CN113512018B - Flavonoid compound and preparation method and application thereof - Google Patents

Flavonoid compound and preparation method and application thereof Download PDF

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CN113512018B
CN113512018B CN202110765443.XA CN202110765443A CN113512018B CN 113512018 B CN113512018 B CN 113512018B CN 202110765443 A CN202110765443 A CN 202110765443A CN 113512018 B CN113512018 B CN 113512018B
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nogo
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flavonoid
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CN113512018A (en
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李青山
张朕
韩际宏
段亚君
龚克
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Hefei University of Technology
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
    • C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
    • C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
    • C07D311/34—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only
    • C07D311/36—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 3 only not hydrogenated in the hetero ring, e.g. isoflavones

Abstract

The invention discloses a flavonoid compound, a preparation method and application thereof, wherein the flavonoid compound comprises flavonoid compounds FLM_1-24, flavonoid derivatives FLM_25-40 and isoflavone derivatives FLM_41-48. The flavonoid compound can be used for preparing a regulator with a regulating effect on the Nogo-B expression of human liver cancer cell line Huh7 cells, and particularly has good inhibitory activity on the Nogo-B expression of human liver cancer cell line Huh7 cells.

Description

Flavonoid compound and preparation method and application thereof
Technical Field
The invention relates to a flavonoid compound, a preparation method and application thereof. The flavonoid compound has good inhibitory activity on Nogo-B expression of human liver cancer cell line Huh7 cells.
Background
Flavonoid compounds (flavanoids) are the generic name for a series of compounds in which two benzene rings are linked to one another by three carbon atoms, i.e. have C 6 -C 3 -C 6 A generic term for a class of compounds of structure. It is widely found in plants in nature, belongs to the secondary metabolites of plants, exists in the form of glycosides or carboglycosyls combined with sugar in the body of the plant in large part, and exists in free form in some cases. The structure types can be divided into: flavonoids, isoflavones, flavonols, dihydroflavonoids, biflavones, etc.
Research shows that flavonoid compounds, derivatives and analogues thereof have multiple biological functions. The flavonoid compounds have the capability of improving the oxidation resistance of animal organisms and scavenging free radicals, and have good effects in preventing and treating cardiovascular diseases, such as arteriosclerosis, reducing blood fat and cholesterol, reducing blood sugar, dilating blood vessels, improving vascular permeability, reducing incidence of coronary heart disease and the like. At the same time, almost all flavonoids have varying degrees of bacteriostatic activity against many microorganisms. The flavonoid compound can also induce apoptosis of cancer cells and tumor cells, play a role in resisting cancer and tumor, and delay apoptosis of normal tissue cells. The flavonoid can improve immunity and promote health.
Nogo-B is one of the members of the Nogo superfamily of reticulins. The Nogo family includes members such as Nogo-A, nogo-C in addition to Nogo-B. There is a clear specificity in the distribution of these members in vivo tissues: nogo-A is highly expressed in the central nervous system, nogo-C is highly expressed in skeletal muscle, and Nogo-B is expressed in most tissues, such as liver, blood vessels, heart, kidney, nervous system, and the like, where the presence of Nogo-B is detected. Nogo-B was functionally found to be an endoplasmic reticulum (endoplasmic reticulum, ER) resident protein, regulating ER structure and function. Nogo-B is involved in a variety of pathological processes in the liver, involving in hepatocyte proliferation and liver regeneration, alcoholic liver disease, liver fibrosis and its end stage cirrhosis, and the like. In 2020, it was found that the absence of Nogo-B expression significantly slowed the symptoms of cholestatic liver disease; nogo-B is involved in the liver glycolipid metabolism by modulating carbohydrate acting element binding protein (ChREBP) and insulin pathway, and reducing Nogo-B expression reduces the occurrence of inflammation, apoptosis, and endoplasmic reticulum stress induced by high glucose or high fructose foods and activates energy metabolism, thereby effectively antagonizing metabolic disorders induced by high glucose or fructose foods, and thus Nogo-B may be an important target for potential treatment of glycolipid metabolism disorders, and can be a target gene for drug design and screening.
The dual-luciferase reporter gene report system has the advantages of high sensitivity, wide dynamic range, flexible application and the like, and is widely applied to the research fields of gene regulation, non-coding RNA targeting interaction and the like. The transcription regulatory element of the target gene is generally constructed into an expression vector with luciferase (Firefly luciferase) to construct a reporter gene plasmid, so that the sequence regulates the transcription expression of Firefly luciferase. The reporter plasmid was then transfected into cells, which were then lysed after various treatments, and the substrate luciferin (luciferin) was added, firefly luciferase catalysing the fluorescence of luciferin (strongest wavelength around 560 nm). The influence of different treatment groups on the transcription control element can be judged by detecting the obtained fluorescence value. In order to avoid errors caused by the difference in efficiency of plasmid transfection of cells, a Renilla luciferase reporter plasmid is usually transferred as an internal reference (the strongest wavelength is about 465 nm), and by this method, the experimental accuracy impaired by the inherent variation factors can be reduced. Such as the number and viability of the cultured cells, and the efficiency of cell transfection and lysis. The experimental reporter gene is coupled to a regulated promoter, and the structure and physiological basis of the regulated gene are researched, so that the transcriptional activation of the drug on the related gene can be judged from the level of the promoter by comparing the fluorescence value of the reporter gene coupled with the promoter after different drug treatments, thereby screening the drug for promoting or inhibiting the expression of the target gene.
