CN111018780B - N-carbonyl-9, 10-dihydroacridine compound and application thereof - Google Patents

Abstract

The invention relates to an N-carbonyl-9, 10-dihydro acridine compound which is characterized in that the structural formula of the compound is shown as the following formula (I); in the formula (I), R1 is alkoxy substituted phenyl, ether substituted phenyl, cyclohexane or cyclopropane. The N-carbonyl-9, 10-dihydroacridine compound has a remarkable inhibition effect on tumor cells, and can be used for preparing anticancer drugs.

Description

N-carbonyl-9, 10-dihydroacridine compound and application thereof

Technical Field

The invention relates to a heterocyclic compound, in particular to a heterocyclic compound containing a hydrogenated acridine ring system, which has anti-tumor biological activity.

Background

Malignant tumors have become the first killer of human diseases, of which breast cancer, lung cancer and cervical cancer are among the most malignant tumors at present. In recent years, the research on anti-tumor drugs by various organizations has been more and more focused, but the number of tumor patients and the death rate are still high. The existing antitumor drugs have complex and various structures, and compounds with different structures show excellent antitumor activity. The heterocyclic structure widely exists in tumor drugs and other disease drugs, has special physiological effects and structural advantages, and is widely applied to drug development.

The invention patent application with the publication number of CN 101555226A discloses an N-benzyl-9, 10-dihydroacridine compound. The background art of the above patent application suggests: some acridine compounds are found to have the effects of antisepsis, antibiosis and the like at the beginning of the 20 th century, and are used as antibacterial and antimalarial drugs in the world war for the first time. Amacridine (AMSA), an anticancer drug, is widely used at home and abroad as a second-line treatment drug for acute leukemia; "9, 10-dihydro acridine is a more important acridine compound, and they have better antioxidant property". However, the results of the studies conducted by the present inventors have revealed that the above-mentioned N-benzyl-9, 10-dihydroacridine compounds are still unsatisfactory in antitumor effect.

Disclosure of Invention

The invention aims to provide an N-carbonyl-9, 10-dihydroacridine compound which has an obvious effect of inhibiting tumor cells.

The scheme for solving the technical problems is as follows:

an N-carbonyl-9, 10-dihydroacridine compound is characterized by having a structural formula shown as a formula (I):

wherein R in formula (I) ¹ Is alkoxy-substituted phenyl, ether-substituted phenyl, cyclohexane or cyclopropane;

preferably, the N-carbonyl-9, 10-dihydroacridine compound is one of the following compounds represented by structural formulas 1 to 7:

the N-carbonyl-9, 10-dihydroacridine compound is prepared by the following method:

(1) Sequentially adding 1mol part of cyclic dibenzoiodonium salt, 2 mol parts of nitrile compound and 2.5 mol parts of potassium phosphate into a reaction bottle with a magnetic stirrer inside, rapidly adding 0.1 mol part of cuprous chloride, plugging a bottle stopper, replacing gas in the reaction bottle with argon for three times, and injecting 10 times of mixed solution into the reaction bottle according to the mass of the cyclic dibenzoiodonium salt; the mixed solution is prepared by the following method: taking 2, 6-tetramethyl-3, 5-heptanedione, 1, 2-dichloroethane, and toluene according to a volume ratio of 2, 6-tetramethyl-3, 5-heptanedione: 1, 2-dichloroethane: toluene = 1: 10, and then adding 5% of water according to the total volume of the mixed solution to mix uniformly to obtain the composition;

(2) Heating to 100 ℃ under the protection of argon, stirring at constant temperature for 17 hours, removing the 1, 2-dichloroethane and the toluene under reduced pressure, dissolving and extracting the residue with dichloromethane for three times, combining organic phases, washing with water and saturated saline solution in sequence, drying with anhydrous sodium sulfate, filtering, and removing the solvent under reduced pressure to obtain a reaction product;

(3) And (3) performing silica gel column chromatography on the obtained reactant, eluting by using petroleum ether-ethyl acetate as an eluent according to the gradient of the petroleum ether-ethyl acetate of 100: 1-20: 1, and purifying to obtain the N-carbonyl-9, 10-dihydroacridine compound.

