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

Abstract

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

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly relates to a hedychium coronarium j. koenig var. zerumbet (pers.) bak. var. flavum roscoe A derivative. Background Art

[0002] Malignant tumors are major diseases threatening the health and lives of humans globally, the main cause of human death in various countries around the world, and one of the most challenging current public health problems, imposing a huge economic and social burden. Chemotherapy plays an important role among the three major therapies for malignant tumors. However, the drugs currently used in chemotherapy have many adverse reactions, and there is an urgent need for new, effective, and safe anti-tumor drugs. Natural products and their derivatives are not only important sources of anti-tumor drugs or lead compounds, but also have low toxicity, which is of great significance for the search for drugs. Summary of the Invention

[0003] To solve the above technical problems, the present invention provides a hedychium coronarium j. koenig var. zerumbet (pers.) bak. var. flavum roscoe A derivative, which is a derivative of a natural product and has cytotoxic activity against tumor cells.

[0004] To achieve the object of the present invention, the technical solution adopted by the present invention is:

[0005] A hedychium coronarium j. koenig var. zerumbet (pers.) bak. var. flavum roscoe A derivative has the following structure:

[0006]

[0007] Wherein, R1 is -C 2 H 4 - or -CH 2 -

[0008] R2 is H, -CH 3 or a halogen.

[0009] The specific structure of the hedychium coronarium j. koenig var. zerumbet (pers.) bak. var. flavum roscoe A derivative of the present invention is as follows:

[0010] or

[0011] The use of the hedychium coronarium j. koenig var. zerumbet (pers.) bak. var. flavum roscoe A derivative of the present invention in the preparation of anti-tumor drugs.

[0012] Preferably, the anti-tumor drug is used for the treatment of human acute promyelocytic leukemia, liver cancer, breast cancer, colon cancer, and lung cancer.

[0013] The preparation method of the hedychium coronarium j. koenig var. zerumbet (pers.) bak. var. flavum roscoe A derivative of the present invention includes the following steps:

[0014] A. Take phenylpropionyl chloride or phenylacetyl chloride, add potassium carbonate to absorb the moisture present in the reagent. After ultrasonic treatment for 30 min, add hedychium coronarium ketone A and react at 50 - 55 °C. After the reaction is complete, add Na 2 CO 3 solution to remove the excess acyl chloride and stir until odorless; after extraction, use anhydrous Na 2 SO 4 to remove water and dry. After concentration and recovery, separate by silica gel column chromatography, elute to obtain the intermediate product;

[0015] B. Dissolve the intermediate product in pyridine, add the photosensitizer rose bengal to promote the photosensitized oxidation reaction, introduce oxygen and stir the reaction under LED light irradiation. After the reaction is complete, recover and concentrate the solvent, separate by silica gel column chromatography, elute, and then purify with silica gel treated with disodium hydrogen phosphate to separate and obtain the product.

[0016] Preferably, the extractant in step A is ethyl acetate.

[0017] Preferably, the eluent in step A is petroleum ether:ethyl acetate with a volume ratio of 30:1.

[0018] Preferably, in step B, gradient elution is carried out with petroleum ether:ethyl acetate in a ratio of 4:1 - 2:1. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 It is the hydrogen spectrum diagram of compound A2.

[0020] Figure 2 It is the carbon spectrum diagram of compound A2. DETAILED DESCRIPTION OF THE INVENTION

[0021] In order to more clearly and detailedly illustrate the technical solution of the present invention, the present invention is further described below through relevant embodiments. The following embodiments are only for specifically illustrating the implementation method of the present invention and do not limit the protection scope of the present invention.

[0022] Example 1

[0023] A hedychium coronarium ketone A derivative has the following structure:

[0024]

[0025] Among them, R1 is -C 2 H 4 - or -CH 2 -

[0026] R2 is H, -CH 3 or halogen.

[0027] Example 2

[0028] The present invention synthesizes the following compound structures:

[0029]

[0030]

[0031]

[0032] Example 3

[0033] Synthesis of Hedychium coronarium J. Koenig A Derivative (Compound A2)

[0034]

[0035] Take an appropriate amount of phenylpropionyl chloride and a small amount of potassium carbonate. After ultrasonic treatment for 30 min, add 244.5 mg of Hedychium coronarium J. Koenig A, heat and stir in an oil bath at 50 °C for 45 min, and detect by TLC that the reaction raw materials are completely consumed. Add 8% Na 2 CO 3 aqueous solution, stir until odorless. Extract with ethyl acetate, wash once with water, collect the ethyl acetate layer, and use anhydrous Na 2 SO 4 to remove water and dry. After concentration and recovery, separate by silica gel column chromatography with 200 - 300 mesh, elute with petroleum ether:ethyl acetate (30:1) to obtain Compound A1.