Disclosure of Invention
The invention aims to provide a flavonoid compound, a preparation method and application thereof. The flavonoid compound has good inhibitory activity on Nogo-B expression of human liver cancer cell line Huh7 cells.
The Huh7 cell is a well-differentiated cell cancer cell line derived from liver cells, and is often used for in-vitro research on pathogenesis of liver cell cancer, liver metabolic diseases, drug metabolism, in-vitro hepatotoxicity experiments and the like. Meanwhile, huh7 cells can highly express non-expressed Nogo-B in normal liver parenchymal cells so as to confirm the inhibiting activity of flavonoid compounds on the expression of the Nogo-B in liver cells.
The flavonoid compounds of the present invention include 5-hydroxyflavone (FLM_1), 6-hydroxyflavone (FLM_2), 7-hydroxyflavone (FLM_3), 3-methoxyflavone (FLM_4), 5-methoxyflavone (FLM_5), 6-methoxyflavone (FLM_6), 7-methoxyflavone (FLM_7), 3-methyl-8-carboxyflavone (FLM_8), 6-methylflavone (FLM_9), 6-aminoflavone (FLM_10), 7-aminoflavone (FLM_11), 3',5, 7-Trihydroxy-4-methoxyflavone (FLM_12), resveratrol (FLM_13), flavonol (FLM_14), 7-hydroxyisoflavone (FLM_15), 7-isopropoxysidone (FLM_16), stigmaside (FLM_17), 3', 7-dimethoxyisoflavone (FLM_18), 3',6, 7-trimethoxyisoflavone (FLM_19), 3', 7-dihydroxyisoflavone (FLM_20), 3 '-methoxy-7-hydroxyisoflavone (FLM_21), 3' -nitro-7-hydroxyisoflavone (FLM_22), 3 '-methoxy-5, 7-dihydroxyisoflavone (FLM_23), 3',5, 7-trihydroxyisoflavone (FLM_24), flavone derivatives (FLM_25-40), isoflavone derivatives (FLM_41-48). Wherein the compounds FLM_1-24 were purchased from MCE (MedChemExpress) official or exploring reagent companies, and the structure was confirmed accurately.
The flavone derivatives (FLM_25-40) in the present invention have the following general formula:
wherein R is 1 Selected from 5-OC 2 H 5 、5-OC 4 H 9 、5-OC 2 H 4 CH＝CH 2 、5-OCH 2 CH(CH 3 ) 2 、5-OCH(CH 3 ) 2 、5-OCOCH 3 、5-OCOC 2 H 5 、5-OCOC 3 H 7 、6-OC 2 H 5 、6-OC 4 H 9 、6-OC 2 H 4 CH＝CH 2 、6-OCH 2 CH(CH 3 ) 2 、6-OCH(CH 3 ) 2 、6-OCOCH 3 、6-OCOC 2 H 5 Or 6-OCOC 3 H 7 。
Specifically, the structural formula of the flavone derivative (FLM_25-40) is preferably as follows:
isoflavone derivatives (FLM_41-48) in the present invention have the following general formula:
wherein R is 2 Selected from C 2 H 5 、C 4 H 9 、C 2 H 4 CH＝CH 2 、CH 2 CH(CH 3 ) 2 、CH(CH 3 ) 2 、COCH 3 、COC 2 H 5 Or COC 3 H 7 。
Specifically, the isoflavone derivative (FLM_41-48) preferably has the following structural formula:
the preparation method of the flavonoid derivative comprises the following steps:
step 1:2, 6-dihydroxyacetophenone (20 mmol) and anhydrous potassium carbonate (140 mmol) are added into a reaction bottle, acetone (120 mL) is added as a solvent, the mixture is heated to 55 ℃ for reflux reaction, benzoyl chloride (40 mmol) is slowly added dropwise under stirring, and the mixture is subjected to reflux reaction for 12h; cooling, suction filtering, washing the filter cake with a small amount of acetone, collecting the obtained filtrate and concentrating it in vacuo, then adding the concentrated solid into a flask containing 10% acetic acid (300 mL), stirring thoroughly, at this time with a large amount of CO 2 The gas is discharged, and yellow solid is precipitated, and stirring is continued for 2 hours until the precipitation is complete; suction filtration, filter cake washing with water, drying and then re-crystallizing with acetone to obtain intermediate A-3-hydroxy-2- (3-oxo-3-phenylpropionyl) phenyl benzoate as yellow solid. In the step 1, the dropping speed of benzoyl chloride cannot be too fast, and the benzoyl chloride is slowly added dropwise, and the control speed is 2mL/min.