The N-carbonyl-9, 10-dihydroacridine compound has a remarkable inhibition effect on tumor cells, and can be used for preparing an anti-cancer drug, wherein the anti-cancer drug is a drug for resisting breast cancer, lung cancer or cervical cancer.

The technical scheme provided by the invention has the following beneficial effects:

the preparation process of the N-carbonyl-9, 10-dihydroacridine compound is simple and convenient, the separation and purification steps are simple and easy to implement, the yield is high, and the N-carbonyl-9, 10-dihydroacridine compound can be used for large-scale production.

The N-carbonyl-9, 10-dihydroacridine compound disclosed by the invention has stronger killing effect on cells of human breast cancer, lung cancer and cervical cancer, and is obviously better than the N-benzyl-9, 10-dihydroacridine compound disclosed by the invention patent application with the publication number of CN 101555226A.

Detailed Description

Example 1 (Synthesis of Compound 1)

Adding the cyclic dibenzoiodonium salt 1a (0.1g, 226.15. Mu. Mol) and p-methoxybenzonitrile 1aa (60.22mg, 452.29. Mu. Mol) and potassium phosphate (120.01mg, 565.37. Mu. Mol) in this order to a reaction flask equipped with a magnetic stirrer, quickly weighing cuprous chloride (2.24mg, 22.61. Mu. Mol) into the reaction flask, plugging the stopper, replacing the gas in the reaction flask with argon gas three times, and then injecting 5mL of a mixed solution resulting from mixing 0.5mL of 2, 6-tetramethyl-3, 5-heptanedione, 2.125mL of 1, 2-dichloroethane, 2.125mL of toluene, and 0.25mL of water into the reaction flask; heating to 100 deg.C under argon, stirring at the temperature for 17 hr, removing 1, 2-dichloroethane and toluene under reduced pressure, dissolving the residue with dichloromethane, washing with water (2.0 mL) and saturated brine (2.0 mL), drying over anhydrous sodium sulfate, filtering, and removing the solvent under reduced pressure to obtain a reaction product; performing silica gel column chromatography on the obtained reactant, eluting by using petroleum ether-ethyl acetate as an eluent according to the gradient of the petroleum ether-ethyl acetate of 100: 1-20: 1, and then purifying by adopting the following method: collecting eluate with test tube, spotting eluate with silica gel plate, running plate with developing agent (petroleum ether/ethyl acetate: 10: 1), identifying product with ultraviolet lamp, collecting eluate containing product, and spin-drying with rotary evaporator to obtain yellow liquid, wherein the yellow liquid is compound 1 (50.1mg, 70.30% yield).

The chemical reaction formula of the preparation method is as follows:

the identification of compound 1 above is as follows:

¹ H NMR(400MHz,DMSO)δ7.45-7.39(m,4H),7.34(d,J＝8.8Hz,2H),7.18-7.10(m,4H),6.83(d,J＝8.8Hz,2H),4.04(s,2H),3.73(s,3H). ¹³ C NMR(101MHz,DMSO)δ167.7,160.7,139.6,133.1,130.9,127.9,127.2,125.9,125.4,124.4,113.2,55.2,33.0.

example 2 (Synthesis of Compound 2)

Adding cyclic dibenzoiodonium salt 1a (0.1g, 226.15. Mu. Mol) and m-methoxybenzonitrile 2aa (60.22mg, 452.29. Mu. Mol) and potassium phosphate (120.01mg, 565.37. Mu. Mol) in this order to a reaction flask equipped with a magnetic stirrer, quickly weighing cuprous chloride (2.24mg, 22.61. Mu. Mol) into the reaction flask, plugging the stopper, replacing the gas in the reaction flask with argon gas three times, and then injecting 5mL of a mixed solution resulting from mixing 0.5mL of 2, 6-tetramethyl-3, 5-heptanedione, 2.125mL of 1, 2-dichloroethane, 2.125mL of toluene, and 0.25mL of water into the reaction flask; heating to 100 deg.C under argon, stirring at the temperature for 17 hr, removing 1, 2-dichloroethane and toluene under reduced pressure, dissolving the residue with dichloromethane, washing with water (2.0 mL) and saturated brine (2.0 mL), drying over anhydrous sodium sulfate, filtering, and removing the solvent under reduced pressure to obtain a reaction product; performing silica gel column chromatography on the obtained reactant, eluting by using petroleum ether-ethyl acetate as an eluent according to the gradient of the petroleum ether-ethyl acetate of 100: 1-20: 1, and then purifying by adopting the following method: collecting eluate in a test tube, spotting eluate on silica gel plate, running plate with developing agent (petroleum ether/ethyl acetate: 10: 1), identifying product with ultraviolet lamp, collecting eluate containing product, and spin-drying with rotary evaporator to obtain yellow liquid, which is compound 2 (55.7mg, 78.11% yield).

