Matrine type alkaloid Flavesin G derivative and application thereof

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a sophocarpidine type alkaloid Flavesin G derivative and application of the sophocarpidine type alkaloid Flavesin G derivative. In order to solve the problem that the existing matrine type alkaloid is insufficient in anti-tumor activity, the Flavesine G derivative with a novel structure is further synthesized on the basis of the matrine type alkaloid Flavesine G, and the synthesized Flavesine G derivative has better anti-lung cancer cell activity than a lead compound Flavesine G. Meanwhile, the derivative has no obvious cytotoxicity to human normal bronchial epithelial cells, and does not interfere with the physiological function of normal cells in a concentration range in which the effective cancer suppression effect is exerted. Therefore, the sophocarpidine type alkaloid Flavesin G derivative provided by the invention has important reference and application values in the aspect of developing anti-cancer drugs.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and particularly relates to a class of Flavesine G derivatives of matrine type alkaloids and application thereof. BACKGROUND

[0002] With the development of social economy, the improvement of people's living standards and the change of dietary structure, the disease spectrum and death spectrum of human beings have changed significantly. Among them, malignant tumor is one of the main causes of death in the world, and has become a major class of diseases that seriously endanger human life and health and restrict social and economic development. Among all malignant tumors, the incidence and mortality of lung cancer rank in the forefront, and non-small cell lung cancer accounts for about 85% of all clinical lung cancer cases. In recent years, the rise of immunotherapy and the discovery of tyrosine kinase inhibitors have brought certain treatment benefits to patients with non-small cell lung cancer, but the high medical cost of immunotherapy will bring huge economic pressure to patients and their families. At the same time, the number of drugs available for radiotherapy and chemotherapy is small and the toxic side effects are large. The above problems lead to the fact that the overall cure rate and survival rate of non-small cell lung cancer in the clinic are still very low. Therefore, there is an urgent need to develop new drug molecules with anti-non-small cell lung cancer activity.

[0003] Sophora plants (such as Sophora flavescens, Sophora alopecuroides, and Radix Sophorae Tonkinensis) have a long history of medicinal use, and matrine type alkaloids are the main components of these plants that exert pharmacological activities. This class of alkaloids has a wide range of pharmacological activities, among which anti-tumor activity is relatively prominent. A large number of studies have shown that matrine type alkaloids are very suitable as lead compounds for structural modification, and on this basis, it is expected to obtain anti-tumor candidate drugs with significantly improved activity and high safety. Among them, Flavesine G is a matrine type alkaloid obtained by extraction and separation from the roots of Sophora flavescens by the previous research group of the present application, and the chemical formula of the compound is: 15 H 20N2O2, full name 4-(5,6,9,10-tetrahydro-4H,8H-pyrido[3,2,1-ij][1,6]naphthyridin-1-yl)butanoic acid, that is, 4-(5,6,9,10-tetrahydro-4H,8H-pyrido[3,2,1-ij][1,6]naphthyridin-1-yl)butanoic acid (Zhang Y B, Luo D, Yang L, et al. Matrine-type alkaloids from the roots of sophora flavescens and Their Antiviral Activities against the Hepatitis B Virus [J]. Journal of Natural Products, 2018, 8(10): 2259-2265.). Compared with conventional matrine-type alkaloids, Flavesine G has better anti-non-small cell lung cancer (A549) activity, but its activity is still low, and improving its anti-non-small cell lung cancer activity through structural modification is a key research direction.

[0004] According to research, the C-15 carboxyl end of Flavesine G has good structural modification potential, and by introducing specific functional groups, it is expected to significantly enhance its binding ability with tumor cell targets, but how to optimize the structure to achieve a breakthrough in anti-non-small cell lung cancer activity has not been clear. Therefore, if Flavesine G is used as a lead compound for structural derivation, it is expected to obtain a new type of high-efficiency low-toxicity anti-lung cancer candidate drug. SUMMARY

[0005] In order to overcome the shortcomings of the prior art, the present application further synthesizes Flavesine G derivatives with novel structures on the basis of matrine-type alkaloid Flavesine G. The derivatives have better anti-lung cancer cell activity than the lead compound Flavesine G, and have no obvious cytotoxicity to human normal bronchial epithelial cells, providing a new choice for developing high-efficiency low-toxicity anticancer drugs, and helping to overcome the limitations of existing anticancer drugs such as drug resistance and safety.

