bath at 50°C for 45 minutes, and TLC detection shows that the reaction raw materials are completely consumed. Add 8% Na2CO3 aqueous solution to the reaction solution and stir until tasteless. Extract with ethyl acetate, wash once with water, collect the ethyl acetate layer, remove water with anhydrous Na2SO4, dry, concentrate and recover, separate by 200-300 mesh silica gel column chromatography, and elute with petroleum ether: ethyl acetate (30:1) to obtain compound A1.

[0036] Compound A1: white powder, yield 77%; 1 H NMR(400MHz,(CD3)2CO):0.96(3H,s,H-18); 0.97(3H,s,H-19); 1.20(3H,s,H-2 0);2.94(1H,d,J=9.6Hz,H-9);6.17(1H,dd,J=15.7,9.6Hz,H-11);6.28(1H,d, J=15.7Hz,H-12);6.75(1H,s,H-14);7.49(1H,d,s,H-15);7.55(1H,s,H-16);5 .48(1H,s,H-17a); 5.48(1H,s,H-17b); 7.18(1H,m,H-7'); 7.24(2H,m,H-6'and 8');7.28(2H,m,H-5'and 9'). 13C NMR (100MHz, CDCl3): δ42.84(C-1),19.82(C-2),43.62(C-3),34.78(C-4),56.00(C-5),71.25(C-6),44.84(C- 7),146.75(C-8),62.22(C-9),40.92(C-10),123.21(C-11),128.92(C-12),125.53(C-13),108.54(C-14),140 .94(C-15),144.40(C-16),111.91(C-17),33.56(C-18),23.87(C-19),17.88(C-20),172.33(C-1'),37.14(C- 2'),31.46(C-3'),141.69(C-4'),129.09(C-5'),129.20(C-6'),128.08(C-7'),129.20(C-8'),129.09(C-9').

[0037] Synthesis of cinnamic acid dianthin A derivative (compound A3)

[0038]

[0039] Add 400.4 mg of dianthin A and 4.0 g of p-methylcinnamoyl chloride to a flask, stir at 80°C for 1 hour, add 100 mL of 8% Na2CO3 solution at room temperature, and stir for 4 hours. Combine the ethyl acetate extracts, dry over anhydrous Na2SO4, and concentrate. The residue is chromatographed on neutral alumina and eluted with petroleum ether / ethyl acetate (40:1) to obtain compound A2.

[0040] Compound A2: white powder, yield 27.07%; 1H NMR (400MHz, (CD3)2CO): 1.01 (3H, s, H-18); 1.05 (3H, s, H-19); 1.32 (3H, s, H-20); 2.61 (1H, d, J = 9.6 Hz, H-9); 6.22 (1H, dd, J = 15.7, 10.0 Hz, H-11); 6.33 (1H, d, J = 15.7, H-12); 6.76 (1H, s, H-14);7.50(1H,d,s,H-15);7.57(1H,s,H-16);4.75(1H,s,H-17a);4.81(1H,s,H-17b);6.56 (1H,d,J=16.1Hz,H-2'); 7.45(1H,d,J=16.1Hz,H-3'); 7.70(1H,m,H-7'); 7.44(2H,m,H-6'and 8');7.66(2H,m,H-5'and 9').13C NMR (100MHz, CDCl3): δ42.95(C-1),19.87(C-2),43.67(C-3),34.89(C-4),56.18(C-5),71.13(C-6),44.88(C- 7),146.89(C-8),62.27(C-9),40.96(C-10),123.29(C-11),128.09(C-12),125.54(C-13),108.55(C-14),140. 96(C-15),144.41(C-16),110.96(C-17),33.62(C-18),23.97(C-19),18.10(C-20),166.45(C-1'),119.80(C-2 '),145.15(C-3'),135.32(C-4'),129.80(C-5'),131.18(C-6'),129.00(C-7'),129.80(C-8'),131.18(C-9').

