CN109265332B - Polyhydroxy chalcone compound and application thereof - Google Patents

Polyhydroxy chalcone compound and application thereof Download PDF

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CN109265332B
CN109265332B CN201811136775.6A CN201811136775A CN109265332B CN 109265332 B CN109265332 B CN 109265332B CN 201811136775 A CN201811136775 A CN 201811136775A CN 109265332 B CN109265332 B CN 109265332B
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戴荣继
丛林
李博
邓玉林
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Abstract

The invention provides a polyhydroxy chalcone compound and application thereof. The compound has a good inhibition effect on the aggregation of the A beta protein, and can effectively eliminate or reduce the toxicity caused by the aggregation of the A beta protein in a cell experiment. Meanwhile, the compound can also be used as a free radical peroxidation inhibitor, and further can inhibit cell iron death, so that the compound can be used for treating Alzheimer's disease or used as a free radical peroxidation inhibitor and the like.

Description

Polyhydroxy chalcone compound and application thereof
Technical Field
The invention relates to the field of medical chemistry, in particular to a polyhydroxy chalcone compound and application thereof.
Background
Alzheimer's Disease (AD) is a progressive degenerative disease of the nervous system, the main pathological features of which are memory impairment, language expression confusion, severe behavioral abnormalities and learning ability deficiency, etc. In 2013, the international association for alzheimer's disease issued a report that statistics show that AD patients worldwide have about 4400 million people, and by 2050, the number of patients is expected to increase to 1.35 million people. There are only 5 drugs currently approved for the treatment of alzheimer's disease, of which 4 are acting on acetylcholinesterase or butyrylcholinesterase, tacrine, donepezil, rivastigmine and galantamine, respectively. Another is memantine, whose action is targeted at the N-methyl-D-aspartate receptor. The medicine can relieve the symptoms of AD patients, but cannot cure the patients or even prevent the disease from deteriorating, so a great deal of manpower and capital are invested in the clinical development of new AD treatment medicines.
Because the pathogenesis of AD is complex and has not been fully elucidated so far, several hypotheses have been proposed for the pathogenesis of AD, the most widely accepted hypothesis by researchers being the β -amyloid hypothesis. Senile plaques generated by the accumulation of beta-amyloid in the brain have high neurotoxicity, so that the A beta protein is considered to be one of the key targets for preventing the worsening of the AD disease and even curing the AD.
The process of AD pathogenesis is often accompanied by oxidative stress, including lipid peroxidation. However, there are studies that have shown that an increase in lipid peroxidation leads to an increase in A β protein by upregulation of β -secretase. Therefore, if the drug can inhibit the aggregation of A beta protein and lipid peroxidation simultaneously, AD can be treated more effectively.
Iron death is a newly discovered apoptosis in recent years characterized by the accumulation of lipid peroxidation and dysregulation of iron ions, which are also present in most neurodegenerative diseases, including AD. Inhibition of cellular iron death is therefore also a potential approach for the treatment of AD.
Chalcone is a common compound in natural products and is an important active ingredient in the traditional Chinese medicine dragon blood. Chalcones have been reported to possess a number of pharmacological activities, such as antioxidant, anti-inflammatory, anti-tumor and neuroprotective effects, among others. Therefore, the inventors have developed the synthesis of chalcone series compounds, and have searched for new compounds and studied their activities.
Disclosure of Invention
The invention aims to provide a polyhydroxy chalcone compound.
The invention also provides the application of the compound, which is the application in preparing medicaments for preventing and treating Alzheimer disease.
The purpose of the invention is realized by the following technical scheme:
a polyhydroxy chalcone compound having a structure according to formula (I):
Figure RE-GDA0001886942180000021
wherein R is1、R2、R3、R4And R5Is hydrogen, hydroxy, C1-8Alkyl or (C)1-8) Alkoxy group of (a); r6、 R7、R8、R9And R10Is hydrogen, halogen, (C)1-8) Alkoxy, hydroxy, CN, NO2、CF3、SH、 NH2、C1-8Alkyl, S-C1-8-alkyl, NHC1-8Alkyl or N (C)1-8-alkyl groups)2。
Preferably, the following components are adopted: r1、R2、R3、R4And R5Is hydrogen, hydroxy, methyl or methoxy; r6、R7、 R8、R9And R10Is hydrogen, halogen, (C)1-3) Alkoxy, hydroxy or C1-3An alkyl group.
Specifically, the polyhydroxy chalcone compound is: (E) -3' -hydroxy-3-methylchalcone, (E) -3' -hydroxy-3, 4-dimethoxychalcone, (E) -3',5' -dihydroxy-3-methylchalcone, (E) -3',5' -dihydroxy-4-methoxychalcone, (E) -2' -hydroxy-3 ',4' -dimethoxymethoxy-3-methylchalcone, (E) -2' -hydroxy-3 ',4' -dimethoxymethoxy-4-chlorochalcone, (E) -2',3',4' -trihydroxy-3-methylchalcone, (E) -2',3',4' -trihydroxy-4-chlorochalcone or (E) -2',3',4' -trihydroxy-3-methoxychalcone.
Preferably, the following components are adopted: (E) -2',3',4' -trihydroxy-3-methylchalcone, (E) -2',3',4' -trihydroxy-4-chlorochalcone or (E) -2',3',4' -trihydroxy-3-methoxychalcone.