[0006] In order to achieve the above purpose, the technical scheme adopted by the present application is:

[0007] The first aspect of the present application provides a matrine-type alkaloid Flavesine G derivative, the derivative comprising at least one of compounds E4, E5, E9, E11 and E12:

[0008]

[0009] The second aspect of the present application provides the use of the Flavesine G derivative of the first aspect in the preparation of an anticancer drug.

[0010] The third aspect of the present application provides the use of the Flavesine G derivative of the first aspect in the preparation of a drug for inhibiting the proliferation of cancer cells.

[0011] Preferably, the anticancer drug is an anti-lung cancer drug. From the mechanism of action, if the target of the drug (such as the proliferation-related pathway) also has abnormal expression in other cancers such as breast cancer and colorectal cancer, it is theoretically possible to be used for the treatment of these cancers after research and verification.

[0012] Preferably, the cancer cells are non-small cell lung cancer cells.

[0013] Lung cancer is a malignant tumor with high morbidity and mortality worldwide, and non-small cell lung cancer (NSCLC) accounts for about 85% of clinical lung cancer cases. Although immunotherapy and tyrosine kinase inhibitors have brought some progress to the treatment of NSCLC, the high cost of immunotherapy and the limitations of radiotherapy and chemotherapy drugs (few in number and high in side effects) have resulted in a low overall cure rate and survival rate in clinical practice, and there is an urgent need for new anti-NSCLC drugs.

[0014] Matrine-type alkaloids are the main pharmacologically active components of Sophora plants, and have a wide range of pharmacological activities, but their anti-tumor activity is insufficient. Among them, the new matrine-type alkaloid Flavesine G is isolated from Sophora root and has anti-NSCLC (A549) activity, but the activity is still low. So far, the key technology for structural modification of Flavesine G to improve its anti-NSCLC activity has not been clear.

[0015] Therefore, the present application synthesizes novel structural derivatives E4, E5, E9, E11 and E12 based on Flavesine G. It is found through research that compared with the lead compound Flavesine G, the synthesized Flavesine G derivatives (E4, E5, E9, E11 and E12) have significantly improved cytotoxicity to non-small cell lung cancer A549 at a concentration of 10 μM, and the activity of compound E4 is slightly better than that of cisplatin; at the same time, these compounds (E4, E5, E9, E11 and E12) do not show obvious cytotoxicity to human normal bronchial epithelial cells 16HBE at a concentration of 50 μM. This finding provides a new idea for the development of high-efficiency and low-toxicity anti-lung cancer drugs.

[0016] The fourth aspect of the present application provides an anticancer drug, which takes the Flavesine G derivative of the first aspect as the main active ingredient.

[0017] Preferably, the matrine-type alkaloid Flavesine G derivative further includes a pharmaceutically acceptable salt of the derivative, a crystal form of the derivative, a solvate of the derivative, or an isotopic substituted compound of the derivative.

[0018] Preferably, the drug further includes pharmaceutically acceptable excipients.

[0019] More preferably, the excipients include at least one of the following: excipients, solubilizers, emulsifiers, colorants, binders, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, flow aids, flavoring agents, preservatives, coating materials, pH adjusters, absorbents, diluents, and antioxidants.

[0020] Preferably, the dosage form of the drug includes tablets, capsules, granules, powders, syrups, oral liquids, or injections.

[0021] Compared with the prior art, the beneficial effects of the present invention are:

[0022] This invention uses the novel matrine-type alkaloid Flavesine G as the parent compound and, through precise chemical modification and structural derivation, yields Flavesine G derivatives (E4, E5, E9, E11, and E12) with novel molecular structures. These derivatives retain the unique active backbone of the natural alkaloid, ensuring basic binding ability to the target site, while targeted structural optimization significantly enhances their anti-non-small cell lung cancer activity. Simultaneously, these derivatives exhibit no significant cytotoxicity to normal human bronchial epithelial cells and, within the concentration range where they exert effective anti-cancer effects, do not interfere with the physiological functions of normal cells, significantly reducing the risk of toxic side effects during clinical application. Therefore, these derivatives, as the main active ingredient in anti-lung cancer preparations, possess both structural innovation, potent anti-tumor activity, and good safety, providing a new direction for anti-lung cancer drug development and demonstrating significant application value. Attached Figure Description

[0023] Figure 1 The image shows the 1H NMR spectrum of compound E4 from Example 1.