[0041] 160.0 mg of compound A2 was dissolved in 15 mL of pyridine, 0.5 mg of rose bengal was added, oxygen was introduced, and the reaction was stirred for 1 h under LED light. TLC detected that the reaction raw materials were completely consumed. After the solvent was recovered and concentrated, the sample was separated by 200-300 mesh silica gel atmospheric pressure column chromatography, eluted with petroleum ether: ethyl acetate (4:1-2:1) gradient, and then purified by 200-300 mesh silica gel treated with disodium hydrogen phosphate to separate compounds A3 and A4.

[0042] Compound A3: white powder, yield 16.03%; 1H NMR(400MHz,(CD3)2CO):0.97(3H,s,H-18); 1.00(3H,s,H-19); 1.31(3H,s,H-20); 2.33(3H ,s,H-10'); 2.67(1H,d,J=10.2Hz,H-9); 6.73(1H,dd,J=16.1,10.2Hz,H-11); 6.37(1H,d,J= 16.1,H-12);5.93(1H,s,H-14);5.57(1H,d,s,H-16);4.69(1H,s,H-17a);4.79(1H,s,H-17b ); 6.43 (1H, d, J = 16.0Hz, H-2'); 7.60 (1H, d, J = 16.0Hz, H-3'); 7.21 (2H, d, J = 8.0Hz, H-5'and 9'); 7.50 (2H, d, J = 8.0Hz, H-6'and 8'). 13 C NMR (100MHz, CDCl3): δ42.70(C-1),19.75(C-2),43.62(C-3),34.82(C-4),55.81(C-5),71.14(C-6),44.68(C- 7),145.94(C-8),62.54(C-9),41.23(C-10),142.81(C-11),124.29(C-12),162.81(C-13),116.19(C-14),172. 06(C-15),98.80(C-16),111.50(C-17),33.46(C-18),23.81(C-19),19.64(C-20),166.91(C-1'),118.34(C-2 '),145.41(C-3'),141.65(C-4'),128.96(C-5'),130.38(C-6'),132.45(C-7'),130.38(C-8'),128.96(C-9').

[0043] Compound A4: white powder, yield 25.36%, 1H NMR(400MHz,(CD3)2CO):0.90(3H,s,H-18); 1.04(3H,s,H-19); 1.31(3H,s,H-20); 2.35(3H ,s,H-10'); 2.60(1H,d,J=10.2Hz,H-9); 7.10(1H,dd,J=15.9,10.2Hz,H-11); 6.23(1H,d,J= 15.9,H-12);7.17(1H,s,H-14);5.60(1H,d,s,H-15);4.68(1H,s,H-17a);4.81(1H,s,H-17b ); 6.48(1H,d,J=16.0Hz,H-2'); 7.64(1H,d,J=16.1Hz,H-3'); 7.24(2H,d,J=8.0Hz,H-5'and 9'); 7.55 (2H, d, J = 8.0Hz, H-6'and 8'). 13 C NMR (100MHz, CDCl3): δ42.86(C-1),19.82(C-2),43.68(C-3),34.89(C-4),55.95(C-5),71.05(C-6),44.79(C- 7),146.39(C-8),62.65(C-9),41.01(C-10),137.84(C-11),122.25(C-12),132.03(C-13),144.23(C-14),97.5 1(C-15),170.61(C-16),111.21(C-17),33.63(C-18),23.95(C-19),18.18(C-20),166.61(C-1'),118.60(C-2 '),145.24(C-3'),141.55(C-4'),129.07(C-5'),130.45(C-6'),132.58(C-7'),130.45(C-8'),129.07(C-9').

[0044] Synthesis of cinnamic acid dianthin A derivative (compound A6)

[0045]

[0046] Take an appropriate amount of cinnamoyl chloride and a small amount of potassium carbonate, ultrasonicate for 10 minutes, add 236.0 mg of Yunnan ginger flower A, heat and stir in an oil bath at 70 ° C for 30 minutes, and TLC detects that the reaction raw materials are completely consumed. Add 8% Na2CO3 aqueous solution to the reaction solution and stir until tasteless. Extract with ethyl acetate, wash once with water, collect the ethyl acetate layer, remove water with anhydrous Na2SO4, dry, concentrate and recover, and separate by 300-400 mesh silica gel column chromatography, elute with petroleum ether: ethyl acetate (25:1) to obtain compound A5.