In step 1, the percentage of acetic acid is not easily too high, and 10% is most preferable.
Step 2: adding the intermediate A obtained in the step 1 and concentrated sulfuric acid (30 mL) into a reaction bottle, and stirring and reacting for 4 hours under ice bath cooling; after the reaction is finished, pouring the reaction solution into a large amount of ice water, placing the ice water in a low-temperature environment, precipitating white solid, carrying out suction filtration, and collecting a filter cake; the filter cake was then added to a 5% potassium carbonate solution (130 mL), heated to 120 ℃ and boiled for 1 hour; cooling, separating out solid, suction filtering, collecting filter cake, dissolving the filter cake with dichloromethane, then carrying out column chromatography separation by using a proper eluent (ethyl acetate: petroleum ether=1:15, v/v), and recrystallizing the separated crude product by using ethanol to obtain an intermediate B-5-hydroxyflavone as yellow solid.
Step 3: placing intermediate B (2 mmol) in a reaction bottle, taking methylene dichloride (50 mL) as a solvent, adding potassium carbonate (6 mmol), adding substituted alkane C1-8 (3 mmol), reacting at normal temperature, detecting the reaction progress by TLC, after the reaction is completed for 4-6 hours, separating by column chromatography by using an eluent (the eluent is determined according to the polarity of different substituents, ethyl acetate: petroleum ether=1:8-1:4, v/v), and recrystallizing the separated crude product by using ethanol to obtain the target compound FLM_25-32.
The structural formula of the substituted alkane C1-8 is as follows:
I-R or Br-R,
wherein R is selected from OC 2 H 5 、OC 4 H 9 、OC 2 H 4 CH＝CH 2 、OCH 2 CH(CH 3 ) 2 、OCH(CH 3 ) 2 、OCOCH 3 、OCOC 2 H 5 Or OCOC 3 H 7 。
Step 4: 6-hydroxyflavone (D) (2 mmol) is placed in a reaction bottle, dichloromethane (50 mL) is used as a solvent, potassium carbonate (6 mmol) is added, substituted alkane C1-8 (3 mmol) is added for reaction at normal temperature, the reaction progress is detected by TLC, after the reaction is completed for 4-6 hours, eluent (the eluent is determined according to the polarity of different substituents), ethyl acetate: petroleum ether=1:8-1:4, v/v) is used for column chromatography separation, and the separated crude product is recrystallized by ethanol to obtain the target compound FLM_33-40.
The structural formula of the substituted alkane C1-8 is as follows:
I-R or Br-R
Wherein R is selected from OC 2 H 5 、OC 4 H 9 、OC 2 H 4 CH＝CH 2 、OCH 2 CH(CH 3 ) 2 、OCH(CH 3 ) 2 、OCOCH 3 、OCOC 2 H 5 Or OCOC 3 H 7 。
The structural formula of the 6-hydroxyflavone (D) is as follows:
step 5: 7-hydroxy-3- (4-methoxyphenyl) -4-hydrogen-chromen-4-one (E) (2 mmol) is placed in a reaction bottle, methylene dichloride (50 mL) is used as a solvent, potassium carbonate (6 mmol) is added, substituted alkane C1-8 (3 mmol) is further added, reaction is carried out at normal temperature, the reaction progress is detected by TLC, after the reaction is carried out for 4-6 hours, column chromatography separation is carried out by using an eluent (the eluent is determined according to the polarity of different substituents, ethyl acetate is ethyl acetate, petroleum ether=1:8-1:4, v/v), and the separated crude product is recrystallized by ethanol to obtain the target compound FLM_41-48.
The structural formula of the substituted alkane C1-8 is as follows:
I-R or Br-R
Wherein R is selected from OC 2 H 5 、OC 4 H 9 、OC 2 H 4 CH＝CH 2 、OCH 2 CH(CH 3 ) 2 、OCH(CH 3 ) 2 、OCOCH 3 、OCOC 2 H 5 Or OCOC 3 H 7 。
The structural formula of the 7-hydroxy-3- (4-methoxyphenyl) -4-hydrogen-chromen-4-one (E) is as follows:
in step 1, the mass ratio of 2, 6-dihydroxyacetophenone to anhydrous potassium carbonate was 1:3.
In step 1, the ratio of the amounts of the substances of 2, 6-dihydroxyacetophenone to benzoyl chloride was 1:2.
In step 3, the mass ratio of intermediate B to substituted alkane C1-8 is 1:1.5.
In step 4, the mass ratio of 6-hydroxyflavone (D) to substituted alkane C1-8 is 1:1.5.
In step 5, the mass ratio of 7-hydroxy-3- (4-methoxyphenyl) -4-hydro-chromen-4-one (E) to the substituted alkane C1-8 was 1:1.5.
In the steps 3, 4 and 5, ethanol solvent is selected for recrystallization, and a small amount of ethyl acetate with the concentration of 1-2mL can be added for dissolution.