The chemical reaction formula of the preparation method is as follows:

the identification of compound 2 above is as follows:

¹ H NMR(400MHz,DMSO)δ7.43-7.39(m,4H),7.20-7.10(m,5H),6.95-6.90(m,3H),4.06(s,2H),3.65(s,3H). ¹³ C NMR(101MHz,DMSO)δ167.7,158.6,139.2,137.2,133.4,129.1,127.2,125.9,125.6,124.5,120.7,116.0,114.0,55.0,32.9.HRMS for C ₂₁ H ₁₈ NO ₂ [M+H] ⁺ Calculated:316.1338,found:316.1322.

example 3 (Synthesis of Compound 3)

Adding cyclic dibenzoiodonium salt 1a (0.1g, 226.15. Mu. Mol) and 3, 5-dimethoxybenzonitrile 3aa (73.80mg, 452.29. Mu. Mol) and potassium phosphate (120.01mg, 565.37. Mu. Mol) in this order to a reaction flask equipped with a magnetic stirrer, quickly weighing cuprous chloride (2.24mg, 22.61. Mu. Mol) into the reaction flask, plugging a stopper, replacing the gas in the reaction flask with argon three times, and then injecting 5mL of a mixed solution into the reaction flask, which is formed by mixing 0.5mL of 2, 6-tetramethyl-3, 5-heptanedione, 2.125mL of 1, 2-dichloroethane, 2.125mL of toluene, and 0.25mL of water; heating to 100 ℃ under the protection of argon, stirring at the temperature for 17 hours, removing 1, 2-dichloroethane and toluene under reduced pressure, dissolving the residue with dichloromethane, sequentially washing with water (2.0 mL) and saturated saline solution (2.0 mL) once, drying with anhydrous sodium sulfate, filtering, removing the solvent under reduced pressure to obtain a reactant, performing silica gel column chromatography on the obtained reactant, eluting with petroleum ether-ethyl acetate as an eluent according to a gradient of 100: 1-20: 1, and purifying by collecting the eluent with a test tube, spotting the eluent with a silica gel plate, then using a developing agent running plate of 10: 1 of petroleum ether-ethyl acetate, using an identification product, collecting the eluent containing the product, and spin-drying with a rotary evaporator to obtain a yellow liquid, wherein the yellow liquid is compound 3 (52.9 mg,74.17% yield).

The chemical reaction formula of the preparation method is as follows:

the identification results of the above compound 3 are as follows:

¹ H NMR(400MHz,DMSO)δ7.45-7.39(m,4H),7.19-7.12(m,4H),6.52(d,J＝6.8Hz,2H),6.49(t,J＝6.8Hz,1H),4.06(s,2H),3.62(s,6H). ¹³ C NMR(101MHz,DMSO)δ167.5,159.8,139.2,137.7,133.4,127.1,125.9,125.6,124.4,106.7,102.1,55.2,32.9.HRMS for C ₂₂ H ₂₀ NO ₃ [M+H] ⁺ Calculated:346.1443,found:346.1447.

example 4 (Synthesis of Compound 4)

