Application of chalcone derivative in preparation of medicine for treating neurodegenerative diseases

Abstract

The invention discloses application of a chalcone derivative in preparation of a medicine for treating neurodegenerative diseases, belongs to the field of medicines, and researches the neuroprotective effect of a compound (2E)-3-(3, 4-dihydroxyphenyl)-1-(4-methoxyphenyl)-2-propylene-1-ketone by utilizing an oxidative stress model of nerve cells. Experimental results show that the compound can effectively inhibit oxidative stress injury of nerve cells, and a new treatment strategy is provided for treating neurodegenerative diseases.

Description

Technical Field

[0001] The invention belongs to the field of medicine, and specifically relates to the use of a chalcone derivative (2E)-3-(3,4-dihydroxyphenyl)-1-(4-methoxyphenyl)-2-propene-1-one in the preparation of a drug for treating neurodegenerative diseases. Background Art

[0002] Neurodegenerative disease is a complex disease characterized by massive loss of specific neurons in the brain and spinal cord. It is a progressive, degenerative, disabling or even fatal disease, such as stroke, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, etc.

[0003] Due to the complexity of brain function, the treatment of neurodegenerative diseases has always been a difficult problem in medicine. The pathology of neurodegenerative diseases involves many molecular mechanisms, such as oxidative stress, mitochondrial damage, and excitotoxicity.

[0004] Chalcone, also known as chalcone or chalcone, is a chemical compound produced in plants. Its scientific name is benzyl acetophenone, styryl phenyl ketone or styryl phenyl ketone (https: / / www.flavonoides.org / zh / Chalcone). Chalcone derivatives have a variety of pharmacological and biological activities, such as antibacterial activity (Dhaliwal, JS; Moshawih, S.; Goh, KW; Loy, MJ; Hossain, MS; Hermansyah, A.; Kotra, V.; Kifli, N.; Goh, HP; Dhaliwal, SKS; et al. Pharmacotherapeutics Applications and Chemistry of Chalcone Derivatives. Molecules 2022, 27, 7062. https: / / doi.org / 10.3390 / molecules27207062), antiviral activity (Hu Die. Synthesis and biological activity of chalcone derivatives containing indole or pyrazole oxime ethers [M]. Guizhou University, 2023.), and antitumor activity (Nadia AA Elkanzi.; Hajer Hrichi; et al. Synthesis of Chalcones Derivatives and Their Biological Activities: A Review. ACS Omega 2022, 7, 27769-27786.), anti-inflammatory activity (Li Dong. Synthesis and anti-inflammatory activity of chalcone derivatives [M]. Guangxi University, 2016.), antioxidant activity (He Liya. Synthesis and pharmacological activity of chalcone derivatives containing quinoline and benzoyl hydrazide [M]. Zhejiang Ocean University, 2022.), in addition, chalcone derivatives also have anti-malarial, anti-tuberculosis, anti-psychotic, analgesic, cardiotonic, blood circulation promoting, cholesterol control and other biological activities. Chalcone derivatives have broad prospects in the field of drug development and application due to their diverse biological activities.

[0005] Chen Lin et al. published a study titled "Progress of Chalcone Derivatives in Diagnosis and Treatment of Alzheimer's Disease. PROGRESS IN PHARMACEUTICAL SCIENCES 2019, 43(4): 293-299" which showed that some compounds have certain potential in the treatment of Alzheimer's disease. However, there are still few reports on the research of chalcone and its derivatives in the treatment of neurodegenerative diseases. Summary of the invention

[0006] In view of the deficiencies in the prior art, the present invention aims to provide an application of a chalcone derivative in the preparation of a drug for treating neurodegenerative diseases.

[0007] The present invention utilizes the oxidative stress model of nerve cells to study the neuroprotective effect of the compound (2E)-3-(3,4-dihydroxyphenyl)-1-(4-methoxyphenyl)-2-propene-1-one, providing important new ideas and potential therapeutic strategies for the treatment of neurodegenerative diseases.