The flavonoid compound is used for preparing a regulatory inhibitor with inhibitory activity on Nogo-B expression of human liver cancer cell line Huh7 cells.
The flavonoid compound has a regulating effect on the expression of Nogo-B in Huh7 cells. Specifically, the flavonoid compound has a remarkable inhibiting effect on the expression of Nogo-B of Huh7 cells.
Drawings
FIG. 1 is the effect of flavonoid FLM_1-24 on Nogo-B transcriptional activity of Huh7 cells.
FIG. 2 is the effect of flavonoid FLM_25-48 on Nogo-B transcriptional activity of Huh7 cells.
Detailed Description
The present invention is further illustrated in detail by the following examples, but it should be noted that the scope of the present invention is not limited by any of these examples.
Example 1: preparation of 5-ethoxy-2-phenyl-4H-chromen-4-one (Compound FLM-25)
1. A250 mL round bottom flask was taken and 2, 6-dihydroxybenzene was usedEthyl ketone (3.04 g,20 mmol) and anhydrous potassium carbonate (19.34 g,140 mmol) were dissolved in 120mL of acetone solvent, heated to 55deg.C for reflux reaction and benzoyl chloride (5.62 g,40 mmol) was slowly added dropwise with stirring, and after the dropwise addition, the mixture was allowed to reflux for 12h. Then cooled, suction filtered, the filter cake washed with a small amount of acetone, the filtrate obtained was collected and concentrated in vacuo. The concentrated solid was then added to a flask containing 10% acetic acid (300 mL) and stirred well at ambient temperature, at which time there was a significant amount of CO 2 The gas evolved and a yellow solid precipitated out, stirring was continued for 2 hours until the precipitation was complete. Suction filtration, washing filter cake with water, drying and re-crystallizing with acetone to obtain yellow solid intermediate 3-hydroxy-2- (3-oxo-3-phenylpropionyl) phenyl benzoate (A).
2. A150 mL round bottom flask was taken and the intermediate phenyl 3-hydroxy-2- (3-oxo-3-phenylpropionyl) benzoate (A) was dissolved in concentrated sulfuric acid (30 mL) and allowed to react with stirring under ice-bath cooling for 4 hours. After the reaction is finished, pouring the reaction solution into a large amount of ice water, placing the ice water in a low-temperature environment, standing, precipitating white solid, carrying out suction filtration, and collecting a filter cake. The filter cake was then added to a 5% potassium carbonate solution (130 mL) and heated to 120 ℃ to boil for 1 hour. Cooling, separating out solid, suction filtering, collecting filter cake, dissolving the filter cake with dichloromethane, then carrying out column chromatography separation by using a proper eluent (ethyl acetate: petroleum ether=1:15, v/v), and recrystallizing the separated crude product by using ethanol to obtain yellow solid intermediate 5-hydroxyflavone (B).
3. A150 mL round bottom flask was taken, intermediate 5-hydroxyflavone (B) (0.48 g,2 mmol) was dissolved in dichloromethane (50 mL) solvent, and potassium carbonate (0.83 g,6 mmol) was added, and ethyl iodide (0.47 g,3 mmol) was further added, and the reaction was carried out at room temperature, and the progress of the reaction was checked by TLC, after about 4-6 hours, the reaction was completed. Column chromatography was performed with an appropriate eluent (ethyl acetate: petroleum ether=1:5, v/v) and the crude product after separation was recrystallized from ethanol to give the target compound flm_25. The product FLM-25 was a white solid with a yield of 32.6% and a melting point of 99-102 ℃. 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.92–7.89(m,2H),7.58–7.49(m,4H),7.13(dd,J＝8.4,1.0Hz,1H),6.83(dd,J＝8.3,0.9Hz,1H),6.72(s,1H),4.22(q,J＝7.0Hz,2H),1.59(t,J＝7.0Hz,3H).HR-MS(ESI):calcd for C 17 H 14 O 3 ,[M+H] + ,267.1021；found 267.1010.
Example 2: preparation of 5-butoxy-2-phenyl-4H-chromen-4-one (Compound FLM-26)
The preparation method is the same as in example 1. Iodobutane was used instead of iodoethane to give a pale yellow solid in 29.7% yield, melting point 92-95 ℃. 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.96–7.86(m,2H),7.64–7.47(m,4H),7.12(dd,J＝8.4,0.9Hz,1H),6.83(dd,J＝8.3,1.0Hz,1H),6.71(s,1H),4.14(t,J＝6.6Hz,2H),2.01–1.89(m,2H),1.63(m,J＝14.8,7.4Hz,2H),1.03(t,J＝7.4Hz,3H).HR-MS(ESI):calcd for C 19 H 18 O 3 ,[M+H] + ,295.1334；found 295.1313.