Adding cyclic dibenzoiodonium salt 1a (0.1g, 226.15. Mu. Mol) and 3,4, 5-trimethoxybenzonitrile 4aa (87.38mg, 452.29. Mu. Mol) and potassium phosphate (120.01mg, 565.37. Mu. Mol) in this order to a reaction flask equipped with a magnetic stirrer, quickly weighing cuprous chloride (2.24mg, 22.61. Mu. Mol) into the reaction flask, plugging the stopper, replacing the gas in the reaction flask with argon gas three times, and then injecting 5mL of a mixed solution into the reaction flask, the mixed solution being formed by mixing 0.5mL of 2, 6-tetramethyl-3, 5-heptanedione, 2.125mL of 1, 2-dichloroethane, 2.125mL of toluene and 0.25mL of water; heating to 100 ℃ under the protection of argon, stirring at the temperature for 17 hours, removing 1, 2-dichloroethane and toluene under reduced pressure, dissolving the residue with dichloromethane, washing with water (2.0 mL) and saturated brine (2.0 mL) in turn, drying over anhydrous sodium sulfate, filtering, and removing the solvent under reduced pressure to obtain a reaction product; performing silica gel column chromatography on the obtained reactant, eluting by using petroleum ether-ethyl acetate as an eluent according to the gradient of the petroleum ether-ethyl acetate of 100: 1-20: 1, and then purifying by adopting the following method: collecting eluate in test tube, spotting eluate with silica gel plate, running plate with petroleum ether/ethyl acetate (10: 1) developing agent, identifying product with ultraviolet lamp, collecting eluate containing product, and spin-drying with rotary evaporator to obtain yellow liquid, which is compound 4 (54.0 mg,75.71% yield).

The chemical reaction formula of the preparation method is as follows:

the identification of compound 4 above is as follows:

¹ H NMR(400MHz,DMSO)δ7.44(t,J＝6.4Hz,4H),7.20-7.13(m,4H),6.66(s,2H),4.09(s,2H),3.64(s,3H),3.58(s,6H). ¹³ C NMR(101MHz,DMSO)δ167.5,152.1,139.5,139.0,133.4,130.5,127.1,125.9,125.5,124.4,106.8,60.1,55.7,32.90.HRMS for C ₂₃ H ₂₂ NO ₄ [M+H] ⁺ Calculated:376.1549,found:376.1532.

example 5 (Synthesis of Compound 5)

Adding cyclic dibenzoiodonium salt 1a (0.1g, 226.15. Mu. Mol) and p-trifluoromethoxybenzonitrile 5aa (84.63mg, 452.29. Mu. Mol) and potassium phosphate (120.01mg, 565.37. Mu. Mol) in this order to a reaction flask equipped with a magnetic stirrer, quickly weighing cuprous chloride (2.24mg, 22.61. Mu. Mol) into the reaction flask, plugging the stopper, replacing the gas in the reaction flask with argon gas three times, and then injecting 5mL of a mixed solution resulting from mixing 0.5mL of 2, 6-tetramethyl-3, 5-heptanedione, 2.125mL of 1, 2-dichloroethane, 2.125mL of toluene, and 0.25mL of water into the reaction flask; heating to 100 ℃ under the protection of argon, stirring at the temperature for 17 hours, removing 1, 2-dichloroethane and toluene under reduced pressure, dissolving the residue with dichloromethane, washing with water (2.0 mL) and saturated brine (2.0 mL) in turn, drying over anhydrous sodium sulfate, filtering, and removing the solvent under reduced pressure to obtain a reaction product; performing silica gel column chromatography on the obtained reactant, eluting by using petroleum ether-ethyl acetate as an eluent according to the gradient of the petroleum ether-ethyl acetate of 100: 1-20: 1, and then purifying by adopting the following method: collecting eluate with test tube, spotting eluate with silica gel plate, running plate with petroleum ether/ethyl acetate 10: 1 developing agent, identifying product with ultraviolet lamp, collecting eluate containing product, and spin-drying with rotary evaporator to obtain yellow liquid, wherein the yellow liquid is compound 5 (57.6 mg,80.76% yield).

The chemical reaction formula of the preparation method is as follows:

the identification of compound 5 above is as follows:

¹ H NMR(400MHz,DMSO)δ7.54(d,J＝8.8Hz,2H),7.43-7.40(m,4H),7.30(d,J＝8.4Hz,2H),7.19-7.16(m,2H),7.14(td,J＝8.0,1.6Hz,2H),4.07(s,2H). ¹³ C NMR(101MHz,DMSO)δ166.8,149.1,149.1,139.0,135.2,133.5,130.9,127.3,125.8,125.7,124.6,120.3,32.9.HRMS for C ₂₁ H ₁₅ F ₃ NO ₂ [M+H] ⁺ Calculated:370.1055,found:370.1059.