The polyhydroxy chalcone compound is prepared by reacting acetophenone compounds and benzaldehyde compounds.
The preparation process comprises the following steps:
1) firstly, dissolving hydroxyl-substituted acetophenone in anhydrous acetone, adding anhydrous potassium carbonate with 2-3 times of equivalent, dropwise adding bromomethyl ether with 3-5 times of equivalent in an ice bath, carrying out reflux reaction for 3-6 h, cooling to room temperature, and carrying out post-treatment to obtain the acetophenone protected by methoxymethyl.
2) And then dissolving the acetophenone protected by the methoxymethyl group and the corresponding benzaldehyde in ethanol and 10% KOH solution, stirring at room temperature for 12-48 h, dropwise adding 10% HCI to adjust the pH to 6, and performing aftertreatment to obtain the corresponding chalcone compound protected by the methoxymethyl group.
3) Dissolving the product obtained in the step 2) in methanol, dropwise adding a 10% HCI aqueous solution under the condition of heating reflux, reacting for 0.5-1 h, and performing post-treatment to obtain the final chalcone target compound.
The polyhydroxy chalcone compound provided by the invention is applied to preparation of medicines for treating Alzheimer's disease and the like or application of the polyhydroxy chalcone compound serving as a free radical peroxidation inhibitor.
The invention can be used independently or made into other clinically usable medicines with different formulations, including powder, injection, capsule, pill, microcapsule, tablet, film, soft capsule, paste, suppository, aerosol, tincture, oral liquid and granule. Pharmaceutically acceptable pharmaceutical adjuvants including filler, binder, wetting agent, disintegrating agent, pH regulator or lubricant can be added according to pharmaceutical preparation.
Compared with the existing A beta protein inhibitor with better effect, the polyhydroxy chalcone compound provided by the invention has better inhibition effect in vitro and in a cell model, and can inhibit cell iron death by inhibiting lipid peroxidation.
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FIG. 1 is a Th T method for detecting the activity of the polyhydroxy chalcone compound;
FIG. 2 shows the cytotoxicity of the polyhydroxy chalcone compounds and the degree of inhibition of toxicity of the compounds on A beta protein aggregation;
FIG. 3 shows the degree of inhibition of lipid peroxidation by the polyhydroxy chalcone compounds.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Example 1
Figure RE-GDA0001886942180000041
(E) Preparation of (6a) 3' -hydroxy-3-methylchalcone
A50 mL three-necked flask was charged with 1.36g (0.01mol) of 3-hydroxyacetophenone, 20mL of ethanol and 10mL of an aqueous solution of KOH (10%), and the mixture was stirred at room temperature to dissolve it sufficiently, and then 1.2g (0.01mol) of 3-methylbenzaldehyde was added thereto and stirred at room temperature for 24 hours. After the reaction was monitored to be complete, 10% HCl was added dropwise to acidify the mixture to PH 6, the mixture was extracted 3 times with 30mL of ethyl acetate, and the ethyl acetate phase was combined, washed with 20mL of saturated brine, concentrated by rotary evaporation, and dried to obtain a yellow solid. Column chromatography (200-400 mesh silica gel) gave 1.77g of yellow powdery solid (6a) in 74.2% yield.
After the detection, the detection result shows that,1h NMR is:1H NMR(700MHz,CDCl3)7.82(d,J＝15.7Hz,1H), 7.72(dd,J＝2.3,1.7Hz,1H),7.59(d,J＝7.7Hz,1H),7.52(d,J＝15.7Hz,1H), 7.44(s,1H),7.43(d,J＝7.7Hz,1H),7.39(t,J＝7.9Hz,1H),7.31(t,J＝7.7Hz,1H), 7.24(d,J＝7.4Hz,1H),7.18(ddd,J＝8.1,2.5,0.7Hz,1H),2.40(s,3H)；
13c NMR is:
13C NMR(100MHz,CDCl3)191.54(s),156.76(s),146.06(s),139.29(s), 138.61(s),134.54(s),131.68(s),129.89(s),129.28(s),128.83(s),125.82(s), 121.63(s),120.86(s),120.77(s),115.42(s),21.28(s)；
HRMS Mass Spectrometry (EI) m/z: c16H14O2Theoretical calculation value: 239.0994, respectively; test values are: 239.1056.
example 2
Figure RE-GDA0001886942180000042
(E) Preparation of (6b) 3' -hydroxy-3, 4-dimethoxychalcone
A50 mL three-necked flask was charged with 1.36g (0.01mol) of 3-hydroxyacetophenone, 20mL of ethanol and 10mL of an aqueous solution of KOH (10%), and after stirring at room temperature to dissolve them sufficiently, 1.66g (0.01mol) of 3, 4-dimethoxybenzaldehyde was added and stirred at room temperature for 24 hours. After the reaction was monitored to be complete, 10% HCl was added dropwise to acidify the mixture to PH 6, the mixture was extracted 3 times with 30mL of ethyl acetate, and the ethyl acetate phase was combined, washed with 20mL of saturated brine, concentrated by rotary evaporation, and dried to obtain a yellow solid. Column chromatography (200-400 mesh silica gel) gave 1.76g of a yellow powdery solid (6b) in 61.9% yield.