[0024] Figure 2 This is the carbon spectrum of compound E4 from Example 1.

[0025] Figure 3 This is a high-resolution mass spectrum of compound E4 from Example 1.

[0026] Figure 4 The image shows the 1H NMR spectrum of compound E5 from Example 1.

[0027] Figure 5Carbon spectrum of compound E5 in Example 1.

[0028] Figure 6 High resolution mass spectrum of compound E5 in Example 1.

[0029] Figure 7 NMR hydrogen spectrum of compound E9 in Example 1.

[0030] Figure 8 Carbon spectrum of compound E9 in Example 1.

[0031] Figure 9 High resolution mass spectrum of compound E9 in Example 1.

[0032] Figure 10 NMR hydrogen spectrum of compound E11 in Example 1.

[0033] Figure 11 Carbon spectrum of compound E11 in Example 1.

[0034] Figure 12 High resolution mass spectrum of compound E11 in Example 1.

[0035] Figure 13 NMR hydrogen spectrum of compound E12 in Example 1.

[0036] Figure 14 Carbon spectrum of compound E12 in Example 1.

[0037] Figure 15 High resolution mass spectrum of compound E12 in Example 1.

[0038] Figure 16 Statistical chart of cytotoxicity data of compounds E4, E5, E9, E11 and E12 on A549 cells in Example 2.

[0039] Figure 17 Statistical chart of cytotoxicity data of compounds E4, E5, E9, E11 and E12 on 16HBE cells in Example 2. DETAILED DESCRIPTION

[0040] The specific embodiments of the present application will be further described with the following non-restrictive examples. It is to be understood that the illustrations used herein are for the purpose of exemplification and are not in limitation of the application. Furthermore, the technical features involved in each of the embodiments of the present application described below can be combined with each other as long as there is no conflict.

[0041] The experimental methods in the following examples are all conventional methods unless otherwise specified. The experimental materials used in the following examples are all commercially available unless otherwise specified.

[0042] Example 1: Synthesis of Flavesine G derivative of Matrine type alkaloid

[0043] This example provides a class of Flavesine G derivatives of Matrine type alkaloid, which are derived from a new Matrine type alkaloid Flavesine G through precise chemical modification and structural derivation. The Flavesine G derivative of Matrine type alkaloid has the structure shown in formula (I):

[0044]

[0045] wherein R is selected from

[0046] The above-mentioned Flavesine G derivatives of Matrine type alkaloid are five in total, including compounds E4, E5, E9, E11 and E12, and the specific synthesis methods are as shown below:

[0047] (1) Preparation of compound E4

[0048] The compound E4 is a derivative of Flavesine G, and its chemical formula is: C 22 H 24 F3N3O, full name 4-(5,6,9,10-tetrahydro-4H,8H-pyrido[3,2,1-ij][1,6]naphthyridin-1-yl)-N-(4-(trifluoromethyl)phenyl)butanamide. The synthesis route of compound E4 is as follows:

[0049]

[0050] The specific preparation method of compound E4 is as follows:

[0051] The reaction raw material Flavesine G (13.00 mg, 0.05 mmol) was weighed into a 25 mL reaction bottle, acetonitrile (3.00 mL) was used as the reaction solvent, 4- trifluoromethylaniline (0.1 mmol, 16.11 mg), TCFH (21.00 mg, 0.075 mmol) and NMI (14.00 μL, 0.175 mmol) were added respectively, and stirred at room temperature overnight. TCL was used to monitor the reaction, and after the reaction was completed, the rotary evaporator was used to concentrate under reduced pressure, and the reaction mixture was redissolved with 30 mL of chloroform, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution respectively (10 mL x 2), and the organic phase was collected, dried with anhydrous sodium sulfate and filtered to remove insoluble impurities. After the solution was concentrated under reduced pressure, the crude product was obtained. Dichloromethane / methanol (V / V = 30:1) was used as the elution solvent, and silica gel column chromatography was used for purification to obtain a yellow solid, with a yield of 10.89 mg and a yield of 54%, which was compound E4 of the matrine type alkaloid Flavesine G derivative. The nuclear magnetic resonance hydrogen spectrum, carbon spectrum and high resolution mass spectrum of compound E4 are shown in Figures 1-3 The nuclear magnetic resonance data are as follows: 1 H NMR (500 MHz, CDCl3) δH 11.03 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.55 (s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 3.28 (ddd, J = 5.0, 6.8, 19.5 Hz, 4H), 2.87 (t, J = 6.6 Hz, 2H), 2.70 (t, J = 6.3 Hz, 2H), 2.57 - 2.51 (m, 2H), 2.46 (t, J = 6.3 Hz, 2H), 2.16 - 2.07 (m, 2H), 2.03 - 1.92 (m, 2H), 1.86 - 1.77 (m, 2H). 13 C NMR (126 MHz, CDCl3) δC 171.9, 152.2, 147.9, 142.3, 134.1, 125.7, 125.7, 125.7, 125.4, 119.4, 115.1, 114.0, 70.6, 50.2, 49.6, 36.4, 30.4, 24.0, 23.6, 22.1, 19.6, 19.5. HR-ESI-MS: m / z calcd for [C 22 H 24 F3N3O+H] + : 404.1944 [M+H] + , found: 404.1942.