[0047] Compound A5: white powder, yield 59.51%; 1 H NMR(400MHz,(CD3)2CO):1.02(3H,s,H-18); 1.06(3H,s,H-19); 1.32(3H,s,H-20); 2.61(1H,d ,J=9.6Hz,H-9); 6.22(1H,dd,J=15.7,10.0Hz,H-11); 6.33(1H,d,J=15.7Hz,H-12); 6.76(1H,s ,H-14);7.50(1H,d,s,H-15);7.57(1H,s,H-16);4.75(1H,s,H-17a);4.81(1H,s,H-17b);6.56 (1H,d,J=16.1Hz,H-2'); 7.45(1H,d,J=16.1Hz,H-3'); 7.70(1H,m,H-7'); 7.44(2H,m,H-6'and 8');7.66(2H,m,H-5'and 9'). 13 C NMR (100MHz, CDCl3): δ42.95(C-1),19.87(C-2),43.67(C-3),34.89(C-4),56.18(C-5),71.13(C-6),44.88(C- 7),146.89(C-8),62.27(C-9),40.96(C-10),123.29(C-11),128.09(C-12),125.54(C-13),108.55(C-14),140. 96(C-15),144.41(C-16),110.96(C-17),33.62(C-18),23.97(C-19),18.10(C-20),166.45(C-1'),119.80(C-2 '),145.15(C-3'),135.32(C-4'),129.80(C-5'),131.18(C-6'),129.00(C-7'),129.80(C-8'),131.18(C-9').

[0048] 200.00 mg of compound A5 was dissolved in 50 ml of dichloromethane, 1 ml of NN-diisopropylethylamine and an appropriate amount of TPP were added, oxygen was introduced after stirring, and the mixture was reacted for 5 hours under low temperature device (-45°C) and LED light irradiation. TLC detected that the reaction raw materials were completely consumed. After the reaction solution recovered the solvent, it was separated by 300-400 mesh silica gel atmospheric pressure column chromatography and eluted with petroleum ether: ethyl acetate (6:1-1:1) gradient to obtain compound A6.

[0049] Compound A6: white powder, yield 24.52%, 1 H NMR(400MHz,(CD3)2CO):1.01(3H,s,H-18); 1.05(3H,s,H-19); 1.34(3H,s,H-20) ;2.71(1H,d,J=9.6Hz,H-9); 6.79(1H,dd,J=16.1,10.2Hz,H-11); 5.98(1H,s,H-14 ); 5.62 (1H, d, s, H-16); 4.74 (1H, s, H-17a); 4.84 (1H, s, H-17b); 6.46 (1H, d, J = 16 .0Hz,H-2'); 6.54(1H,d,J=16.0Hz,H-3'); 7.43(1H,m,H-7'); 7.66(2H,m,H-6'and 8');7.68(2H,m,H-5'and 9'). 13 C NMR (100MHz, CDCl3): δ42.79(C-1),19.84(C-2),43.64(C-3),34.92(C-4),55.81(C-5),71.13(C-6),44.74(C- 7),146.00(C-8),62.55(C-9),41.31(C-10),142.62(C-11),124.39(C-12),162.50(C-13),116.46(C-14),171. 34(C-15),98.58(C-16),111.66(C-17),33.62(C-18),23.96(C-19),18.22(C-20),171.34(C-1'),119.69(C-2 '),145.27(C-3'),135.27(C-4'),129.82(C-5'),131.23(C-6'),129.04(C-7'),131.23(C-8'),129.82(C-9').

[0050] Synthesis of Compound A7

[0051] Take an appropriate amount of phenylacetyl chloride and a small amount of potassium carbonate, ultrasonicate for 30 minutes, add 218.5 mg of Yunnan ginger flower A, heat and stir in an oil bath at 55 ° C for 30 minutes, and detect that the reaction raw materials are completely consumed by TLC. Add 8% Na2CO3 aqueous solution to the reaction solution and stir until tasteless. Extract with ethyl acetate, wash once with water, collect the ethyl acetate layer, remove water with anhydrous Na2SO4, dry, concentrate and recover, and separate by 200-300 mesh silica gel column chromatography, elute with petroleum ether: ethyl acetate (30:1) to obtain compound A7.