After the detection, the detection result shows that,1h NMR is:1H NMR(700MHz,CDCl3)7.75(d,J＝15.6Hz,1H), 7.67(dd,J＝8.4,1.8Hz,1H),7.61(d,J＝1.8Hz,1H),7.51(d,J＝15.6Hz,1H), 7.27(d,J＝5.8Hz,1H),7.19(d,J＝7.7Hz,1H),7.16(s,1H),6.94(dd,J＝8.1,1.9 Hz,1H),6.91(d,J＝8.4Hz,1H),3.96(s,3H),3.94(s,3H)；
13c NMR is:
13C NMR(175MHz,CDCl3)189.51(s),156.57(s),153.56(s),149.24(s), 144.57(s),136.35(s),130.98(s),130.14(s),123.47(s),121.74(s),120.73(s), 117.93(s),115.19(s),110.84(s),110.09(s),56.13(s),56.03(s)；
HRMS Mass Spectrometry (EI) m/z: c17H16O4Theoretical calculation value: 285.1049, test value: 285.1113.
example 3
Figure RE-GDA0001886942180000051
(E) Preparation of (E) -3',5' -dihydroxy-3-methylchalcone (10a)
1) Step 1: synthesis of 3-hydroxy-5-methoxy acetophenone
A50 mL three-necked flask was charged with 1.52g (0.01mol) of 3, 5-dihydroxyacetophenone, 30mL of anhydrous acetone and 2.76g (0.02mol) of anhydrous potassium carbonate, stirred in an ice bath for 30min, slowly added dropwise with a mixture of 4mL (0.05mol) of bromomethyl ether and 5mL of acetone, and refluxed for 4 hours. After the reaction was monitored by TLC to completion, it was cooled to room temperature and filtered of impurities, and after rotary evaporation of the dry solvent, column chromatography on silica gel gave 1.58g of oily liquid in 65.8% yield.
2) Step 2: (E) synthesis of (E) -3 '-hydroxy-5' -methoxymethoxy-3-methylchalcone
A50 mL three-necked flask was charged with an aqueous solution of 2.40g (0.01mol) of 3-hydroxy-5-methoxymethoxyacetophenone, 20mL of ethanol and 10mL of KOH (10%), and stirred at room temperature to sufficiently dissolve the compounds, and then 1.66g (0.01mol) of 3-methylbenzaldehyde was added thereto and stirred at room temperature for 24 hours. After the reaction was monitored to be complete, 10% HCl was added dropwise to acidify the mixture to PH 6, the mixture was extracted 3 times with 30mL of ethyl acetate, and the ethyl acetate phase was combined, washed with 20mL of saturated brine, concentrated by rotary evaporation, and dried to obtain a yellow solid. Column chromatography (200-400 mesh silica gel) gave 2.55g of a yellow powdery solid in 74.5% yield.
After the detection, the detection result shows that,1h NMR is:
1H NMR(400MHz,CDCl3)13.31(s,1H),7.84(d,J＝4.8Hz,1H),7.81(d,J ＝1.4Hz,1H),7.53(d,J＝15.5Hz,1H),7.43(s,H),7.42(d,J＝6.1Hz,1H),7.29(t, J＝7.8Hz,1H),7.21(d,J＝7.5Hz,1H),6.63(d,J＝2.4Hz,1H),6.57(dd,J＝8.9, 2.4Hz,1H),5.20(s,2H),3.47(s,3H),2.38(s,3H)；
13c NMR is:
13C NMR(175MHz,CDCl3)192.07(s),166.25(s),163.66(s),144.84(s), 138.69(s),134.69(s),131.64(s),131.40(s),129.16(s),128.90(s),119.97(s), 114.97(s),108.24(s),103.94(s),94.03(s),56.42(s),21.36(s)；
HRMS Mass Spectrometry (EI) m/z: c18H18O4Theoretical calculation value: 299.1205, test value: 299.1289.
3) and step 3: (E) synthesis of (E) -3',5' -dihydroxy-3-methylchalcone (10a)
In a 50mL three-necked flask, 0.342g (1mmol) of 3 '-hydroxy-5' -methoxymethoxy-3-methylchalcone and 20mL of methanol were placed, and after heating and refluxing, 5mL of a 10% HCl aqueous solution was slowly dropped and reacted for half an hour under refluxing conditions. After the reaction was completed, it was cooled to room temperature, diluted with 40mL of water, extracted three times with 50mL of ethyl acetate, the organic phase solutions were combined, the solvent was rotary evaporated and dried, and recrystallized from a mixed solution of ethyl acetate and petroleum ether to give 10a 0.171g of a yellow powdery solid in 67.4% yield.
After the detection, the detection result shows that,1h NMR is:
1H NMR(400MHz,MeOD)7.94(d,J＝8.9Hz,1H),7.76(d,J＝15.5Hz, 1H),7.70(d,J＝15.5Hz,1H),7.50(s,1H),7.49(d,J＝8.7Hz,1H),7.28(t,J＝7.5 Hz,1H),7.21(d,J＝7.5Hz,1H),6.42(dd,J＝8.9,2.4Hz,1H),6.31(d,J＝2.4Hz, 1H),2.36(s,3H)；
13c NMR is:
13C NMR(175MHz,MeOD)191.95(s),166.24(s),165.21(s),143.97(s), 138.49(s),134.85(s),132.19(s),131.03(s),128.93(s),128.51(s),125.49(s), 120.13(s),113.30(s),107.89(s),102.46(s),19.95(s)；
HRMS Mass Spectrometry (EI) m/z: c16H14O3Theoretical calculation value: 255.0943, test value: 255.1020.
example 4
Figure RE-GDA0001886942180000071
(E) Preparation of (E) -3',5' -dihydroxy-4-methoxychalcone (10b)
1) Step 1: synthesis of 3-hydroxy-5-methoxy acetophenone
The preparation method is the same as that of step 1 of example 3.