[0052] (2) Preparation of compound E5

[0053] The compound E5 is a derivative of Flavesine G, with the chemical formula: C 23 H 29 N3O, namely 4-(5,6,9,10-tetrahydro-4H,8H-pyrido[3,2,1-ij][1,6]naphthyridin-1-yl)-N-(4- ethylphenyl)butanamide, i.e., N-(4-ethylphenyl)-4-(5,6,9,10-tetrahydro-4H,8H-pyrido[3,2,1- ij][1,6]naphthyridin-1-yl)butanamide. The synthesis route of compound E5 is as follows:

[0054]

[0055] The specific preparation method of compound E5 is as follows:

[0056] The reaction raw material Flavesine G (13.00 mg, 0.05 mmol) was weighed into a 25 mL reaction bottle, acetonitrile (3.00 mL) was used as the reaction solvent, 4- ethylaniline (0.1 mmol, 12.12 mg), TCFH (21.00 mg, 0.075 mmol) and NMI (14.00 μL, 0.175 mmol) were added respectively, and stirred at room temperature overnight. The reaction was monitored by TCL, after the reaction was completed, the reaction mixture was concentrated under reduced pressure by a rotary evaporator, and then redissolved in 30 mL of chloroform, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution twice (10 mL x 2) respectively, and the organic phase was collected, dried with anhydrous sodium sulfate, filtered to remove insoluble impurities, and concentrated under reduced pressure to obtain the crude product. The white viscous solid was obtained by silica gel column chromatography using dichloromethane / methanol (V / V = 30:1) as the eluent, the yield was 13.99 mg, and the yield was 77%, which was the compound E5 of the matrine type alkaloid Flavesine G derivative. The nuclear magnetic resonance hydrogen spectrum, carbon spectrum and high resolution mass spectrum of compound E5 are shown in Figures 4-6 The nuclear magnetic resonance data are as follows: 1H NMR (400 MHz, CDC13) δ 9.37 (s, 1H), 7.59 - 7.53 (m, 2H), 7.44 (s, 1H), 7.10 - 7.03 (m, 2H), 3.37 (t, J = 5.9 Hz, 2H), 3.30 (t, J = 5.8 Hz, 2H), 2.95 (t, J = 6.8 Hz, 2H), 2.72 (t, J = 6.3 Hz, 2H), 2.66 (t, J = 6.5 Hz, 2H), 2.57 (q, J = 7.6 Hz, 2H), 2.36 (t, J = 6.3 Hz, 2H), 2.17 (p, J = 6.7 Hz, 2H), 2.04 - 1.94 (m, 2H), 1.77 (p, J = 6.2 Hz, 2H), 1.18 (t, J = 7.6 Hz, 3H). 13 C NMR (101 MHz, CDC13) δ 171.1, 152.0, 148.0, 139.4, 136.8, 134.4, 128.0, 119.7, 115.1, 114.2, 50.2, 49.6, 36.4, 30.7, 28.4, 23.9, 23.3, 22.1, 19.6, 15.9. HR-ESI-MS: m / z calcd for [C 23 H 29 N3O+H] + : 364.2383 [M+H] + , found: 364.2372.