[0052] Compound A7: yield was 92.4%, 1 H NMR(400MHz,(CD3)2CO):0.92(3H,s,H-18); 0.95(3H,s,H-19); 1.10(3H,s,H-2 0); 2.52 (1H, d, J = 9.7Hz, H-9); 6.15 (1H, dd, J = 15.8, 9.7Hz, H-11); 6.28 (1H, d, J=15.8Hz,H-12);6.74(1H,s,H-14);7.48(1H,d,s,H-15);7.54(1H,s,H-16);4 .65(1H,s,H-17a); 4.67(1H,s,H-17b); 7.24(1H,m,H-6'); 7.30(2H,m,H-5'and 7');7.31(2H,m,H-4'and 8'). 13 C NMR (100MHz, CDCl3): δ42.81(C-1),19.82(C-2),43.63(C-3),34.76(C-4),56.04(C-5),71.62(C-6),44.83 (C-7),146.58(C-8),62.24(C-9),40.93(C-10),123.20(C-11),128.63(C-12),125.52(C-13),108.55(C-1 4),140.94(C-15),144.41(C-16),111.95(C-17),33.60(C-18),23.91(C-19),17.81(C-20),171.14(C-1') ,42.65(C-2'),135.34(C-3'),130.27(C-4'),129.16(C-5'),128.06(C-6'),129.16(C-7'),130.27(C-8').

[0053] Synthesis of cinnamic acid dianthin A derivative (compound A9)

[0054] Take an appropriate amount of 4-fluorocinnamoyl chloride and a small amount of cesium carbonate, ultrasonicate for 10 minutes, add 165.4 mg of Yunnan ginger flower A, heat and stir in an oil bath at 70 ° C for 1.5 hours, and detect that the reaction raw materials are completely consumed by TLC. Add 8% Na2CO3 aqueous solution to the reaction solution and stir. Extract with ethyl acetate, wash with water once, collect the ethyl acetate layer, remove water and dry with anhydrous Na2SO4, concentrate and recover, and separate by 200-300 mesh neutral alumina column chromatography, elute with petroleum ether: ethyl acetate (40:1) to remove the remaining 4-fluorocinnamoyl chloride. Separate by 300-400 mesh silica gel column chromatography, elute with petroleum ether: ethyl acetate (30:1) to obtain compound A8.

[0055] Compound A8: 1 H NMR(400MHz,(CD3)2CO):1.00(3H,s,H-18); 1.04(3H,s,H-19); 1.28(3H,s,H-20); 2.60(1H ,d,J=9.5Hz,H-9); 6.23(1H,dd,J=15.7,9.5Hz,H-11); 6.33(1H,d,J=15.7Hz,H-12); 6.76(1 H,s,H-14);7.50(1H,d,s,H-15);7.56(1H,s,H-16);4.74(1H,s,H-17a);4.79(1H,s,H-17b ); 6.51 (1H, d, J = 16.0Hz, H-2'); 7.66 (1H, d, J = 16.0Hz, H-3'); 7.20 (2H, d, J = 8.8Hz, H-6'and 8'); 7.76 (2H, d, J = 8.7Hz, H-5'and 9'). 13 C NMR (100MHz, CDCl3): δ142.92(C-1),19.86(C-2),43.65(C-3),34.88(C-4),56.15(C-5),71.37(C-6),44.86(C- 7),146.88(C-8),62.25(C-9),40.94(C-10),123.28(C-11),128.06(C-12),125.53(C-13),108.53(C-14),140. 97(C-15),144.42(C-16),110.95(C-17),33.60(C-18),23.97(C-19),18.09(C-20),166.39(C-1'),119.71(C-2 '),143.85(C-3'),131.85(C-4'),131.31(C-5'),116.79(C-6'),132.56(C-7'),116.79(C-8'),131.31(C-9').