2) Step 2: (E) synthesis of (E) -3 '-hydroxy-5' -methoxymethoxy-4-methoxychalcone
A50 mL three-necked flask was charged with 2.40g (0.01mol) of 3-hydroxy-5-methoxymethylacetophenone, 20mL of ethanol and 10mL of KOH (10%) as an aqueous solution, and stirred at room temperature to be sufficiently dissolved, and then 1.36g (0.01mol) of 4-methoxybenzaldehyde was added thereto and stirred at room temperature for 24 hours. After the reaction was monitored to be complete, 10% HCl was added dropwise to acidify the mixture to PH 6, the mixture was extracted 3 times with 30mL of ethyl acetate, and the ethyl acetate phase was combined, washed with 20mL of saturated brine, concentrated by rotary evaporation, and dried to obtain a yellow solid. Column chromatography (200-400 mesh silica gel) gave 2.29g of a yellow powdery solid in 64.2% yield.
After the detection, the detection result shows that,1h NMR is:
1H NMR(400MHz,CDCl3)13.28(s,1H),7.82(d,J＝4.5Hz,1H),7.79(d,J＝1.9 Hz,1H),7.52(d,J＝15.4Hz,1H),7.31(t,J＝7.9Hz,1H),7.21(d,J＝7.7Hz,1H), 7.12(s,1H),6.95(dd,J＝8.1,2.4Hz,1H),6.62(d,J＝2.4Hz,1H),6.57(dd,J＝8.9, 2.4Hz,1H),5.20(s,2H),3.83(s,3H),3.47(s,3H)；
13c NMR is:
13C NMR(175MHz,CDCl3)191.97(s),166.24(s),163.70(s),159.97(s),144.51 (s),136.09(s),131.40(s),130.00(s),121.17(s),120.48(s),116.39(s),114.92(s), 113.68(s),108.27(s),103.93(s),94.02(s),56.42(s),55.34(s).
HRMS Mass Spectrometry (EI) m/z: c18H18O5Theoretical calculation value: 315.1154, test value: 315.1233.
3) and step 3: (E) synthesis of (E) -3',5' -dihydroxy-4-methoxychalcone (10b)
In a 50mL three-necked flask, 0.358g (1mmol) of 3 '-hydroxy-5' -methoxymethoxy-4-methoxychalcone and 20mL of methanol were placed, and after heating and refluxing, 5mL of a 10% HCl aqueous solution was slowly dropped, and the reaction was carried out under refluxing conditions for half an hour. After the reaction was complete, the reaction mixture was cooled to room temperature, diluted with 40mL of water and extracted three times with 50mL of ethyl acetate, the organic phase solutions were combined and the solvent was rotary evaporated and dried, and recrystallized from a mixture of ethyl acetate and petroleum ether to give 10b 0.198g of a yellow powdery solid with a yield of 73.4%.
After the detection, the detection result shows that,1h NMR is:
1H NMR(400MHz,MeOD)7.92(d,J＝8.9Hz,1H),7.73(d,J＝15.5Hz,1H), 7.67(d,J＝15.5Hz,1H),7.32–7.17(m,3H),6.93(dd,J＝7.8,1.8Hz,1H),6.41 (dd,J＝8.9,2.4Hz,1H),6.31(d,J＝2.4Hz,1H),3.80(s,3H)；
13c NMR is:
13C NMR(175MHz,MeOD)191.86(s),166.22(s),165.21(s),160.10(s),143.71 (s),136.22(s),132.24(s),129.58(s),120.94(s),120.58(s),116.12(s),113.32(s), 113.12(s),107.91(s),102.48(s),54.42(s)；
HRMS Mass Spectrometry (EI) m/z C16H14O4Theoretical calculation value: 271.0892, test value: 271.0946.
example 5
Figure RE-GDA0001886942180000081
(E) Preparation of (14a) 2',3',4' -trihydroxy-3-methylchalcone
1) Step 1: synthesis of 2-hydroxy-3, 4-dimethoxymethylacetophenone
A50 mL three-necked flask was charged with 1.68g (0.01mol) of 2,3, 4-trihydroxyacetophenone, 30mL of anhydrous acetone and 2.76g (0.02mol) of anhydrous potassium carbonate, stirred in an ice bath for 30min, slowly added dropwise with a mixture of 6mL (0.05mol) of bromomethyl ether and 5mL of acetone, and reacted under reflux for 4 h. After the reaction was monitored by TLC to completion, it was cooled to room temperature and filtered of impurities, and after rotary evaporation of the dry solvent, column chromatography on silica gel gave 1.01g of oily liquid in 42.2% yield.