Example 3: preparation of 5- (but-3-en-1-yloxy) -2-phenyl-4H-chromen-4-one (Compound FLM-27)
The preparation method is the same as in example 1. Iodobutene was used in place of iodoethane to give a pale yellow solid in 34.2% yield with a melting point of 94-97 ℃. 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.92(dd,J＝6.8,2.9Hz,2H),7.64–7.44(m,4H),7.15(d,J＝8.4Hz,1H),6.83(d,J＝8.2Hz,1H),6.72(s,1H),6.06(m,J＝17.1,10.3,6.8Hz,1H),5.26(dd,J＝17.1,1.9Hz,1H),5.17(dd,J＝10.4,1.8Hz,1H),4.18(t,J＝6.9Hz,2H),2.74(q,J＝6.9Hz,2H).HR-MS(ESI):calcd for C 19 H 16 O 3 ,[M+H] + ,293.1178；found 293.1154.
Example 4: preparation of 5-isobutoxy-2-phenyl-4H-chromen-4-one (Compound FLM-28)
The preparation method is the same as in example 1. 1-iodo-2-methylpropane was used instead of ethyl iodide to give a pale yellow solid in 31.6% yield with a melting point of 76-79 ℃. 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.98–7.86(m,2H),7.60–7.47(m,4H),7.12(dd,J＝8.4,1.0Hz,1H),6.81(dd,J＝8.3,1.0Hz,1H),6.70(s,1H),3.89(d,J＝6.7Hz,2H),2.31(m,J＝13.4,6.7Hz,1H),1.15(d,J＝6.8Hz,6H).HR-MS(ESI):calcd for C 19 H 18 O 3 ,[M+H] + ,295.1334；found 295.1330.
Example 5: preparation of 5-isopropoxy-2-phenyl-4H-chromen-4-one (Compound FLM_29)
The preparation method is the same as in example 1. The ethyl iodide is replaced by isopropyl iodide to obtain light yellow solid with the yield of 33.6 percent and the melting point of 85-87 ℃. 1 H NMR(400MHz,CDCl 3 )δ(ppm)8.00–7.81(m,2H),7.53(m,J＝7.2,4.9,2.2Hz,4H),7.13(d,J＝8.1Hz,1H),6.86(d,J＝8.2Hz,1H),6.69(d,J＝2.1Hz,1H),4.66(m,J＝6.0,2.1Hz,1H),1.48(dd,J＝6.0,2.1Hz,6H).HR-MS(ESI):calcd for C 18 H 16 O 3 ,[M+H] + ,281.1178；found 281.1118.
Example 6: preparation of 4-oxo-2-phenyl-4H-chromen-5-yl acetate (Compound FLM-30)
The preparation method is the same as in example 1. Acetyl chloride was used instead of ethyl iodide to give a white solid with a yield of 31.3% and a melting point of 130-133 ℃. 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.96–7.86(m,2H),7.69(t,J＝8.2Hz,1H),7.64–7.47(m,4H),7.06(dd,J＝7.9,1.1Hz,1H),6.71(s,1H),2.48(s,3H).HR-MS(ESI):calcd for C 17 H 12 O 4 ,[M+H] + ,281.0814；found 281.0791.
Example 7: preparation of 4-oxo-2-phenyl-4H-chromen-5-yl propionate (Compound FLM-31)
The preparation method is the same as in example 1. Propionyl chloride was used instead of ethyl iodide to give a white solid with a yield of 29.3% and a melting point of 124-126 ℃. 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.97–7.85(m,2H),7.68(t,J＝8.2Hz,1H),7.61–7.45(m,4H),7.05(dd,J＝7.8,1.1Hz,1H),6.70(s,1H),2.82(q,J＝7.5Hz,2H),1.36(t,J＝7.5Hz,3H).HR-MS(ESI):calcd for C 18 H 14 O 4 ,[M+H] + ,295.0970；found 295.0963.
Example 8: preparation of 4-oxo-2-phenyl-4H-chromen-5-yl butyrate (Compound FLM-32)
The preparation method is the same as in example 1. The ethyl iodide was replaced with butyryl chloride to give a white solid with a yield of 33.6% and a melting point of 117-120 ℃. 1 HNMR(400MHz,CDCl 3 )δ(ppm)7.91–7.87(m,2H),7.67(dd,J＝8.5,7.9Hz,1H),7.60–7.45(m,4H),7.04(dd,J＝7.9,1.1Hz,1H),6.69(s,1H),2.77(t,J＝7.5Hz,2H),1.89(m,J＝7.4Hz,2H),1.11(t,J＝7.4Hz,3H).HR-MS(ESI):calcd for C 19 H 16 O 4 ,[M+H] + ,309.1127；found 309.1107.