[0056] 84.3 mg of compound A8 was dissolved in 7.5 ml of pyridine, and an appropriate amount of rose bengal was added. Oxygen was introduced and stirred under LED light for 1.0 h. TLC detected that the reaction raw materials were completely consumed. After the solvent was recovered and concentrated, the sample was separated by 200-300 mesh silica gel atmospheric pressure column chromatography, eluted with petroleum ether: ethyl acetate (4:1), and then purified by 200-300 mesh silica gel treated with disodium hydrogen phosphate to separate compounds A9 and A10.

[0057] Compound 9: yield 26.6%, 1 H NMR(400MHz,(CD3)2CO):1.00(3H,s,H-18);1.04(3H,s,H-19);1.32(3H,s,H-20);2.7 1(1H,d,J=10.2Hz,H-9); 6.78(1H,dd,J=16.0,10.2Hz,H-11); 6.51(1H,d,J=16.0Hz,H- 12);5.96(1H,s,H-14);5.61(1H,s,H-16);4.72(1H,s,H-17a);4.83(1H,s,H-17b);6. 46(1H,d,J=16.0Hz,H-2'); 7.66(1H,d,J=16.0Hz,H-3'); 7.20(2H,d,J=8.8Hz,H-6'and 8'); 7.75 (2H, d, J = 8.7Hz, H-5'and 9'). 13 C NMR (100MHz, CDCl3): δ42.76(C-1),19.82(C-2),43.63(C-3),34.91(C-4),55.80(C-5),71.16(C-6),44.74(C- 7),146.00(C-8),62.54(C-9),41.30(C-10),142.60(C-11),124.38(C-12),162.49(C-13),116.46(C-14),171. 33(C-15),98.55(C-16),111.64(C-17),33.59(C-18),23.94(C-19),18.21(C-20),166.39(C-1'),119.62(C-2 '),143.95(C-3'),131.84(C-4'),131.34(C-5'),116.80(C-6'),163.72(C-7'),116.80(C-8'),131.34(C-9').

[0058] Compound 10: yield 44.3%, 1H NMR(400MHz,(CD3)2CO):1.00(3H,s,H-18); 1.03(3H,s,H-19); 1.30(3H,s,H-20); 2.6 1(1H,d,J=10.2Hz,H-9); 7.10(1H,dd,J=15.9,10.2Hz,H-11); 6.23(1H,d,J=15.9Hz,H- 12);7.17(1H,s,H-14);5.61(1H,s,H-16);4.05(1H,s,H-17a);4.68(1H,s,H-17b);6. 51(1H,d,J=16.0Hz,H-2'); 7.65(1H,d,J=16.0Hz,H-3'); 7.20(2H,d,J=8.8Hz,H-6'and 8'); 7.75 (2H, d, J = 8.7Hz, H-5'and 9'). 13 C NMR (100MHz, CDCl3): δ42.83(C-1),19.81(C-2),43.67(C-3),34.88(C-4),55.92(C-5),71.20(C-6),44.78(C- 7),146.35(C-8),62.63(C-9),41.03(C-10),137.81(C-11),122.27(C-12),165.70(C-13),144.27(C-14),97.5 2(C-15),170.62(C-16),111.23(C-17),33.61(C-18),23.95(C-19),18.19(C-20),166.40(C-1'),119.64(C-2 '),143.94(C-3'),132.00(C-4'),131.35(C-5'),116.79(C-6'),163.72(C-7'),116.79(C-8'),131.35(C-9').

[0059] Synthesis of cinnamic acid dianthin A derivative (compound A11)

[0060] The synthesis method is the same as compound A9, using p-chlorocinnamoyl chloride as raw material to react with dianthin A.