2) Step 2: (E) synthesis of (E) -2' -hydroxy-3 ',4' -dimethoxymethoxy-3-methylchalcone (13a)
A50 mL three-necked flask was charged with 2.41g (0.01mol) of 2-hydroxy-3, 4-dimethoxymethoxyacetophenone, 20mL of ethanol and 10mL of an aqueous solution of KOH (10%), and after stirring at room temperature to sufficiently dissolve the compounds, 1.20g (0.01mol) of 3-methylbenzaldehyde was added and stirred at room temperature for 24 hours. After the reaction was monitored to be complete, 10% HCl was added dropwise to acidify the mixture to PH 6, the mixture was extracted 3 times with 30mL of ethyl acetate, and the ethyl acetate phase was combined, washed with 20mL of saturated brine, concentrated by rotary evaporation, and dried to obtain a yellow solid. Column chromatography (200-400 mesh silica gel) gave 2.53g of a yellow powdery solid in 70.7% yield.
Through detection:1h NMR is:
1H NMR(400MHz,CDCl3)13.34(s,1H),7.84(d,J＝15.5Hz,1H),7.65(d,J＝ 9.2Hz,1H),7.53(d,J＝15.5Hz,1H),7.45–7.40(m,2H),7.29(t,J＝7.8Hz,1H), 7.21(d,J＝7.5Hz,1H),6.73(d,J＝9.1Hz,1H),5.28(s,2H),5.22(s,2H),3.65(s, 3H),3.50(s,3H),2.38(s,3H)；
13C NMR was:
13C NMR(175MHz,CDCl3)192.72(s),158.63(s),156.38(s),145.18(s),138.73 (s),134.62(s),134.02(s),131.73(s),129.21(s),128.93(s),126.12(s),125.92(s), 119.97(s),116.13(s),106.06(s),98.04(s),94.63(s),57.31(s),56.53(s),21.37(s)；
HRMS Mass Spectrometry (EI) m/z: c20H22O6Theoretical calculation value: 359.1416, test value: 359.1492.
3) and step 3: (E) synthesis of (E) -2',3',4' -hydroxy-3-methylchalcone (14a)
A50 mL three-necked flask was charged with 0.358g (1mmol) of 13a and 20mL of methanol, heated to reflux, and then 5mL of a 10% aqueous HCl solution was slowly added dropwise to the mixture, followed by reaction under reflux for half an hour. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with 40mL of water, extracted three times with 50mL of ethyl acetate, the organic phase solutions were combined, the solvent was rotary evaporated and dried, and recrystallized from a mixed solution of ethyl acetate and petroleum ether to give 10b 0.242g of a yellow powdery solid with a yield of 89.6%.
After the detection, the detection result shows that,1h NMR is:
1H NMR(400MHz,Acetone)13.53(s,1H),8.29(s,1H),7.93(d,J＝15.5Hz,1H), 7.84(d,J＝15.5Hz,1H),7.73(d,J＝8.9Hz,1H),7.68(s,1H),7.62(d,J＝7.6Hz, 1H),7.33(t,J＝7.6Hz,1H),7.26(d,J＝7.5Hz,1H),6.53(d,J＝8.9Hz,1H),2.37 (s,3H)；
13c NMR is:
13C NMR(176MHz,Acetone)192.51(s),153.44(s),152.04(s),144.12(s), 138.58(s),134.95(s),132.41(s),131.40(s),129.26(s),128.85(s),126.15(s), 122.58(s),120.55(s),113.86(s),107.59(s),20.42(s)；
HRMS Mass Spectrometry (EI) m/z: c16H14O4Theoretical calculation value: 271.0892, test value: 271.0951.
example 6
Figure RE-GDA0001886942180000101
(E) Preparation of (E) -2',3',4' -trihydroxy-3-methoxychalcone (14b)
1) Step 1: synthesis of 2-hydroxy-3, 4-dimethoxymethylacetophenone
The preparation method is the same as the step 1 of the example 5.
2) Step 2: (E) synthesis of (E) -2' -hydroxy-3 ',4' -dimethoxymethoxy-3-methoxychalcone (13b)
A50 mL three-necked flask was charged with 2.41g (0.01mol) of 2-hydroxy-3, 4-dimethoxyacetophenone, 20mL of ethanol and 10mL of an aqueous solution of KOH (10%), and after stirring at room temperature to sufficiently dissolve them, 1.40g (0.01mol) of 3-methoxybenzaldehyde was added and stirred at room temperature for 24 hours. After the reaction was monitored to be complete, 10% HCl was added dropwise to acidify the mixture to PH 6, the mixture was extracted 3 times with 30mL ethyl acetate, and the ethyl acetate phase was combined, washed with 20mL saturated brine, concentrated by rotary evaporation, and dried to obtain a yellow solid. Column chromatography (200-400 mesh silica gel) gave 2.59g of a yellow powdery solid in 68.4% yield.
After the detection, the detection result shows that,1h NMR is:
1H NMR(400MHz,Acetone)13.59(s,1H),8.01(d,J＝9.2Hz,1H),7.89(d,J＝ 15.4Hz,1H),7.85–7.80(m,3H),7.03(s,1H),7.01(s,1H),6.80(d,J＝9.1Hz,1H), 5.35(s,2H),5.15(s,2H),3.87(s,4H),3.60(s,4H),3.49(s,4H)；
13c NMR is:
13C NMR(175MHz,CDCl3)192.67(s),161.96(s),158.59(s),156.20(s),144.84 (s),134.02(s),130.50(s),127.42(s),125.94(s),117.68(s),116.19(s),114.51(s), 105.97(s),98.04(s),94.63(s),57.30(s),56.52(s),55.47(s)；
HRMS Mass Spectrometry (EI) m/z: c20H22O7Theoretical calculation value: 375.1366, test value: 375.1434.