[0036] Compound A1: White powder, yield 77%; 1 H NMR(400MHz,(CD 3 ) 2 CO):0.96(3H,s,H-18);0.97(3H,s,H-19);1.20(3H,s,H-20);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’). 13 C NMR(100MHz,CDCl 3): δ 42.84 (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] Dissolve 153.6 mg of compound A1 in 15 ml of pyridine, add an appropriate amount of rose bengal, introduce oxygen, stir and react under LED light irradiation for 1.5 h, and detect by TLC that the reaction raw materials are completely consumed. After recovering and concentrating the solvent, the sample is separated by normal pressure column chromatography on 200 - 300 mesh silica gel, eluted with a gradient of petroleum ether: ethyl acetate (4:1 - 2:1), and then purified by 200 - 300 mesh silica gel treated with disodium hydrogen phosphate to obtain compounds A2 and A3.

[0038] Compound A2: light yellow transparent solid, yield 18.8%, 1 H NMR (400 MHz, (CD 3 ) 2 CO): 0.96 (3H, s, H-18); 0.97 (3H, s, H-19); 1.21 (3H, s, H-20); 2.96 (1H, d, J = 10.6 Hz, H-9); 6.73 (1H, dd, J = 16.0, 10.2 Hz, H-11); 6.43 (1H, d, J = 15.6 Hz, H-12); 6.00 (1H, s, H-14); 5.47 (1H, s, H-16); 4.67 (1H, s, H-17a); 4.71 (1H, s, H-17b); 7.18 (1H, m, H-7'); 7.23 (2H, m, H-6' and 8'); 7.22 (2H, m, H-5' and 9'). 13 C NMR (100 MHz, CDCl 3): δ 42.69 (C-1), 19.80 (C-2), 43.60 (C-3), 34.82 (C-4), 55.65 (C-5), 71.07 (C-6), 44.72 (C-7), 145.83 (C-8), 62.51 (C-9), 41.28 (C-10), 142.61 (C-11), 124.32 (C-12), 162.50 (C-13), 116.41 (C-14), 171.37 (C-15), 98.55 (C-16), 111.62 (C-17), 33.58 (C-18), 23.88 (C-19), 17.96 (C-20), 172.36 (C-1'), 37.11 (C-2'), 31.46 (C-3'), 141.65 (C-4'), 129.11 (C-5'), 129.23 (C-6'), 126.96 (C-7'), 129.23 (C-8'), 129.11 (C-9').

[0039] Compound A3: Colorless oily liquid, yield 39.04%, 1 H NMR (400 MHz, (CD 3 ) 2 CO): 0.95 (3H, s, H-18); 0.96 (3H, s, H-19); 1.20 (3H, s, H-20); 2.93 (1H, d, J = 10.2 Hz, H-9); 7.05 (1H, dd, J = 15.9, 10.2 Hz, H-11); 6.18 (1H, d, J = 15.6 Hz, H-12); 6.00 (1H, s, H-14); 5.46 (1H, s, H-15); 4.63 (1H, s, H-17a); 4.70 (1H, s, H-17b); 7.17 (1H, m, H-7'); 7.23 (2H, m, H-6' and 8'); 7.27 (2H, m, H-5' and 9'). 13 C NMR (100 MHz, CDCl 3): δ 42.74 (C-1), 19.79 (C-2), 43.63 (C-3), 34.80 (C-4), 55.78 (C-5), 71.14 (C-6), 44.76 (C-7), 146.19 (C-8), 62.60 (C-9), 41.00 (C-10), 137.81 (C-11), 122.18 (C-12), 132.02 (C-13), 144.19 (C-14), 97.52 (C-15), 170.62 (C-16), 111.21 (C-17), 33.59 (C-18), 23.89 (C-19), 17.98 (C-20), 172.37 (C-1'), 37.09 (C-2'), 31.46 (C-3'), 141.65 (C-4'), 129.11 (C-5'), 129.22 (C-6'), 126.94 (C-7'), 129.22 (C-8'), 129.11 (C-9').