[0061] Compound 11: yield 28.9%, 1H NMR(400MHz,(CD3)2CO):1.12(3H,s,H-18);1.03(3H,s,H-19);1.45(3H,s,H-20);2.2 4(1H,d,J=10.2Hz,H-9); 6.69(1H,dd,J=16.0,10.2Hz,H-11); 6.23(1H,d,J=16.0Hz,H- 12);6.25(1H,s,H-14);6.12(1H,s,H-16);5.10(1H,s,H-17a);4.83(1H,s,H-17b);6. 23(1H,d,J=16.0Hz,H-2'); 7.01(1H,d,J=16.0Hz,H-3'); 8.31(2H,d,J=8.8Hz,H-6'and 8'); 7.54 (2H, d, J = 8.7Hz, H-5'and 9'). 13 C NMR (100MHz, CDCl3): δ42.21(C-1),19.82(C-2),44.65(C-3),35.42(C-4),57.12(C-5),70.36(C-6),44.74(C- 7),146.55(C-8),60.12(C-9),42.78(C-10),140.51(C-11),124.38(C-12),166.50(C-13),112.33(C-14),170. 78(C-15),99.00(C-16),111.81(C-17),33.85(C-18),25.42(C-19),20.13(C-20),162.36(C-1'),119.55(C-2 '),143.23(C-3'),130.82(C-4'),131.20(C-5'),112.89(C-6'),160.41(C-7'),116.02(C-8'),129.54(C-9').

[0062] Synthesis of Compound A12

[0063] Weigh 120.8 mg of raw material Yunnan gingerol A, dissolve it in 1.2 ml of tetrahydrofuran, add 0.6 ml of pyridine, add 0.96 ml of octanoyl chloride, react for 2.5 hours in an oil bath at 60 ° C, and detect by TLC until the reaction is complete. Add 10 ml of 10% sodium carbonate aqueous solution to the reaction solution, stir for 2 hours until the excess octanoyl chloride is completely hydrolyzed; then extract the reaction solution with ethyl acetate three times, wash it with distilled water once, collect and combine the ethyl acetate layer, add anhydrous sodium sulfate and place it overnight, and dry it for 12 hours. Filter to remove solid impurities in the organic layer, evaporate the solution to dryness, separate it by 300-400 mesh silica gel column chromatography, and gradient elute it with petroleum ether / chloroform (2:1-1:1). Obtain 120.1 mg of intermediate product.

[0064] 107.7 mg of the intermediate product was weighed and dissolved in 5 ml of pyridine dried with molecular sieves, and an appropriate amount of rose bengal was added. At the same time, oxygen was introduced and stirred. The reaction was carried out under LED light for 3 hours, and TLC was detected until the reaction was complete. After the reaction solution was recovered and concentrated, the sample was separated by atmospheric pressure column chromatography on 200-300 mesh weak alkaline silica gel (containing 8% sodium hydrogen phosphate activated silica gel), and petroleum ether / ethyl acetate (4:1-2:1) gradient elution was used to separate compound A12.

[0065] Compound A12: white powder, yield 30.2%, 1 H NMR(500MHz,(CD3)2CO):0.96(3H,s,H-18);1.04(3H,s,H-19);1.22(3H,s,H-20);2.00(3H,t,H-8');2.66(1H,d,J=8.1Hz,H-9);6.67(1H ,dd,J=15.9,10.2Hz,H-11); 6.44(1H,d,J=15.7Hz,H-12); 5.98(1H,s,H-14); 5.45(1H,d,s,H-16); 4.7(1H,s,H-17a); 4.81(1H,s,H-17b); 13CNMR(125MHz, CDCl3): δ43.68(C-1),19.81(C-2),44.71(C-3),35.52(C-4),55.70(C-5),70.77(C-6),43 .56(C-7),146.07(C-8),62.56(C-9),42.72(C-10),142.58(C-11),124.34(C-12),162.47(C-13),111.47 (C-14),171.30(C-15),98.52(C-16),111.35(C-17),34.85(C-18),23.92(C-19),17.98(C-20),171.98(C -1'),34.83(C-2'),25.67(C-3'),30.12(C-4'),30.28(C-5'),32.41(C-6'),23.23(C-7'),14.31(C-8').