Example 9: preparation of 6-ethoxy-2-phenyl-4H-chromen-4-one (Compound FLM-33)
1. A150 mL round bottom flask was taken, 6-hydroxyflavone (D) (0.48 g,2 mmol) was dissolved in dichloromethane (50 mL) solvent, and potassium carbonate (0.83 g,6 mmol) was added followed by ethyl iodide (0.47 g,3 mmol) at ambient temperatureThe reaction was completed after about 4-6 hours by detecting the progress of the reaction by TLC. Column chromatography was performed with an appropriate eluent (ethyl acetate: petroleum ether=1:6, v/v) and the crude product after separation was recrystallized from ethanol to give the target compound flm_33. The product FLM-33 was a white solid with a yield of 30.5% and a melting point of 126-129 ℃. 1 H NMR(600MHz,CDCl 3 )δ(ppm)7.95–7.89(m,2H),7.57(d,J＝3.1Hz,1H),7.55–7.47(m,4H),7.31–7.24(m,2H),6.81(s,1H),4.14(q,J＝7.0Hz,2H),1.45(t,J＝7.0Hz,3H).HR-MS(ESI):calcd for C 17 H 14 O 3 ,[M+H] + ,267.1021；found 267.1013.
Example 10: preparation of 6-butoxy-2-phenyl-4H-chromen-4-one (Compound FLM-34)
The preparation method is the same as in example 9. Iodobutane was used instead of iodoethane to give a white solid with a yield of 29.6% and a melting point of 84-87 ℃. 1 HNMR(600MHz,CDCl 3 )δ(ppm)7.93–7.88(m,2H),7.57(d,J＝3.1Hz,1H),7.55–7.46(m,4H),7.30–7.24(m,1H),6.80(s,1H),4.06(t,J＝6.5Hz,2H),1.84–1.75(m,2H),1.51(m,J＝7.4Hz,2H),0.98(t,J＝7.4Hz,3H).HR-MS(ESI):calcd for C 19 H 18 O 3 ,[M+H] + ,295.1334；found 295.1321.
Example 11: preparation of 6- (but-3-en-1-yloxy) -2-phenyl-4H-chromen-4-one (Compound FLM-35)
The preparation method is the same as in example 9. Iodobutene was used instead of iodoethane to give a pale yellow solid with a yield of 32.6% and a melting point of 98-101 ℃. 1 HNMR(400MHz,CDCl 3 )δ(ppm)7.94(m,J＝6.7,2.8,2.2Hz,2H),7.61(d,J＝3.1Hz,1H),7.57–7.51(m,4H),7.32(dd,J＝9.1,3.1Hz,1H),6.84(s,1H),5.94(m,J＝17.0,10.2,6.7Hz,1H),5.27–5.11(m,2H),4.15(t,J＝6.7Hz,2H),2.61(m,J＝6.7,1.4Hz,2H).HR-MS(ESI):calcd for C 19 H 16 O 3 ,[M+H] + ,293.1178；found 293.1187.
Example 12: preparation of 6-isobutoxy-2-phenyl-4H-chromen-4-one (Compound FLM-36)
The preparation method is the same as in example 9. 1-iodo-2-methylpropane was used instead of ethyl iodide to give a pale yellow solid with a yield of 35.2% and a melting point of 92-96 ℃. 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.96–7.92(m,2H),7.59(d,J＝3.1Hz,1H),7.56–7.51(m,4H),7.32(dd,J＝9.1,3.1Hz,1H),6.84(s,1H),3.85(d,J＝6.6Hz,2H),2.14(m,J＝13.3,6.7Hz,1H),1.07(d,J＝6.7Hz,6H).HR-MS(ESI):calcd for C 19 H 18 O 3 ,[M+H] + ,295.1334；found 295.1318.
Example 13: preparation of 6-isopropoxy-2-phenyl-4H-chromen-4-one (Compound FLM-37)
The preparation method is the same as in example 9. The ethyl iodide was replaced by isopropyl iodide to give a pale yellow solid with a yield of 33.7% and a melting point of 91-94 ℃. 1 HNMR(400MHz,CDCl 3 )δ(ppm)7.96–7.92(m,2H),7.62(d,J＝3.2Hz,1H),7.58–7.50(m,4H),7.30–7.25(m,1H),6.83(s,1H),4.72(m,J＝6.1Hz,1H),1.40(d,J＝6.0Hz,6H).HR-MS(ESI):calcd for C 18 H 16 O 3 ,[M+H] + ,281.1178；found 281.1132.
Example 14: preparation of 4-oxo-2-phenyl-4H-chromen-6-yl acetate (Compound FLM-38)
The preparation method is the same as in example 9.Substitution of ethyl iodide with acetyl chloride gives a pale yellow solid with a yield of 33.7% and a melting point of 91-94 ℃. 1 H NMR(600MHz,CDCl 3 )δ(ppm)7.94–7.91(m,3H),7.60(d,J＝9.0Hz,1H),7.58–7.50(m,3H),7.45(dd,J＝9.0,2.8Hz,1H),6.82(s,1H),2.35(s,3H).HR-MS(ESI):calcd for C 17 H 12 O 4 ,[M+H] + ,281.0814；found 281.0800.