[0040] Synthesis of Hedychium yunnanense A Derivative (Compound A4)

[0041] Using 4-fluorobenzoyl chloride as raw material to react with Hedychium yunnanense A, the synthesis method is the same as that of Compound A2.

[0042] Compound A4: Light yellow transparent solid, the yield is 20.5%; 1 H NMR (400 MHz, (CD 3 ) 2 CO): 0.96 (3H, s, H-18); 0.95 (3H, s, H-19); 1.22 (3H, s, H-20); 2.96 (1H, d, J = 10.6 Hz, H-9); 6.65 (1H, dd, J = 16.0, 10.2 Hz, H-11); 6.54 (1H, d, J = 15.6 Hz, H-12); 6.12 (1H, s, H-14); 5.43 (1H, s, H-16); 4.67 (1H, s, H-17a); 4.56 (1H, s, H-17b); 7.08 (1H, m, H-7'); 7.21 (2H, m, H-6' and 8'); 7.20 (2H, m, H-5' and 9'). 13 C NMR (100 MHz, CDCl 3): δ 42.55 (C-1), 19.75 (C-2), 43.75 (C-3), 34.91 (C-4), 55.56 (C-5), 71.12 (C-6), 44.52 (C-7), 145.56 (C-8), 62.74 (C-9), 41.18 (C-10), 142.58 (C-11), 124.12 (C-12), 162.45 (C-13), 116.35 (C-14), 171.37 (C-15), 98.62 (C-16), 111.35 (C-17), 33.67 (C-18), 23.88 (C-19), 18.10 (C-20), 172.26 (C-1'), 37.31 (C-2'), 31.52 (C-3'), 141.52 (C-4'), 128.89 (C-5'), 129.41 (C-6'), 127.02 (C-7'), 129.36 (C-8'), 128.86 (C-9').

[0043] Synthesis of Hedychium yunnanense A Derivative (Compound A5)

[0044] Using p-methylbenzoyl chloride as raw material to react with Hedychium yunnanense A, the synthesis method is the same as that of Compound A2.

[0045] Compound A5: Light yellow transparent solid, yield 22.5%, 1 H NMR (400 MHz, (CD 3 ) 2 CO): 0.94 (3H, s, H-18); 0.96 (3H, s, H-19); 1.22 (3H, s, H-20); 2.96 (1H, d, J = 10.6 Hz, H-9); 6.78 (1H, dd, J = 16.0, 10.2 Hz, H-11); 6.45 (1H, d, J = 15.6 Hz, H-12); 6.05 (1H, s, H-14); 5.48 (1H, s, H-16); 4.67 (1H, s, H-17a); 4.72 (1H, s, H-17b); 7.16 (1H, m, H-7'); 7.23 (2H, m, H-6' and 8'); 7.21 (2H, m, H-5' and 9'). 13 C NMR (100 MHz, CDCl 3): δ 42.69 (C-1), 19.80 (C-2), 43.60 (C-3), 34.82 (C-4), 55.65 (C-5), 71.07 (C-6), 44.72 (C-7), 145.83 (C-8), 62.51 (C-9), 41.28 (C-10), 142.61 (C-11), 124.32 (C-12), 162.50 (C-13), 116.41 (C-14), 171.37 (C-15), 98.55 (C-16), 111.62 (C-17), 33.58 (C-18), 23.88 (C-19), 17.96 (C-20), 172.36 (C-1'), 37.11 (C-2'), 31.46 (C-3'), 141.65 (C-4'), 129.11 (C-5'), 129.23 (C-6'), 126.96 (C-7'), 129.23 (C-8'), 129.25 (C-9').

[0046] Synthesis of Hedychium yunnanense Gagnep. A Derivative (Compound A7)

[0047] Take an appropriate amount of phenylacetyl chloride and a small amount of potassium carbonate. After ultrasonic treatment for 30 min, add 218.5 mg of Hedychium yunnanense Gagnep. A, heat and stir in an oil bath at 55 °C for 30 min, and detect by TLC that the reaction raw materials are completely consumed. Add 8% Na 2 CO 3 aqueous solution, stir until odorless. Extract with ethyl acetate, wash once with water, collect the ethyl acetate layer, and use anhydrous Na 2 SO 4 to remove water and dry. After concentration and recovery, separate by silica gel column chromatography with 200 - 300 mesh, elute with petroleum ether:ethyl acetate (30:1) to obtain Compound A6.