example 6 (Synthesis of Compound 6)

Adding the cyclic dibenzoiodonium salt 1a (0.1g, 226.15. Mu. Mol), propionitrile 6aa (30.34mg, 452.29. Mu. Mol) and potassium phosphate (120.01mg, 565.37. Mu. Mol) in this order to a reaction flask equipped with a magnetic stirrer, quickly weighing cuprous chloride (2.24mg, 22.61. Mu. Mol) into the reaction flask, plugging the stopper, replacing the gas in the reaction flask with argon gas three times, and then injecting 5mL of a mixed solution prepared by mixing 0.5mL of 2, 6-tetramethyl-3, 5-heptanedione, 2.125mL of 1, 2-dichloroethane, 2.125mL of toluene and 0.25mL of water into the reaction flask; heating to 100 deg.C under argon, stirring at the temperature for 17 hr, removing 1, 2-dichloroethane and toluene under reduced pressure, dissolving the residue with dichloromethane, washing with water (2.0 mL) and saturated brine (2.0 mL), drying over anhydrous sodium sulfate, filtering, and removing the solvent under reduced pressure to obtain a reaction product; performing silica gel column chromatography on the obtained reactant, eluting by using petroleum ether-ethyl acetate as an eluent according to the gradient of the petroleum ether-ethyl acetate of 100: 1-20: 1, and then purifying by adopting the following method: collecting eluate with test tube, spotting eluate with silica gel plate, running plate with petroleum ether/ethyl acetate (10: 1) developing agent, identifying product with ultraviolet lamp, collecting eluate containing product, and spin-drying with rotary evaporator to obtain yellow liquid as compound 6 (35.8mg, 63.50% yield).

The chemical reaction formula of the preparation method is as follows:

the identification results of the above compound 6 are as follows:

¹ H NMR(400MHz,DMSO)δ7.66(d,J＝8.0Hz,2H),7.39(d,J＝7.2Hz,2H),7.30(m,2H),7.23(t,J＝7.2Hz,2H),3.86(s,2H),2.04-1.98(m,1H),1.02-0.99(m,2H),0.87-0.83(m,2H). ¹³ C NMR(101MHz,DMSO)δ171.0,138.9,133.9,127.3,125.9,125.6,124.9,32.97,13.29,9.24.HRMS for C ₁₇ H ₁₆ NO[M+H] ⁺ Calculated:250.1232,found:250.1237.

example 7 (Synthesis of Compound 7)

Adding the cyclic dibenzoiodonium salt 1a (0.1g, 226.15. Mu. Mol), cyclohexylnitrile 7aa (49.38mg, 452.29. Mu. Mol) and potassium phosphate (120.01mg, 565.37. Mu. Mol) in this order to a reaction flask equipped with a magnetic stirrer, quickly weighing cuprous chloride (2.24mg, 22.61. Mu. Mol) into the reaction flask, plugging the stopper, replacing the gas in the reaction flask with argon gas three times, and then injecting 5mL of a mixed solution prepared by mixing 0.5mL of 2, 6-tetramethyl-3, 5-heptanedione, 2.125mL of 1, 2-dichloroethane, 2.125mL of toluene, and 0.25mL of water into the reaction flask; heating to 100 deg.C under argon, stirring at the temperature for 17 hr, removing 1, 2-dichloroethane and toluene under reduced pressure, dissolving the residue with dichloromethane, washing with water (2.0 mL) and saturated brine (2.0 mL), drying over anhydrous sodium sulfate, filtering, and removing the solvent under reduced pressure to obtain a reaction product; performing silica gel column chromatography on the obtained reactant, eluting by using petroleum ether-ethyl acetate as an eluent according to the gradient of the petroleum ether-ethyl acetate of 100: 1-20: 1, and then purifying by adopting the following method: collecting eluate with test tube, spotting eluate with silica gel plate, running plate with developing agent (petroleum ether/ethyl acetate: 10: 1), identifying product with ultraviolet lamp, collecting eluate containing product, and spin-drying with rotary evaporator to obtain yellow liquid, which is compound 7 (38.1mg, 57.82% yield).