Example 15: preparation of 4-oxo-2-phenyl-4H-chromen-6-yl propionate (Compound FLM-39)
The preparation method is the same as in example 9. Propionyl chloride was used instead of ethyl iodide to give a white solid with a yield of 32.6% and a melting point of 109-110 ℃. 1 HNMR(600MHz,DMSO-d 6 )δ(ppm)8.30(s,1H),7.94(d,J＝8.7Hz,1H),7.54–7.44(m,2H),7.00–6.95(m,2H),6.91(dd,J＝8.7,2.2Hz,1H),6.82(d,J＝2.2Hz,1H),3.77(s,3H),2.48(m,J＝1.9Hz,2H).HR-MS(ESI):calcd for C 18 H 14 O 4 ,[M+H] + ,295.0970；found295.0959.
Example 16: preparation of 4-oxo-2-phenyl-4H-chromen-6-yl butyrate (Compound FLM-40)
The preparation method is the same as in example 9. Butyryl chloride was used in place of ethyl iodide to give a white solid with a yield of 35.3% and a melting point of 124-127 ℃. 1 H NMR(400MHz,CDCl 3 )δ(ppm)7.96–7.92(m,3H),7.62(d,J＝9.0Hz,1H),7.60–7.52(m,3H),7.46(dd,J＝9.0,2.8Hz,1H),6.84(s,1H),2.60(t,J＝7.4Hz,2H),1.83(m,J＝7.4Hz,2H),1.09(t,J＝7.4Hz,3H).HR-MS(ESI):calcd for C 19 H 16 O 4 ,[M+H] + ,309.1127；found 309.1097.
Example 17: preparation of 7-ethoxy-3- (4-methoxyphenyl) -4H-chromen-4-one (Compound FLM-41)
1. A150 mL round bottom flask was taken, 7-hydroxy-3- (4-methoxyphenyl) -4-hydro-chromen-4-one (E) (2 mmol) (0.54 g,2 mmol) was dissolved in dichloromethane (50 mL) solvent, and potassium carbonate (0.83 g,6 mmol) was added, and ethyl iodide (0.47 g,3 mmol) was further added to react at normal temperature, and the progress of the reaction was checked by TLC after about 4-6 hours. Column chromatography was performed with an appropriate eluent (ethyl acetate: petroleum ether=1:5, v/v) and the crude product after separation was recrystallized from ethanol to give the target compound flm_41. The product FLM-41 was a pale yellow solid with a yield of 29.5%, melting point 122-125 ℃. 1 H NMR(600MHz,Chloroform-d)δ8.19(d,J＝8.9Hz,1H),7.90(s,1H),7.52–7.47(m,2H),6.98–6.94(m,3H),6.82(d,J＝2.4Hz,1H),4.12(q,J＝7.0Hz,2H),3.83(s,3H),1.47(t,J＝7.0Hz,3H).HR-MS(ESI):calcd for C 18 H 16 O 4 ,[M+H] + ,297.1127；found 297.1123.
Example 18: preparation of 7-butoxy-3- (4-methoxyphenyl) -4H-chromen-4-one (Compound FLM-42)
The preparation method is the same as in example 17. Iodobutane was used instead of iodoethane to give a white solid with a yield of 37.5% and a melting point of 124-127 ℃. 1 H NMR(600MHz,CDCl 3 )δ(ppm)8.19(d,J＝8.9Hz,1H),7.91(s,1H),7.53–7.46(m,2H),7.00–6.94(m,3H),6.83(d,J＝2.4Hz,1H),4.06(t,J＝6.5Hz,2H),3.84(s,3H),1.82(m,J＝7.9,6.5Hz,2H),1.56–1.50(m,2H),1.00(t,J＝7.4Hz,3H).HR-MS(ESI):calcd for C 20 H 20 O 4 ,[M+H] + ,325.1440；found 325.1395.
Example 19: preparation of 7- (but-3-en-1-yloxy) -3- (4-methoxyphenyl) -4H-chromen-4-one (Compound FLM-43)
The preparation method is the same as in example 17. Iodobutene was used instead of iodoethane to give a white solid with a yield of 32.9% and a melting point of 128-130 ℃. 1 H NMR(400MHz,CDCl 3 )δ(ppm)8.23(d,J＝8.9Hz,1H),7.94(s,1H),7.60–7.45(m,2H),7.05–6.95(m,3H),6.87(d,J＝2.4Hz,1H),5.94(m,J＝17.0,10.2,6.7Hz,1H),5.26–5.15(m,2H),4.14(t,J＝6.7Hz,2H),3.87(s,3H),2.63(m,J＝6.7,1.4Hz,2H).HR-MS(ESI):calcd for C 20 H 18 O 4 ,[M+H] + ,323.1283；found 323.1274.
Example 20: preparation of 7-isobutoxy-3- (4-methoxyphenyl) -4H-chromen-4-one (Compound FLM-44)
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The preparation method is the same as in example 17. 1-iodo-2-methylpropane was used instead of ethyl iodide to give a pale yellow solid with a yield of 32.9% and a melting point of 129-131 ℃. 1 H NMR(400MHz,CDCl 3 )δ(ppm)8.22(d,J＝8.9Hz,1H),7.93(s,1H),7.60–7.46(m,2H),7.09–6.92(m,3H),6.85(d,J＝2.4Hz,1H),3.86(s,3H),3.84(d,J＝6.5Hz,2H),2.16(m,J＝13.2,6.6Hz,1H),1.09(d,J＝6.7Hz,6H).HR-MS(ESI):calcd for C 20 H 20 O 4 ,[M+H] + ,325.1440；found 325.1413.