[0057] (3) Preparation of compound E9

[0058] The compound E9 is a derivative of Flavesine G, with the chemical formula of: 23 H 26 F3N3O, which is 4-(5,6,9,10-tetrahydro-4H,8H-pyrido[3,2,1- ij][l,6]naphthyridin-l-yl)-N-(4-(trifluoromethyl)benzyl)butanamide. The synthetic route of compound E9 is as follows:

[0059]

[0060] The specific preparation method of compound E9 is as follows:

[0061] The reaction raw material Flavesine G (13.00 mg, 0.05 mmol) was weighed into a 25 mL reaction bottle, acetonitrile (3.00 mL) was used as the reaction solvent, 4- trifluoromethylbenzylamine (0.1 mmol, 17.52 mg), TCFH (21.00 mg, 0.075 mmol) and NMI (14.00 μL, 0.175 mmol) were added respectively, and stirred at room temperature overnight. TCL was used to monitor the reaction, and after the reaction was completed, the rotary evaporator was used to concentrate under reduced pressure, and the reaction mixture was redissolved with 30 mL of chloroform, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution respectively (10 mL x 2), and the organic phase was collected. Anhydrous sodium sulfate was used to dry the organic phase and filter out the insoluble impurities. After the solution was concentrated under reduced pressure, the crude product was obtained. Dichloromethane / methanol (V / V = 30:1) was used as the elution solvent, and silica gel column chromatography was used for purification to obtain a yellowish solid, with a yield of 16.28 mg, a yield of 78%, which was compound E9 of the matrine type alkaloid Flavesine G derivative. The nuclear magnetic resonance hydrogen spectrum, carbon spectrum and high resolution mass spectrum of compound E9 are shown in Figures 7-9 . The nuclear magnetic resonance data are as follows: 1 HNMR (500 MHz, CDCl3) δH 14.06 (s, 1H), 8.36 (t, J = 6.2 Hz, 1H), 7.63 (s, 1H), 7.52 (d, J = 8.2 Hz, 2H), 7.47 (d, J = 8.1 Hz, 2H), 4.44 (d, J = 6.0 Hz, 2H), 3.45-3.36 (m, 4H), 2.86 (t, J = 7.5 Hz, 2H), 2.68 (t, J = 6.5 Hz, 4H), 2.50 (t, J = 7.1 Hz, 2H), 2.07 (p, J = 7.3 Hz, 2H), 2.03-1.93 (m, 5H). 13 C NMR (126 MHz, CDCl3) δC 172.8, 152.3, 148.6, 143.4, 134.3, 128.1, 128.1, 125.3, 125.3, 125.3, 114.9, 113.6, 50.3, 49.6, 42.8, 35.6, 29.9, 29.7, 24.3, 24.1, 22.0, 19.8, 19.6. HR-ESI-MS: m / z calcd for [C 23 H 26 F3N3O+H] + : 418.2101 [M+H] + , found: 418.2095.

[0062] (4) Preparation of compound E11

[0063] The compound E11 is a derivative of Flavesine G, with the chemical formula: C 22 H 26 ClN3O, namely 4-(5,6,9,10-tetrahydro-4H,8H-pyrido[3,2,1-ij][1,6]naphthyridin-1-yl)-N-(4-chlorobenzyl)butanamide, i.e., N-(4-chlorobenzyl)-4-(5,6,9,10-tetrahydro-4H,8H-pyrido[3,2,1-ij][1,6]naphthyridin-1-yl)butanamide. The synthesis route of compound E11 is as follows:

[0064]

[0065] The specific preparation method of compound E11 is as follows:

[0066] The reaction raw material Flavesine G (13.00 mg, 0.05 mmol) was weighed into a 25 mL reaction bottle, acetonitrile (3.00 mL) was used as the reaction solvent, 4-chlorobenzylamine (0.1 mmol, 14.16 mg), TCFH (21.00 mg, 0.075 mmol) and NMI (14.00 μL, 0.175 mmol) were added respectively, and stirred at room temperature overnight. The reaction was monitored by TCL, after the reaction was completed, the reaction mixture was concentrated under reduced pressure by a rotary evaporator, and then redissolved in 30 mL of chloroform, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution (10 mL x 2) respectively twice, and then the organic phase was collected, dried with anhydrous sodium sulfate and filtered to remove insoluble impurities. After the solution was concentrated under reduced pressure, the crude product was obtained. The yellow viscous solid was purified by silica gel column chromatography using dichloromethane / methanol (V / V = 30:1) as the elution solvent, and the yield was 15.93 mg, the yield was 83%, which was the compound E11 of the matrine type alkaloid Flavesine G derivative. The nuclear magnetic resonance hydrogen spectrum, carbon spectrum and high resolution mass spectrum of compound E11 are shown in Figures 10-12 The nuclear magnetic resonance data are as follows: 1 HNMR (500 MHz, CDCl3) δH 8.13 (s, 1H), 7.60 (s, 1H), 7.27 (s, 4H), 4.42 (d, J = 5.8 Hz, 2H), 3.25-3.17 (m, 4H), 2.69 (t, J = 7.0 Hz, 2H), 2.66-2.60 (m, 4H), 2.27 (dd, J = 6.3, 7.6 Hz, 2H), 2.02-1.88 (m, 7H). 13C NMR (126 MHz, CDC13) δ 173.6, 154.9, 148.7, 144.0, 137.7, 132.9, 129.3, 128.7, 114.0, 113.0, 49.8, 49.0, 42.9, 35.5, 32.4, 24.8, 24.5, 23.0, 21.1, 21.1. HR-ESI-MS: m / z calcd for [C 22 H 26 ClN3O+H] + : 384.1837 [M+H] + , found: 384.1836.

[0067] (5) Preparation of compound E12

[0068] The compound E12 is a derivative of Flavesine G, with the chemical formula of: 22 H 26 BrN3O, namely 4-(5,6,9,10-tetrahydro-4H,8H-pyrido[3,2,1- ij][1,6]naphthyridin-1-yl)-N-(4-bromobenzyl)butanamide, i.e., N-(4-bromobenzyl)-4-(5,6,9,10-tetrahydro-4H,8H-pyrido[3,2,1-ij][1,6]naphthyridin-1-yl)butanamide. The synthetic route of the compound E12 is as follows:

[0069]

[0070] The specific preparation method of the compound E12 is as follows:

[0071] The reaction raw material Flavesine G (13.00 mg, 0.05 mmol) was weighed into a 25 mL reaction bottle, acetonitrile (3.00 mL) was used as the reaction solvent, 4-bromobenzylamine (0.1 mmol, 18.60 mg), TCFH (21.00 mg, 0.075 mmol) and NMI (14.00 μL, 0.175 mmol) were added respectively, and stirred at room temperature overnight. TCL was used to monitor the reaction. After the reaction was completed, the reaction mixture was concentrated under reduced pressure with a rotary evaporator, redissolved with 30 mL of chloroform, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution (10 mL x 2) respectively twice, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate and filtered to remove insoluble impurities. The solution was concentrated under reduced pressure to obtain the crude product. Dichloromethane / methanol (V / V = 30:1) was used as the elution solvent, and silica gel column chromatography was used for purification to obtain a yellow-brown sticky solid, with a yield of 18.42 mg and a yield of 86%, which was compound E12 of the matrine type alkaloid Flavesine G derivative. The nuclear magnetic resonance hydrogen spectrum, carbon spectrum and high resolution mass spectrum of compound E12 are shown in Figures 13-15 1 HNMR (500 MHz, CDCl3) δH 8.09 (t, J = 5.9 Hz, 1H), 7.60 (s, 1H), 7.43-7.37 (m, 2H), 7.25-7.18 (m, 2H), 4.35 (d, J = 5.9 Hz, 2H), 3.32 (ddd, J = 4.9, 6.5, 11.3 Hz, 4H), 2.78 (t, J = 7.3 Hz, 2H), 2.66 (td, J = 4.1, 6.4 Hz, 4H), 2.38 (t, J = 7.0 Hz, 2H), 2.02 (dt, J = 7.2, 13.6 Hz, 3H), 1.99-1.91 (m, 4H). 13 C NMR (126 MHz, CDCl3) δC 173.1, 151.4, 150.7, 138.6, 138.2, 131.5, 129.7, 120.9, 114.5, 113.4, 50.1, 49.4, 42.8, 35.6, 31.1, 24.5, 24.3, 22.5, 20.4, 20.3. HR-ESI-MS: m / z calcd for [C 22 H 26 BrN3O+H] + : 428.1332 [M+H] + , found: 428.1331.