[0048] Compound A6: The yield is 92.4%, 1 H NMR (400 MHz, (CD 3 ) 2CO): 0.92 (3H, s, H-18); 0.95 (3H, s, H-19); 1.10 (3H, s, H-20); 2.52 (1H, d, J = 9.7 Hz, H-9); 6.15 (1H, dd, J = 15.8, 9.7 Hz, H-11); 6.28 (1H, d, J = 15.8 Hz, 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 (100 MHz, CDCl 3 ): δ 42.81 (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-14), 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').

[0049] Dissolve 113.4 mg of compound A6 in 10 ml of pyridine, add an appropriate amount of rose bengal, introduce oxygen, stir and react under LED light irradiation for 30 min, and detect by TLC that the reaction raw materials are completely consumed. After recovering and concentrating the solvent, the sample is separated by normal pressure column chromatography on silica gel of 200 - 300 mesh, eluted with a gradient of petroleum ether: ethyl acetate (4:1 - 2:1), and then purified by silica gel of 200 - 300 mesh treated with disodium hydrogen phosphate to obtain compounds A7 and A8.

[0050] Compound A7: Yield 27.9%, 1 H NMR (400 MHz, (CD 3 ) 2CO): 0.91 (3H, s, H-18); 0.94 (3H, s, H-19); 1.10 (3H, s, H-20); 2.63 (1H, d, J = 10.2 Hz, H-9); 6.70 (1H, dd, J = 16.0, 10.2 Hz, H-11); 6.41 (1H, d, J = 15.9 Hz, H-12); 5.94 (1H, s, H-14); 5.46 (1H, d, s, H-16); 4.65 (1H, s, H-17a); 4.67 (1H, s, H-17b); 7.24 (1H, m, H-6’); 7.29 (2H, m, H-5’ and 7’); 7.31 (2H, m, H-4’ and 8’). 13 C NMR (100 MHz, CDCl 3 ): δ 42.64 (C-1), 19.78 (C-2), 43.60 (C-3), 34.78 (C-4), 55.68 (C-5), 71.42 (C-6), 44.70 (C-7), 145.69 (C-8), 62.54 (C-9), 41.27 (C-10), 142.58 (C-11), 124.30 (C-12), 162.48 (C-13), 116.43 (C-14), 171.32 (C-15), 98.54 (C-16), 111.57 (C-17), 33.57 (C-18), 23.88 (C-19), 17.88 (C-20), 171.15 (C-1'), 42.59 (C-2'), 135.29 (C-3'), 130.27 (C-4'), 129.17 (C-5'), 127.65 (C-6'), 129.17 (C-7'), 130.27 (C-8').

[0051] Compound A8: Yield 12.1%, 1 H NMR (400 MHz, (CD 3 ) 2 CO): 0.91 (3H, s, H-18); 0.94 (3H, s, H-19); 1.09 (3H, s, H-20); 2.53 (1H, d, J = 10.2 Hz, H-9); 7.02 (1H, dd, J = 15.8, 10.2 Hz, H-11); 6.18 (1H, d, J = 15.7 Hz, H-12); 7.16 (1H, s, H-14); 5.45 (1H, d, s, H-15); 4.60 (1H, s, H-17a); 4.65 (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 (100 MHz, CDCl 3 ): δ 42.67 (C-1), 19.75 (C-2), 43.63 (C-3), 34.75 (C-4), 55.80 (C-5), 71.48 (C-6), 44.73 (C-7), 146.05 (C-8), 62.62 (C-9), 41.01 (C-10), 137.80 (C-11), 122.15 (C-12), 132.01 (C-13), 144.21 (C-14), 97.51 (C-15), 170.59 (C-16), 111.15 (C-17), 33.56 (C-18), 23.86 (C-19), 17.86 (C-20), 171.16 (C-1'), 42.63 (C-2'), 135.31 (C-3'), 130.29 (C-4'), 129.16 (C-5'), 127.63 (C-6'), 129.16 (C-7'), 130.29 (C-8').

[0052] Synthesis of Hedychium yunnanense A Derivative (Compound A9)

[0053] Using p-methylphenylacetyl chloride as the raw material to react with Hedychium yunnanense A, the synthesis method is the same as that of Compound A7.