[0066] Synthesis of Compound A13

[0067] Weigh 106mg of p-ethylbenzoic acid, add 8mg of DMAP, dissolve in 6ml of 1,2-dichloroethane dried over anhydrous calcium chloride, add 179.5mg of DIC, stir at room temperature for 30min, and finally add 101.0mg of Yunnan gingerol A. After reacting at room temperature for 7h, TLC detection is performed until the reaction is complete. Hydrolysis: add 1ml of distilled water and 5ml of petroleum ether, continue stirring for 10min and then ultrasonicate for 20min; Extraction: the reaction solution is partitioned once with 15ml of petroleum ether and 10ml of 70% methanol, and then the 70% methanol layer is extracted with 10ml of petroleum ether, and the petroleum ether layers extracted twice are combined; after concentrating the petroleum ether layer, the sample is separated by 300-400 mesh silica gel column chromatography, and the gradient elution is petroleum ether / chloroform (8:1-3:1). 52.9mg of intermediate product is obtained.

[0068] 41.3 mg of the intermediate product was weighed and dissolved in 5 ml of pyridine dried over molecular sieves, an appropriate amount of TPP was added, oxygen was introduced and stirred, and the reaction was carried out under LED light for 4 hours, and TLC was used to detect the reaction until it was complete. After the solvent was recovered and concentrated, the sample was separated by atmospheric pressure column chromatography on 200-300 mesh weak alkaline silica gel (containing 8% sodium hydrogen phosphate activated silica gel), and petroleum ether / ethyl acetate (5:1-0:1) gradient elution was performed to separate compound A13.

[0069] Compound A13: oil, yield 39.2%, 1H NMR(500MHz,(CD3)2CO):0.91(3H,s,H-18);0.98(3H,s,H-19);1.19(3H,s,H-2 0); 3.05 (1H, d, J = 8.1Hz, H-9); 5.87 (1H, t, J = 3.0Hz, H-7); 4.95 (br.s, H-17a); 5 .34(1H,br.s,H-17b); 6.67(1H,dd,J=16.5,10.5Hz,H-11); 5.94(1H,s,H-14); 6.45(1H,d,J=16.5Hz,H-12); 6.44(1H,s,H-16); 8.05(2H,d,J=8.13Hz,H-3'and H-7');7.44(2H,d,J=8.91Hz,H-4'and H-6'); 13 CNMR (125MHz, CDCl3): δ41.02(C-1),19.64(C-2),42.73(C-3),33.90(C-4),59.00(C-5),29.87(C-6),76.11(C -7),146.53(C-8),58.76(C-9),40.08(C-10),141.58(C-11),124.83(C-12),162.35(C-13),116.60(C-14),17 1.25(C-15),98.50(C-16),115.45(C-17),33.47(C-18),21.85(C-19),14.57(C-20),165.60(C-1'),128.87(C -2'),130.34(C-3'),130.34(C-4'),141.69(C-5'),129.36(C-6'),129.52(C-7'),29.48(C-8'),14.64(C-9').

[0070] Antitumor activity screening

[0071] The MTS method was used to screen the biological activity of compound A1-13 against five human tumor cell lines, namely HL-60, SMMC-7721, A-549, MCF-7, and SW480, with cisplatin and paclitaxel as positive controls (experimental results are shown in Table 1). Experimental method: a single cell suspension was prepared with culture medium (DMEM or RMPI1640) containing 10% fetal bovine serum, and 5000 to 10000 cells were inoculated into a 96-well plate in each well, with a volume of 100 μL per well. Adherent cells were cultured for 12 h in advance; a solution of the compound to be tested (a fixed concentration of 40 μM was used for primary screening, and compounds that inhibited tumor cell growth by 50% at this concentration were set to enter gradient rescreening at 5 concentrations) was added, with a final volume of 200 μL per well, and 3 replicate wells were set for each treatment; after culturing at 37°C for 48 h, the culture supernatant in the well was carefully aspirated, 20 μL of MTS solution and 100 μL of culture medium were added to each well, and the incubation continued for 4 h to allow the reaction to proceed fully; a wavelength of 490 nm was selected, and the light absorption value of each well was read by an enzyme-linked immunosorbent assay (Bio-Rad 680), and the results were recorded. A cell growth curve was drawn with concentration as the horizontal axis and cell survival rate as the vertical axis, and the IC of the compound was calculated using the two-point method (Reed and Muench method) 50 value.