The chemical reaction formula of the preparation method is as follows:

the identification results of the above compound 7 are as follows:

¹ H NMR(400MHz,DMSO)δ7.58(d,J＝7.6Hz,2H),7.39(d,J＝7.2Hz,2H),7.30(t,J＝7.6Hz,2H),7.23(t,J＝7.2Hz,2H),3.79(s,2H),2.98(dt,J＝3.2Hz,8.4Hz,1H),1.73-1.63(m,4H),1.57(d,J＝11.6Hz,1H),1.43-1.34(m,2H),1.14-0.99(m,3H). ¹³ C NMR(101MHz,DMSO)δ173.9,139.1,134.6,127.3,126.0,125.8,124.9,40.6,33.0,29.1,25.3,25.1.HRMS for C ₂₀ H ₂₂ NO[M+H] ⁺ Calculated:292.1701,found:292.1691.

example 8 (study of the inhibitory Effect of the Compound of the present invention on tumor cells)

The tumor cells studied in this experiment were: MCF-7 (human breast cancer cell), MB-468 (human breast cancer cell), A549 (human lung cancer cell) Hela (human cervical cancer cell)

1. Purpose and principle of experiment

Purpose of the experiment: the inhibitory effects of the compounds 1 to 7 synthesized in examples 1 to 7 on the proliferation of different types of tumor cells were examined by the MTT method.

The experimental principle is as follows: MTT colorimetry is a method for detecting survival and growth of cells, and its principle is that succinate dehydrogenase in mitochondria of living cells can reduce exogenous MTT to water-insoluble blue-violet crystalline formazan, which is deposited in cells, while dead cells lack this function. Dimethyl sulfoxide (DMSO) can dissolve formazan in living cells, an enzyme linked immunosorbent assay detector is used for detecting an absorbance value (OD value) at 490nM, the quantity of the living cells can be reflected according to the absorbance value, and in a certain range, the smaller the OD value is, the weaker the cell activity is, and the better the proliferation inhibition effect of the drug is.

2. Basic information of reagent

Name of reagent	Brand
		RPMI-1640 medium powder	Gibco
Fetal bovine serum	Capricorn Scientific
		Dimethyl sulfoxide (DMSO)	Sigma
Tetramethyl azo blue (MTT)	Sigma
		Colchicine and Paclitaxel	InvivoChem

3. Reagent preparation

1. RPMI-1640 complete medium

Preparing 1L of RPMI-1640 culture medium, taking a corresponding amount of RPMI-1640 powder, dissolving in a beaker containing 800ml of triple distilled water, and stirring for 4h until the powder is completely dissolved. 2g of NaHCO were added ₃ Stirring until completely dissolved. Adjusting the pH value with 1mol/L hydrochloric acid to 7.2-7.4, and metering to 1L. Filtering with filter membrane with pore diameter of 0.22 μm, filtering with high pressure filter, packaging, and storing at 4 deg.C. When in use, 5% of serum is added to form a complete culture medium, and the culture medium can be used for cell culture.

2、MTT

Wrapping 50ml of centrifuge tube with tinfoil paper in dark, precisely weighing 250mg of MTT powder, adding into the centrifuge tube, adding 50ml of PBS to completely dissolve the MTT powder, filtering with 0.22 μm filter membrane for sterilization, packaging, and storing in dark at-20 deg.C.

3. Compound configuration

The high pressure EP tube is used to weigh the compound, and the corresponding amount of DMSO is added to the EP tube to make the liquid 20mM stock solution, which is diluted with the corresponding amount of culture medium to make the working solution with concentration of 100. Mu.M, 50. Mu.M, 25. Mu.M, 12.5. Mu.M, 6.25. Mu.M, 3.125. Mu.M, 1.5625. Mu.M, 0.78125. Mu.M, 0.390625. Mu.M.

4. Procedure of experiment

(1) Taking cells in logarithmic growth phase, digesting, and adjusting cell number concentration to 5 × 10 ⁴ Each well was inoculated into a 96-well plate at 100. Mu.l/well. At 37 ℃,5% CO ₂ Culturing overnight in a cell culture box until the cells adhere to the wall.