[0054] Compound A9: Yield 30.2%, 1 H NMR (400 MHz, (CD 3 ) 2 CO): 0.92 (3H, s, H-18); 0.95 (3H, s, H-19); 1.12 (3H, s, H-20); 2.52 (1H, d, J = 10.2 Hz, H-9); 6.85 (1H, dd, J = 16.0, 10.2 Hz, H-11); 6.41 (1H, d, J = 15.5 Hz, H-12); 5.92 (1H, s, H-14); 5.45 (1H, d, s, H-16); 4.58 (1H, s, H-17a); 4.62 (1H, s, H-17b); 7.22 (1H, m, H-6’); 7.25 (2H, m, H-5’ and 7’); 7.30 (2H, m, H-4’ and 8’). 13 C NMR (100 MHz, CDCl 3): δ 42.54 (C-1), 19.68 (C-2), 43.65 (C-3), 34.88 (C-4), 55.78 (C-5), 71.40 (C-6), 44.76 (C-7), 145.88 (C-8), 62.63 (C-9), 41.54 (C-10), 142.52 (C-11), 124.22 (C-12), 162.42 (C-13), 116.10 (C-14), 171.32 (C-15), 98.55 (C-16), 111.58 (C-17), 33.41 (C-18), 23.78 (C-19), 17.88 (C-20), 171.10 (C-1'), 42.32 (C-2'), 135.75 (C-3'), 130.02 (C-4'), 129.01 (C-5'), 127.52 (C-6'), 129.02 (C-7'), 130.12 (C-8').

[0055] Synthesis of Hedychium yunnanense A derivative (Compound A10)

[0056] Using 4-fluorobenzeneacetyl chloride as a raw material to react with Hedychium yunnanense A, the synthesis method is the same as that of Compound A7.

[0057] Compound A10: Yield 30.2%, 1 H NMR (400 MHz, (CD 3 ) 2 CO): 0.92 (3H, s, H-18); 0.94 (3H, s, H-19); 1.09 (3H, s, H-20); 2.32 (1H, d, J = 10.2 Hz, H-9); 6.45 (1H, dd, J = 16.1, 10.2 Hz, H-11); 6.23 (1H, d, J = 15.9 Hz, H-12); 5.87 (1H, s, H-14); 5.45 (1H, d, s, H-16); 4.65 (1H, s, H-17a); 4.67 (1H, s, H-17b); 7.23 (1H, m, H-6’); 7.26 (2H, m, H-5’ and 7’); 7.21 (2H, m, H-4’ and 8’). 13 C NMR (100 MHz, CDCl 3): δ 42.32 (C-1), 19.45 (C-2), 43.23 (C-3), 34.34 (C-4), 55.88 (C-5), 71.67 (C-6), 44.76 (C-7), 145.89 (C-8), 62.99 (C-9), 41.32 (C-10), 142.34 (C-11), 124.12 (C-12), 162.54 (C-13), 116.56 (C-14), 171.30 (C-15), 99.20 (C-16), 111.41 (C-17), 33.57 (C-18), 23.88 (C-19), 17.98 (C-20), 171.12 (C-1'), 42.47 (C-2'), 135.14 (C-3'), 130.65 (C-4'), 129.23 (C-5'), 127.85 (C-6'), 129.01 (C-7'), 130.35 (C-8').

[0058] Synthesis of Hedychium yunnanense A derivative (Compound A11)

[0059] Using 4-chlorophenylacetyl chloride as raw material to react with Hedychium yunnanense A, the synthesis method is the same as that of Compound A7.

[0060] Compound A11: Yield 30.2%, 1 H NMR (400 MHz, (CD 3 ) 2 CO): 0.91 (3H, s, H-18); 0.96 (3H, s, H-19); 1.09 (3H, s, H-20); 2.77 (1H, d, J = 10.2 Hz, H-9); 6.56 (1H, dd, J = 16.0, 10.2 Hz, H-11); 6.45 (1H, d, J = 15.9 Hz, H-12); 6.12 (1H, s, H-14); 5.23 (1H, d, s, H-16); 4.67 (1H, s, H-17a); 4.88 (1H, s, H-17b); 7.09 (1H, m, H-6’); 7.21 (2H, m, H-5’ and 7’); 7.36 (2H, m, H-4’ and 8’). 13 C NMR (100 MHz, CDCl 3): δ 42.87 (C-1), 19.34 (C-2), 43.61 (C-3), 34.75 (C-4), 55.68 (C-5), 71.52 (C-6), 44.78 (C-7), 145.34 (C-8), 62.65 (C-9), 41.76 (C-10), 142.82 (C-11), 124.73 (C-12), 162.36 (C-13), 116.13 (C-14), 171.12 (C-15), 98.37 (C-16), 111.64 (C-17), 33.76 (C-18), 23.88 (C-19), 17.46 (C-20), 171.12 (C-1'), 42.39 (C-2'), 135.87 (C-3'), 130.53 (C-4'), 128.12 (C-5'), 127.53 (C-6'), 128.87 (C-7'), 130.05 (C-8').