[0072] Example 2: Cytotoxicity test of matrine type alkaloid Flavesine G derivatives (E4, E5, E9, E11 and E12) on A549 cells and 16HBE cells​

[0073] 1. Experimental method:

[0074] MTT method was used to determine the proliferation inhibition effect of Flavesine G derivative (E4, E5, E9, E11 and E12) alkaloids on non-small cell lung cancer cells (A549) and human normal bronchial epithelial cells (16HBE). The cells in logarithmic growth phase were prepared into a single cell suspension of 3-4x10 3 cells / mL, inoculated into 96-well plates (100 μL per well), and placed in a cell culture incubator (37℃, 5% CO2) for 24 hours. The drug administration group was added with the corresponding concentration of the test compound, and a positive control group (cisplatin) and a blank group were set up, with 3 replicate wells in each group. After 72 hours, 20 μL of MTT (5 mg / mL) was added to each well, and incubation was continued for 4 hours. The culture medium was then discarded, 200 μL of DMSO was added to each well, the 96-well plate was shaken for 15 minutes, and the absorbance value at 570 nm was determined using an enzyme marker. The inhibition rate was calculated according to the following formula:

[0075] Cell inhibition rate (%) = (OD 空白组 -OD 给药组 ) / OD 空白组 x 100%.

[0076] 2. Experimental results:

[0077] It was found that Flavesine G derivatives (E4, E5, E9, E11 and E12) significantly improved the cytotoxicity of non-small cell lung cancer A549 at a concentration of 10 μM, and the activity of compound E4 was slightly better than that of cisplatin ( Figure 16 ), indicating that the derivatives can efficiently and specifically inhibit the proliferation of non-small cell lung cancer cells. At the same time, these compounds (E4, E5, E9, E11 and E12) did not exhibit obvious cytotoxicity to human normal bronchial epithelial cells 16HBE at a concentration of 50 μM ( Figure 17 ), and had good safety and did not interfere with the physiological function of normal cells, which can significantly reduce the risk of toxic side effects in clinical application.

[0078] As can be seen from the above, the present application further derives Flavesine G derivatives (E4, E5, E9, E11 and E12) with novel structures on the basis of novel Flavesine G alkaloids. The synthesized new derivatives have better anti-non-small cell lung cancer activity, can effectively inhibit the proliferation of non-small cell lung cancer cells, and do not interfere with the physiological function of normal cells in the concentration range of exerting effective anticancer effect, and are expected to be used as main pharmaceutical ingredients to be made into preparations for use as lung cancer drugs, and have important reference and application value in the development of lung cancer drugs.

[0079] The embodiments of the present application are described in detail above, but the present application is not limited to the embodiments described. Various changes, modifications, replacements, and variations of the embodiments can be made by those skilled in the art without departing from the principles and spirit of the present application, and still fall within the scope of the present application.

Claims

1. A Flavesine G derivative of the matrine type alkaloid, characterized in that, The derivative includes at least one of compounds E4, E5, E9, E11 and E12:

2. Use of the Flavesine G derivative of the matrine type alkaloid according to claim 1 in the preparation of an anticancer drug.

3. Use of the Flavesine G derivative of the matrine type alkaloid according to claim 1 in the preparation of a drug for inhibiting the proliferation of cancer cells.

4. Use according to claim 2, characterized in that, The anticancer drug is an anti-lung cancer drug.

5. Use according to claim 3, characterized in that, The cancer cells are non-small cell lung cancer cells.

6. An anticancer drug, characterized by comprising the compound according to claim 1 or 2. The drug takes the Flavesine G derivative of the matrine type alkaloid according to claim 1 as the main active ingredient.

7. The anticancer drug according to claim 6, wherein The Flavesine G derivative of the matrine type alkaloid also includes a pharmaceutically acceptable salt of the derivative, a crystal form of the derivative, a solvate of the derivative, or an isotopically substituted compound of the derivative.

8. The anticancer drug according to claim 6, wherein The drug also includes a pharmaceutically acceptable excipient.

9. The anticancer drug according to claim 8, wherein The excipient includes at least one of an excipient, a solubilizer, an emulsifier, a coloring agent, a binder, a disintegrant, a filler, a lubricant, a wetting agent, an osmotic pressure regulator, a stabilizer, a glidant, a flavoring agent, a preservative, a coating material, a pH regulator, an absorbent, a diluent, and an antioxidant.

10. The anticancer drug according to claim 8, wherein The dosage form of the drug includes a tablet, a capsule, a granule, a powder, a syrup, an oral solution, or an injection.

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