3) and step 3: (E) synthesis of (E) -2',3',4' -hydroxy-3-methoxychalcone (14b)
A50 mL three-necked flask was charged with 0.378g (1mmol) of 13b and 20mL of methanol, heated to reflux, and then 5mL of a 10% aqueous HCl solution was slowly added dropwise to the mixture, followed by reaction under reflux for half an hour. After the reaction is completed, the reaction product is cooled to room temperature, 40mL of water is added for dilution, the mixture is extracted three times by 50mL of ethyl acetate, organic phase solutions are combined, the solvent is evaporated in a rotary mode and dried, and the mixture is recrystallized by a mixed solution of ethyl acetate and petroleum ether to obtain yellow powdery solid 10b 0.256g, and the yield is 88.3%.
After the detection, the detection result shows that,1h NMR is:
1H NMR(400MHz,CDCl3)13.62(s,1H),7.87(d,J＝15.4Hz,1H),7.62(d,J＝ 8.7Hz,2H),7.49-7.45(m,2H),6.95(d,J＝8.7Hz,1H),6.57(d,J＝8.9Hz,1H), 3.87(s,3H)；
13c NMR is:
13C NMR(175MHz,MeOD)192.60(s),161.94(s),153.04(s),151.96(s),143.72 (s),132.37(s),130.20(s),127.51(s),121.97(s),117.80(s),114.07(s),113.76(s), 107.20(s),54.49(s)；
HRMS Mass Spectrometry (EI) m/z: c16H14O5Theoretical calculation value: 287.0841, test value: 287.0917.
example 7
Figure RE-GDA0001886942180000121
(E) Preparation of (E) -2',3',4' -trihydroxy-4-chlorochalcone (14c)
1) Step 1: synthesis of 2-hydroxy-3, 4-dimethoxymethylacetophenone
The preparation method is the same as the step 1 of the example 5.
2) Step 2: (E) synthesis of (E) -2' -hydroxy-3 ',4' -dimethoxymethoxy-4-chlorochalcone (13c)
A50 mL three-necked flask was charged with 2.41g (0.01mol) of 2-hydroxy-3, 4-dimethoxyacetophenone, 20mL of ethanol and 10mL of an aqueous solution of KOH (10%), and after stirring at room temperature to sufficiently dissolve them, 1.36g (0.01mol) of 4-chlorobenzaldehyde was added and stirred at room temperature for 24 hours. After the reaction was monitored to be complete, 10% HCl was added dropwise to acidify the mixture to PH 6, the mixture was extracted 3 times with 30mL of ethyl acetate, and the ethyl acetate phase was combined, washed with 20mL of saturated brine, concentrated by rotary evaporation, and dried to obtain a yellow solid. Column chromatography (200-400 mesh silica gel) gave 2.43g of a yellow powdery solid with a yield of 65.0%.
After the detection, the detection result shows that,1H NMR：
1H NMR(400MHz,CDCl3)13.18(s,1H),7.79(d,J＝15.5Hz,1H),7.67–7.61 (m,2H),7.54(d,J＝15.5Hz,1H),7.49(d,J＝7.0Hz,1H),7.41–7.32(m,2H),6.76 (d,J＝9.1Hz,1H),5.30(s,2H),5.22(s,2H),3.66(s,3H),3.52(s,3H)；
13c NMR is:
13C NMR(100MHz,CDCl3)196.65(s),161.94(s),160.53(s),146.71(s),140.83 (s),138.60(s),137.51(s),134.09(s),134.03(s),131.91(s),130.87(s),130.66(s), 125.80(s),119.64(s),109.96(s),101.66(s),98.34(s),60.13(s),59.40(s)；
HRMS Mass Spectrometry (EI) m/z: c19H19ClO6Theoretical calculation value: 379.0870, test value: 379.0940.
3) and step 3: (E) synthesis of (E) -2',3',4' -hydroxy-4-chlorochalcone (14c)
A50 mL three-necked flask was charged with 0.374g (1mmol) of 13c and 20mL of methanol, heated to reflux, and then 5mL of a 10% aqueous HCl solution was slowly added dropwise to the mixture, followed by reaction under reflux for half an hour. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with 40mL of water, extracted three times with 50mL of ethyl acetate, the organic phase solutions were combined, the solvent was rotary evaporated and dried, and recrystallized from a mixed solution of ethyl acetate and petroleum ether to give 10b 0.252g of a yellow powdery solid with a yield of 88.4%.
After the detection, the detection result shows that,1H NMR：
1H NMR(400MHz,MeOD)7.82(d,J＝15.5Hz,1H),7.77(s,1H),7.75(d,J＝ 15.5Hz,1H),7.67-7.62(m,1H),7.59(d,J＝8.9Hz,1H),7.41(d,J＝5.0Hz,2H), 6.49(d,J＝8.9Hz,1H)；
13c NMR is:
13C NMR(175MHz,MeOD)192.20(s),153.11(s),152.44(s),141.77(s),137.05 (s),134.62(s),132.38(s),130.11(s),129.84(s),127.86(s),126.67(s),122.33(s), 122.15(s),113.68(s),107.40(s)；
HRMS Mass Spectrometry (EI) m/z: c15H11ClO4Theoretical calculation value: 291.0346, test value: 291.0569.
experimental example 1
The influence of the polyhydroxy chalcone compound on the aggregation degree of the A beta protein is detected by adopting a Th T method.