[0061] Synthesis of Hedychium yunnanense A Derivative (Compound A12)

[0062] Weigh 120.8 mg of raw material Hedychium yunnanense A, dissolve it in 1.2 ml of tetrahydrofuran, add 0.6 ml of pyridine, dropwise add 0.96 ml of octanoyl chloride, and react under an oil bath at 60 °C for 2.5 h. Detect by TLC until the reaction is complete. Add 10 ml of 10% aqueous sodium carbonate 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 and wash it with distilled water once. Collect and combine the ethyl acetate layers, add anhydrous sodium sulfate and let it stand overnight for 12 h of drying. Filter to remove the solid impurities in the organic layer, evaporate the solution to dryness, and separate by silica gel column chromatography with 300 - 400 mesh, eluting with a gradient of petroleum ether / chloroform (2:1 - 1:1). Obtain 120.1 mg of the intermediate product.

[0063] Weigh 107.7 mg of the intermediate product and dissolve it in 5 ml of pyridine dried with molecular sieve, add an appropriate amount of rose bengal, simultaneously introduce oxygen and stir, and react under LED light irradiation for 3 h. Detect by TLC until the reaction is complete. After concentrating and recovering the reaction solution, the sample is separated by normal pressure column chromatography on 200 - 300 mesh weakly basic silica gel (activated silica gel containing 8% disodium hydrogen phosphate), eluting with a gradient of petroleum ether / ethyl acetate (4:1 - 2:1) to separate and obtain Compound A12.

[0064] Compound A12: white powder, yield 30.2%, 1 H NMR (500 MHz, (CD 3 ) 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 = 8.1 Hz, H-9); 6.67 (1H, dd, J = 15.9, 10.2 Hz, H-11); 6.44 (1H, d, J = 15.7 Hz, 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); 13 CNMR (125 MHz, CDCl 3 ): δ 43.68 (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').

[0065] Synthesis of Hedychium coronarium J. Koenig flavone A derivative (Compound A13)

[0066] Weigh 106 mg of p-ethylbenzoic acid, add 8 mg of DMAP, dissolve it in 6 ml of 1,2-dichloroethane dried over anhydrous calcium chloride, add 179.5 mg of DIC, stir for 30 min at room temperature, and finally add 101.0 mg of Hedychium coronarium J. Koenig flavone A. React at room temperature for 7 h, and detect by TLC until the reaction is complete. Hydrolysis: Add 1 ml of distilled water and 5 ml of petroleum ether, continue to stir for 10 min and then sonicate for 20 min; Extraction: The reaction solution is partitioned once with 15 ml of petroleum ether and 10 ml of 70% methanol, and then the 70% methanol layer is extracted with 10 ml of petroleum ether. The petroleum ether layers from the two extractions are combined; After concentrating the petroleum ether layer, the sample is separated by silica gel column chromatography with 300 - 400 mesh, and eluted with a gradient of petroleum ether / chloroform (8:1 - 3:1). 52.9 mg of the intermediate product is obtained.

[0067] Weigh 41.3 mg of the intermediate product and dissolve it in 5 ml of pyridine dried over molecular sieves. Add an appropriate amount of TPP, introduce oxygen and stir. After reacting for 4 h under the illumination of LED light, monitor the reaction by TLC until it is complete. After recovering and concentrating the solvent, the sample is separated by normal pressure column chromatography on 200 - 300 mesh weakly basic silica gel (activated silica gel containing 8% disodium hydrogen phosphate), eluted with a gradient of petroleum ether / ethyl acetate (5:1 - 0:1), and compound A13 is obtained.

[0068] Compound A13: An oily substance, with a yield of 39.2%, 1 H NMR(500MHz,(CD 3 ) 2 CO): 0.91(3H, s, H - 18); 0.98(3H, s, H - 19); 1.19(3H, s, H - 20); 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, CDCl 3 ): 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), 171.25(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').