[0008] The chalcone derivative of the present invention specifically refers to the compound (2E)-3-(3,4-dihydroxyphenyl)-1-(4-methoxyphenyl)-2-propene-1-one, English name: 2-Propen-1-one, 3-(3,4-dihydroxyphenyl)-1-(4-methoxyphenyl)-, (2E), CAS: 152809-80-8, molecular formula C 16 H 14 O4, molecular weight 270.28, structural formula:

[0009]

[0010] The present invention has found through experiments that the compound (2E)-3-(3,4-dihydroxyphenyl)-1-(4-methoxyphenyl)-2-propene-1-one at a concentration of 1 μM to 20 μM can prevent the decrease in cell survival rate induced by H2O2, wherein the compound (2E)-3-(3,4-dihydroxyphenyl)-1-(4-methoxyphenyl)-2-propene-1-one at a concentration of 1 μM and 5 μM significantly prevented the decrease in cell survival rate induced by H2O2 (P<0.001), and the ability to resist H2O2 oxidative stress increased with the increase in the concentration of the compound. Compared with the control group, the 5 μM compound restored 90% of the cell activity, with no significant difference.

[0011] The present invention also provides the use of the compound (2E)-3-(3,4-dihydroxyphenyl)-1-(4-methoxyphenyl)-2-propene-1-one in the preparation of a drug for inhibiting oxidative stress damage of nerve cells.

[0012] Since oxidative stress-induced nerve damage is the main pathological mechanism of neurodegenerative diseases, all drugs that can inhibit oxidative stress damage are likely to be potential drugs for treating neurodegenerative diseases. On PC12 neural cells, the compound (2E)-3-(3,4-dihydroxyphenyl)-1-(4-methoxyphenyl)-2-propene-1-one has an antioxidant effect at low concentrations, so the present invention also provides the use of the compound in the preparation of drugs for treating neurodegenerative diseases.

[0013] Beneficial effects of the present invention:

[0014] The drug capable of inhibiting oxidative stress damage provided by the present invention is an old drug with a new use and is a potential drug for treating neurodegenerative diseases.

[0015] The technical solution of the present invention not only provides a new perspective for understanding the occurrence and development of neurodegenerative diseases, but also provides potential candidate drugs for drug research and development. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 The compound (2E)-3-(3,4-dihydroxyphenyl)-1-(4-methoxyphenyl)-2-propene-1-one of the present invention 1 H NMR spectrum;

[0017] Figure 2 The compound (2E)-3-(3,4-dihydroxyphenyl)-1-(4-methoxyphenyl)-2-propene-1-one of the present invention 13 C NMR spectrum;

[0018] Figure 3 is the HRMS spectrum of the compound (2E)-3-(3,4-dihydroxyphenyl)-1-(4-methoxyphenyl)-2-propen-1-one of the present invention;

[0019] Figure 4 The results of the CCK-8 assay for cell activity of the present invention; **P<0.01, ***P<0.001, NS indicates no significant difference. DETAILED DESCRIPTION

[0020] The present invention is further described in detail below with specific embodiments, but it should not be understood that the scope of the above subject matter of the present invention is limited to the following embodiments, and all technologies realized based on the content of the present invention belong to the scope of the present invention.

[0021] Unless otherwise specified, all reagents and materials used in the present invention are commercially available.

[0022] Example 1: Preparation of Compound (2E)-3-(3,4-dihydroxyphenyl)-1-(4-methoxyphenyl)-2-propen-1-one

[0023] 162 mg of 4-methoxyacetophenone was added to a 10 mL round-bottom flask, 1.5 mL of anhydrous ethanol was added to dissolve, 1 mL of 60% sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for 10 min. 153.02 mg of 3,4-dihydroxybenzaldehyde was added, and the mixture was stirred at 85 ° C for 10 min. The mixture was cooled to room temperature, acidified with hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1-1:10, v / v) to obtain 107.6 mg of the product with a yield of 36.9%.

[0024] like Figure 1 As shown, 1 H NMR (400MHz, DMSO-d6) δ8.15–8.07(m,2H),7.62(d,J=15.5Hz,1H),7.56(d,J=15.5Hz,1H),7.25(d ,J=2.1Hz,1H),7.17(dd,J=8.2,2.1Hz,1H),7.11–7.02(m,2H),6.81(d,J=8.1Hz,1H),3.86(s,3H).

[0025] like Figure 2 As shown, 13 C NMR (101MHz, DMSO-d6) δ187.24,162.96,148.54,145.59,144.08,130.85,130.66,126.42,121.99,118.37,115.74,115.51,113.95,55.53.