(2) The original medium was aspirated, and different concentrations of compounds were added to each group, at 100. Mu.M, 50. Mu.M, 25. Mu.M, 12.5. Mu.M, 6.25. Mu.M, 3.125. Mu.M, 1.5625. Mu.M, 0.78125. Mu.M, 0.390625. Mu.M, respectively. Control group was 0.1% DMSO, and the culture was continued in a cell incubator for 48 hours.

(3) Mu.l of MTT solution was added to each well and incubated for 4h in an incubator.

(4) The medium was discarded, 100. Mu.l DMSO was added to each well, and the solution was shaken for 15min to dissolve formazan crystals sufficiently.

(5) The absorbance at 490nm was measured using an enzyme linked immunosorbent assay.

(6) The cell growth inhibition rate was calculated according to the following formula:

inhibition rate = [ (As-Ab)/(Ac-Ab) ] 100%

As: absorbance of assay well (cell, MTT, compound)

Ac: absorbance of control wells (cell, MTT, no Compound)

Ab: absorbance of blank well (without cell and Compound, with MTT)

IC of compounds was calculated by GraphPad Prism 5 software based on the inhibition rate of drug on cell proliferation at different doses ₅₀ 。

The results of the activity measurements are shown in table 1 below:

anti-cancer cell proliferation Effect of the Compounds of Table 1

The control compounds a and b are N-benzyl-9, 10-dihydroacridine and N- (3,4,5-trimethoxy) benzyl-9, 10-dihydroacridine, respectively, which are the compounds disclosed in patent application examples 1 and 6 of publication No. CN 101555226A.

5. And (4) conclusion:

as can be seen from table 1, the compound of the invention has significant effect on inhibiting tumor cells, and the compounds 1 to 7 have stronger activity on inhibiting cancer cells compared with the control compound a; compounds 1-7 have greater inhibitory activity against cancer cells than control compound b; compared with a control compound, namely, colchicine, compounds 1-7 have the same inhibitory activity on cancer cells as compound No. 4; compounds No. 4 have comparable inhibitory activity against cancer cells as compared to the control compound, paclitaxel, compounds 1-7.

Claims (3)

1. An N-carbonyl-9, 10-dihydroacridine compound, which is one of the compounds shown in the following structural formulas 3-7:

。

2. the method of claim 1, wherein the compound is prepared by the following steps:

(1) Sequentially adding 1mol part of cyclic dibenzoiodonium salt, 2 mol parts of nitrile compound and 2.5 mol parts of potassium phosphate into a reaction bottle with a magnetic stirrer inside, rapidly adding 0.1 mol part of cuprous chloride, plugging a bottle stopper, replacing gas in the reaction bottle with argon for three times, and injecting 10 times of mixed solution into the reaction bottle according to the mass of the cyclic dibenzoiodonium salt; the mixed solution is prepared by the following method: taking 2, 6-tetramethyl-3, 5-heptanedione, 1, 2-dichloroethane, toluene and toluene according to the volume ratio of 2, 6-tetramethyl-3, 5-heptanedione to 1, 2-dichloroethane to toluene =1 to 10, and then adding 5% of water according to the total volume of the mixed solution to mix uniformly to obtain the composition; wherein, the cyclic dibenzoiodonium salt is shown as the structural formula

The nitrile compound is 3, 5-dimethoxybenzonitrile, 3,4, 5-trimethoxybenzonitrile, p-trifluoromethoxybenzonitrile, cyclopropylnitrile or cyclohexylnitrile;

(2) Heating to 100 ℃ under the protection of argon, stirring at constant temperature for 17 hours, removing the 1, 2-dichloroethane and toluene under reduced pressure, dissolving and extracting the residue with dichloromethane for three times, combining organic phases, washing with water and saturated saline solution in sequence, drying with anhydrous sodium sulfate, filtering, and removing the solvent under reduced pressure to obtain a reaction product;

(3) And (3) performing silica gel column chromatography on the obtained reactant, eluting by using petroleum ether-ethyl acetate as an eluent according to the gradient of the petroleum ether-ethyl acetate of 100: 1-20: 1, and purifying to obtain the N-carbonyl-9, 10-dihydroacridine compound.

3. The use of N-carbonyl-9, 10-dihydroacridine compounds as claimed in claim 1 for the preparation of anticancer drugs, wherein said anticancer drugs are anti-breast cancer, anti-lung cancer or anti-cervical cancer drugs.