1. The specific operation method for detecting the aggregation degree of the derivative on the A beta protein (beta amyloid) by the Th T method comprises the following steps:
1) adding Abeta42 monomer with protein concentration of 25 μmol/L into 96-well plate, and performing shake culture at 37 deg.C;
2) setting the drug concentration (μ M/L) to 25 μ M, adding the corresponding concentration of derivatives, positive drug curcumine (curcumin) and epigallocatechin gallate (EGCG) into corresponding holes, and setting three groups in parallel;
3) the 96-well plate was incubated in a shaker for 7 days (conditions 37 ℃);
4) at each time point, 95. mu.L of sample was added to 5. mu.L of 100. mu.M ThT solution and mixed well;
5) detecting the absorbance of the protein by using a fluorescence spectrophotometer, wherein the excitation wavelength is 440nm, and the emission wavelength is 485 nm;
6) percent inhibition was calculated as (1-IF)i/IFc)×100％，IFiAnd IFcThe fluorescence intensity with and without the addition of the derivatizing compound, respectively.
The activity results of the polyhydroxy chalcone compounds described in this experimental example 1 are shown in fig. 1. Inhibitory activity of the tested compounds on a β protein aggregation: compound 14a-c >10a-b >6a-b ≈ 13a-c, where the inhibition rate of compound 14a-c is 76.3% to 70.3% higher than the positive control EGCG (52.9%) and curcumin (51.4%).
Experimental example 2
The cell toxicity of the polyhydroxy chalcone compound and the influence of the compound on the degree of toxicity inhibition caused by A beta protein aggregation are detected through cell experiments.
1. The specific operation method for detecting the cytotoxicity of the polyhydroxy chalcone compound by the cell experiment comprises the following steps:
1) human neuroblastoma cells (SH-SY5Y) [ purchased from Chinese academy of sciences ] were counted and seeded in 96-well plates at 100. mu.L/well and 2 ten thousand cells/well.
2) Standing at 37 deg.C with 5% CO2After 24h incubation in the incubator, the final concentrations of the test compounds were 40 μ M and 10 μ M in the wells corresponding to the compound groups.
3) After placing the 96-well plate back into the incubator for further incubation for 24h, 20. mu.L of MTS was added to each well and incubation was continued for 4 h.
4) The absorbance at 490nm of each well was measured with a microplate reader and the experiment was repeated three times in parallel.
The activity results of the polyhydroxy chalcone compounds described in this experimental example 2 are shown in fig. 2-a.
2. The specific operation method for detecting the influence of the polyhydroxy chalcone compound on the toxicity inhibition degree caused by the aggregation of the Abeta protein by a cell experiment comprises the following steps:
1) human neuroblastoma cells (SH-SY5Y) were counted and seeded in 96-well plates at 100. mu.L/well with 2 ten thousand cells per well.
2) Standing at 37 deg.C with 5% CO2After 24h incubation in the incubator, the test compound and 10. mu. M A. beta. protein were added to the wells corresponding to the compound groups at final concentrations of 20. mu.M, 10. mu.M, 1. mu.M and 0.5. mu.M, respectively.
3) After placing the 96-well plate back into the incubator for further incubation for 24h, 20. mu.L of MTS was added to each well and incubation was continued for 4 h.
4) The absorbance at 490nm of each well was measured with a microplate reader and the experiment was repeated three times in parallel.
The activity results of the polyhydroxychalcone compounds described in this experimental example 2 are shown in FIGS. 2-B and 2-C.
The activity test result shows that the tested compound has no cytotoxicity at the concentration of 40 mu M. Wherein compounds 14a-c at concentrations of 20 μ M and 10 μ M can help cells to almost completely inhibit A β protein aggregation-induced toxicity. Under the action of the concentration range, the activity of the compound is superior to that of curcumin and basically consistent with that of EGCG. When the concentration is reduced to 1 mu M and 0.5 mu M, the activity effect of the EGCG is still better than that of the positive control.
Experimental example 3
The influence of the polyhydroxy chalcone compound on the inhibition degree of cell iron death is detected through a cell experiment.
1. The specific operation method for detecting the influence of the polyhydroxy chalcone compound on the inhibition degree of iron death caused by erastin in a cell experiment comprises the following steps:
1) human embryonic kidney cells (HEK-293) were counted and plated in 96-well plates at 100. mu.L per well and 5 thousand cells per well.
2) Standing at 37 deg.C with 5% CO2After the culture in an incubator for 24h, respectively adding final concentrations into the corresponding holes of the compound groups10 μ M, 1 μ M, 800nM, 500nM, 200nM, 100nM of the compound to be tested and 10 μ M erastin.
3) After placing the 96-well plate back into the incubator for further incubation for 24h, 20. mu.L of MTS was added to each well and incubation was continued for 4 h.
4) The absorbance at 490nm of each well was measured with a microplate reader and the experiment was repeated three times in parallel.
2. The specific operation method for detecting the influence of the polyhydroxy chalcone compound on the inhibition degree of the iron death caused by the RSL-3 in the cell experiment comprises the following steps:
the procedure was as in method 1 of Experimental example 3, except that 500nM RSL-3 was used instead of erastin.