[0026] like Figure 3 As shown, HRMS (ESI) calculated for C 16 H 14 O4[M+H] + :271.0965,found271.0969.

[0027] Example 2: Study on the Antioxidative Stress Effect of Chalcone Derivatives of the Present Invention

[0028] 1. Experimental Methods

[0029] 1.1 Establishment of oxidative stress model of PC12 cells

[0030] PC12 cells were purchased from Wuhan Pronocell Life Science Co., Ltd. and cultured in DMEM containing 10% FBS, 100 U / mL penicillin and 100 U / mL streptomycin at 37°C in a cell culture incubator with 95% air and 5% CO2. 5 The cells were plated in 96-well plates at a density of 100 μM / well. After 24 hours, PC12 cells were first treated with 300 μM H2O2 for 30 minutes. Then, the compound (2E)-3-(3,4-dihydroxyphenyl)-1-(4-methoxyphenyl)-2-propene-1-one was added, and the final concentrations of the compound were 1, 5, 10, 20 and 40 μM, respectively. After 24 hours, the cell activity was detected by Cell Counting Kit-8 (CCK-8 kit).

[0031] 1.2CCK-8 detection

[0032] According to the instructions of the reagent, the cell viability was detected using the CCK-8 kit. After PC12 cells seeded in a 96-well plate were treated with compound (2E)-3-(3,4-dihydroxyphenyl)-1-(4-methoxyphenyl)-2-propene-1-one for 24 h, 10 μL of CCK-8 solution was added to each well and incubated at 37°C for 30 min. Thereafter, the absorbance (OD value) at 450 nm was measured using a microplate reader (BioTek).

[0033] The cell viability calculation formula is as follows:

[0034]

[0035] 2. Experimental results

[0036] The compound (2E)-3-(3,4-dihydroxyphenyl)-1-(4-methoxyphenyl)-2-propen-1-one significantly inhibited H2O2-mediated oxidative stress-induced PC12 cell loss and increased cell activity.

[0037] In order to further study the role of the compound (2E)-3-(3,4-dihydroxyphenyl)-1-(4-methoxyphenyl)-2-propene-1-one (hereinafter referred to as the drug) in vivo, we used H2O2 to induce oxidative stress damage in PC12 cells. PC12 cells were first incubated with 300μM H2O2 for 30min, and then treated with drugs at different final concentrations (1, 5, 10, 20 and 40μM). After incubation for 24h, CCK-8 was used to detect cell activity. Figure 4As shown in the figure, compared with the control group, 300μM H2O2 induced a 55% reduction in cell viability and a significant decrease in cell viability (P<0.001). Compared with the H2O2 group, 1μM and 5μM concentrations of the drug significantly prevented the decrease in cell viability induced by H2O2 (P<0.001), and the ability to resist H2O2 oxidative stress increased with the increase in drug concentration. Compared with the control group, 5μM of the drug restored 90% of cell viability, with no significant difference. After that, as the drug concentration (10μM, 20μM, 40μM) increased, the biological activity of the drug decreased. The 40μM drug no longer had significant antioxidant activity.

[0038] Since oxidative stress-induced neural damage is the main pathological mechanism of neurodegenerative diseases, all drugs that can inhibit oxidative stress damage are likely to be potential drugs for the treatment of neurodegenerative diseases. Our research found that the compound (2E)-3-(3,4-dihydroxyphenyl)-1-(4-methoxyphenyl)-2-propene-1-one has an antioxidant effect on PC12 neural cells at low concentrations, so it is inferred that it has therapeutic potential in the treatment of neurodegenerative diseases.

Claims

1. Use of a chalcone derivative in the preparation of a drug for treating neurodegenerative diseases.

2. Use of a chalcone derivative in the preparation of a drug for inhibiting oxidative stress damage to nerve cells.

3. The use according to claim 1 or 2, characterized in that: The chalcone derivative specifically refers to the compound (2E)-3-(3,4-dihydroxyphenyl)-1-(4-methoxyphenyl)-2-propene-1-one, with the structural formula:

4. The use according to claim 1 or 2, characterized in that: The effective concentration of the chalcone derivative for inhibiting oxidative stress damage of nerve cells is 1 μM-20 μM.

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