[0072] Table 1 IC50 of the test compounds on the proliferation of HL-60, SMMC-7721, A-549, MCF-7 and SW480 tumor cells 50 (μM)

[0073]

[0074] As can be seen from Table 1, the cinnamic acid-based dianthin A derivative compounds having the mother core structure of the present invention all exhibited anti-tumor activity, and had significant activity against five tumor cell lines (human myeloblastic acute leukemia cells HL-60, human liver cancer cells SMMC-7721, human lung cancer cells A549, human breast cancer cells MCF-7 and human colon cancer cells SW480). In particular, the biological activities of compounds A3, A6 and A9 against SMMC-7721, A549, MCF-7 and SW480 cell lines were better than cisplatin.

[0075] The Yunnan gingerol A of the present invention is purchased from Shanghai Qincheng Biotechnology Co., Ltd., and the organic reagents (chemically pure) used are all purchased from the Chemical Reagent Glass Instrument Purchasing Station of Kunming Pharmaceutical Company, and are all analytically pure; the column chromatography silica gel is silica gel H and 200-300 mesh and 300-400 mesh silica gel produced by Qingdao Ocean Chemical Plant, and the thin layer chromatography silica gel is silica gel G produced by Qingdao Ocean Chemical Plant.

[0076] The above-mentioned embodiments only express the specific implementation of the present invention, and the description thereof is relatively specific and detailed, but it cannot be understood as limiting the scope of the present invention. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, which all belong to the protection scope of the present invention.

Claims

1. A cinnamic acid dianthin A derivative, characterized in that: The structure is as follows: Wherein, R is H, -CH3 or halogen.

2. The cinnamic acid dianthin A derivative according to claim 1, characterized in that: The specific structure is as follows: Wherein, R is H, -CH3 or fluorine.

3. Use of the cinnamic acid dianganin A derivative according to claim 1 or 2 in the preparation of anti-tumor drugs.

4. Use of the cinnamic acid dianganin A derivative according to claim 3 in the preparation of anti-tumor drugs, characterized in that: The anti-tumor drug is used for treating human acute promyelocytic leukemia, liver cancer, breast cancer, colon cancer and lung cancer.

5. The method for preparing the cinnamic acid dianganin A derivative according to claim 1 or 2, characterized in that: The following steps are involved: A. A cinnamoyl chloride compound is reacted with diangingerol A to undergo chlorination reaction. After the reaction is complete, a Na2CO3 solution is added to the reaction solution, and the mixture is stirred and extracted. The mixture is dried with anhydrous Na2SO4, concentrated and recovered, and separated and eluted by silica gel column chromatography to obtain an intermediate product. B. Dissolve the intermediate product in an organic solvent, add rose bengal, introduce oxygen, and stir to react under LED light. After the reaction is complete, recover and concentrate the solvent, separate and elute through silica gel column chromatography to obtain the product.

6. The method for preparing the cinnamic acid dianthin A derivative according to claim 5, characterized in that: In the step A, potassium carbonate or cesium carbonate is first added to the cinnamoyl chloride compound, and then ultrasonicated for 10-30 minutes, and then dianthin A is added.

7. The method for preparing the cinnamic acid dianthin A derivative according to claim 5, characterized in that: The extractant in step A is ethyl acetate, and after drying and concentration, petroleum ether:ethyl acetate is used for secondary elution.

8. The method for preparing the cinnamic acid dianthin A derivative according to claim 5, characterized in that: The organic solvent in step B is pyridine or dichloromethane.

9. The method for preparing the cinnamic acid dianthin A derivative according to claim 5, characterized in that: The eluent of step B is petroleum ether:ethyl acetate, and the mixture is first separated by chromatography on a neutral alumina column and then by secondary chromatography on a silica gel column.

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