The activity results of the polyhydroxychalcones described in this example 3 are shown in table 1 below.
TABLE 1
Figure RE-GDA0001886942180000151
Remarking: 1) the numerical values in the table are expressed as mean values of three experiments +/-standard deviation;
2)IC50the inhibition rate of N represents that the compound is less than 10 percent under the concentration of 10 mu M, namely the compound is inactive.
And (4) conclusion: the compounds 14a-c show better iron death inhibition effect in two different cell models of iron death initiators, and the half inhibition rate is between 3.88 and 0.45 mu m. The control drug EGCG did not have the effect of inhibiting iron death.
Experimental example 4
The influence of the polyhydroxy chalcone compound disclosed by the embodiment of the invention on the inhibition degree of the lipid peroxidation level is detected through a cell experiment.
1. The specific operation method for detecting the influence of the polyhydroxy chalcone compound on the inhibition degree of lipid peroxidation caused by the A beta protein through a cell experiment comprises the following steps:
1) human neuroblastoma cells (SH-SY5Y) were counted and seeded in 96-well plates at 100. mu.L/well with 2 ten thousand cells per well.
2) The mixture was left to stand at 37 c,5％CO2after 24h incubation in the incubator, the test compound was added to the wells corresponding to the compound groups at a final concentration of 10. mu.M and 10. mu. M A. beta. protein or 1mM maleic acid (DEM), respectively.
3) Cells were digested with pancreatin and transferred to test tubes, and 1. mu.M BODIPY-C11 was added581/591Placing in an incubator for 30 minutes
4) It was tested by flow cytometry and the experiment was repeated in parallel three times.
2. The specific operation method for detecting the influence of the polyhydroxy chalcone compound on the inhibition degree of lipid peroxidation caused by cell iron death in the cell experiment comprises the following steps:
1) human embryonic kidney cells (HEK-293) were counted and plated in 96-well plates at 100. mu.L per well and 5 thousand cells per well.
2) Standing at 37 deg.C with 5% CO2After 24h incubation in the incubator, the final concentration of 10. mu.M of the test compound and 10. mu.M of RSL-3 or 1mM maleic acid (DEM) were added to the wells corresponding to the compound groups, respectively.
3) Cells were digested with pancreatin and transferred to test tubes, and 1. mu.M BODIPY-C11 was added581/591Placing in an incubator for 30 minutes
4) It was tested by flow cytometry and the experiment was repeated in parallel three times.
The activity results of the polyhydroxy chalcone compounds described in this experimental example 4 are shown in fig. 3.
And (4) conclusion: the A beta protein and RSL-3 can obviously improve the lipid peroxidation degree of cells, and the compounds 14a-c can reduce the lipid peroxidation level to the level of normal cells, indicating that the series of compounds have the function of reducing the lipid peroxidation level of the cells.
As described above, the compounds of the present invention have a good inhibitory effect on the aggregation of a β protein and can also inhibit the death of iron cells, and among them, the compounds 14a, 14b and 14c have an effect superior to that of the positive drugs zingiberin and EGCG, and are expected to be further developed for the treatment of alzheimer's disease and the like or as free radical peroxidation inhibitors.
Although the present invention and its advantages have been described in detail, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims. Moreover, the scope of the present application is not intended to be limited to the particular embodiments of the process, machine, means, methods and steps described in the specification. As one of ordinary skill in the art will readily appreciate from the disclosure of the present invention, processes, machines, means, methods, or steps, presently existing or later to be developed that perform substantially the same function or achieve substantially the same result as the corresponding embodiments described herein may be utilized according to the present invention. Accordingly, the appended claims are intended to include within their scope such processes, devices, means, methods, or steps.

Claims (5)

1. A polyhydroxy chalcone compound, wherein the compound is: (E) -2',3',4' -trihydroxy-3-methylchalcone, (E) -2',3',4' -trihydroxy-4-chlorochalcone or (E) -2',3',4' -trihydroxy-3-methoxychalcone.
2. The method for preparing polyhydroxychalcone compounds according to claim 1, wherein acetophenone compounds and benzaldehyde compounds are reacted.
3. The preparation method according to claim 2, which is characterized by comprising the following steps:
1) firstly, dissolving hydroxyl-substituted acetophenone in anhydrous acetone, adding anhydrous potassium carbonate with 2-3 times of equivalent, dropwise adding bromomethyl ether with 3-5 times of equivalent in an ice bath, carrying out reflux reaction for 3-6 h, cooling to room temperature, and carrying out post-treatment to obtain methoxy methyl protected acetophenone;
2) dissolving the acetophenone protected by the methoxymethyl group and the corresponding benzaldehyde in ethanol and 10% KOH solution, stirring at room temperature for 12-48 h, dropwise adding 10% HCl to adjust the pH value to 6, and performing post-treatment to obtain a corresponding chalcone compound protected by the methoxymethyl group;
3) dissolving the product obtained in the step 2) in methanol, dropwise adding a 10% HCl aqueous solution under a heating reflux condition, reacting for 0.5-1 h, and performing post-treatment to obtain a final chalcone target compound.
4. Use of a compound according to claim 1 for the preparation of a medicament for the prophylaxis and treatment of alzheimer's disease.
5. Use of a compound according to claim 1 for the preparation of an inhibitor for free radical peroxidation.
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