[0069] Antitumor activity screening

[0070] The biological activity of compound A1-13 against five human tumor cell lines, namely HL-60, SMMC-7721, A-549, MCF-7, and SW480, was screened using the MTS method, with cisplatin and paclitaxel as positive controls (the experimental results are shown in Table 1). Experimental method: A single cell suspension was prepared with a culture medium containing 10% fetal bovine serum (DMEM or RMPI1640), and 5000-10000 cells per well were inoculated into a 96-well plate, with a volume of 100 μL per well. Adherent cells were seeded 12 h in advance; the test compound solution was added (initial screening at a fixed concentration of 40 μM, and 5 concentrations were set for gradient rescreening for compounds with 50% growth inhibition of tumor cells at this concentration), with a final volume of 200 μL per well, and 3 replicates were set for each treatment; after culturing at 37 °C for 48 h, the culture supernatant in the wells was carefully aspirated, 20 μL of MTS solution and 100 μL of culture medium were added to each well, and incubation was continued for 4 h to allow the reaction to proceed fully; at a wavelength of 490 nm, the optical absorption values of each well were read using an enzyme-linked immunosorbent assay detector (Bio-Rad 680), the results were recorded, a cell growth curve was plotted with the concentration as the abscissa and the cell survival rate as the ordinate, and the IC 50 value was calculated using the two-point method (Reed and Muench method).

[0071] Table 1 Half-maximal inhibitory concentration IC 50 (μM) of the test compounds against the proliferation of HL-60, SMMC-7721, A-549, MCF-7, and SW480 tumor cells

[0072]

[0073] As can be seen from Table 1, except for A1, A6, and A8, the curcumenol A-derived compounds with the parent nucleus structure of the present invention all showed anti-tumor activity. Compounds A2 and A7 had significant activity against five tumor cell lines (human promyelocytic leukemia cell line HL-60, human hepatocellular carcinoma cell line SMMC-7721, human lung cancer cell line A549, human breast cancer cell line MCF-7, and human colon cancer cell line SW480), and their biological activity against SMMC-7721, A549, MCF-7, and SW480 cell lines was superior to that of cisplatin.

[0074] Curcumenol A of the present invention was purchased from Shanghai Qincheng Biotechnology Co., Ltd. All the organic reagents (chemically pure) were purchased from the Chemical Reagent and Glassware Procurement Station of Kunming Pharmaceutical Company and were all of analytical purity; the column chromatography silica gel was silica gel H produced by Qingdao Marine Chemical Factory and silica gel with 200-300 mesh and 300-400 mesh, and the thin layer chromatography silica gel was silica gel G produced by Qingdao Marine Chemical Factory.

[0075] The above-described embodiments merely represent specific implementation manners of the present invention. The description thereof is relatively specific and detailed, but it should not be construed as a limitation to the scope of the patent of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the concept of the present invention, several modifications and improvements can still be made, and these all fall within the protection scope of the present invention.

Claims

1. A dianthin A derivative, characterized in that: The structure is as follows: Wherein, R1 is -C2H4- or -CH2- R2 is H, -CH3 or halogen.

2. The dianthin A derivative according to claim 1, characterized in that: The specific structure is as follows: or 3. Use of the dianthin A derivative according to claim 1 or 2 in the preparation of anti-tumor drugs.

4. The use of the dianthin 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 dianginsenoside A derivative according to claim 1 or 2, characterized in that: The following steps are involved: A. Take phenylpropionyl chloride or phenylacetyl chloride, add potassium carbonate, ultrasonicate for 30 minutes, add diangingerol A, react at 50-55°C, add Na2CO3 solution to the reaction solution after the reaction is complete, stir until tasteless; after extraction, use anhydrous Na2SO4 to remove water and dry, concentrate and recover, separate and elute through silica gel column chromatography to obtain an intermediate product; B. Dissolve the intermediate product in pyridine, 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, and purify through silica gel treated with disodium hydrogen phosphate to separate the product.

6. The method for preparing the dianthin A derivative according to claim 5, characterized in that: The extractant in step A is ethyl acetate.

7. The method for preparing the dianthin A derivative according to claim 5, characterized in that: The eluent of step A is petroleum ether:ethyl acetate in a volume ratio of 30:

1.

8. The method for preparing the dianthin A derivative according to claim 5, characterized in that: In the step B, petroleum ether:ethyl acetate is used for gradient elution at a ratio of 4:1-2:1.

Images