Example 21: preparation of 7-isobutoxy-3- (4-methoxyphenyl) -4H-chromen-4-one (Compound FLM-45)
The preparation method is the same as in example 17. 1-iodo-2-methylpropane was used instead of ethyl iodide to give a pale yellow solid with a yield of 32.9% and a melting point of 129-131 ℃. 1 H NMR(600MHz,CDCl 3 )δ(ppm)8.20(d,J＝8.9Hz,1H),7.92(s,1H),7.51(d,J＝8.4Hz,2H),7.02–6.93(m,3H),6.83(s,1H),4.68(m,J＝5.9Hz,1H),3.85(s,3H),1.41(d,J＝6.0Hz,6H).HR-MS(ESI):calcd for C 19 H 18 O 4 ,[M+H] + ,311.1283；found 311.1281.
Example 22: preparation of 3- (4-methoxyphenyl) -4-oxo-4H-chromen-7-yl acetate (Compound FLM-46)
The preparation method is the same as in example 17. Acetyl chloride was used instead of ethyl iodide to give a white solid with a yield of 36.5% and a melting point of 155-158 ℃. 1 H NMR(600MHz,CDCl 3 )δ(ppm)8.33(dd,J＝8.7,1.0Hz,1H),7.99(d,J＝1.1Hz,1H),7.54–7.48(m,2H),7.31(dd,J＝2.3,1.0Hz,1H),7.17(m,J＝8.8,2.2,1.1Hz,1H),7.01–6.96(m,2H),3.85(d,J＝1.1Hz,3H),2.37(d,J＝1.1Hz,3H).HR-MS(ESI):calcd for C 18 H 15 O 5 ,[M+H] + ,311.0919；found 311.0902.
Example 23: preparation of 3- (4-methoxyphenyl) -4-oxo-4H-chromen-7-yl propionate (Compound FLM-47)
The preparation method is the same as in example 17. Propionyl chloride was used instead of ethyl iodide to give a white solid with a yield of 33.5% and a melting point of 111-113 ℃. 1 H NMR(600MHz,CDCl 3 )δ(ppm)8.33(d,J＝8.7Hz,1H),7.99(s,1H),7.51(d,J＝8.6Hz,2H),7.31(d,J＝2.1Hz,1H),7.17(dd,J＝8.7,2.1Hz,1H),7.01–6.96(m,2H),3.85(s,3H),2.66(m,J＝7.5Hz,2H),1.30(t,J＝7.5Hz,3H).HR-MS(ESI):calcd for C 19 H 16 O 5 ,[M+H] + ,325.1076；found 325.1034.
Example 24: preparation of 3- (4-methoxyphenyl) -4-oxo-4H-chromen-7-yl butyrate (Compound FLM-48)
The preparation method is the same as in example 17. Butyryl chloride was used in place of ethyl iodide to give a white solid in 29.3% yield with a melting point of 112-114 ℃. 1 H NMR(600MHz,CDCl 3 )δ(ppm)8.33(d,J＝8.7Hz,1H),7.98(s,1H),7.52–7.49(m,2H),7.30(d,J＝1.9Hz,1H),7.19–7.13(m,1H),7.02–6.96(m,2H),3.85(s,3H),2.61(t,J＝7.4Hz,2H),1.82(m,J＝7.3Hz,2H),1.08(t,J＝7.4Hz,3H).HR-MS(ESI):calcd for C 20 H 18 O 5 ,[M+H] + ,339.1232；found 339.1209.
Example 22: culture of Huh7 cells
We selected human hepatoma cell line Huh7 cells for culture. Huh7 cells were cultured in DMEM high-sugar culture medium containing 10% of newborn calf serum and 100U/mL penicillin, streptomycin, and the incubator culture conditions were set to 5% CO 2 The cells were changed every other day at 37℃and observed for growth every day. Discarding old cell culture solution when Huh7 cells grow to 70-80% fusion degree, washing cells with PBS for 2 times, adding 0.25% trypsin, observing cell morphology change under an inverted microscope, discarding digestive juice when cytoplasmatic retraction occurs and cytoplasmatic rounding occurs, immediately adding cell culture solution containing 10% serum to terminate digestion, sucking the culture solution with a straw, repeatedly gently blowing off adherent cells to make them fall off and suspend, adjusting cell density, inoculating into a new culture dish, and placing in 5% CO 2 Culturing in an incubator at 37 ℃.
Example 23: detection of Nogo-B transcriptional Activity of Huh7 cells by flavonoid Compounds
We used the dual luciferase reporter gene system to determine the effect of flavonoids and isoflavonoids on the Nogo-B transcriptional activity of Huh7 cells. Huh7 cells were seeded in 48-well plates and cultured for about 10-24h until the confluency of cells in the well plates reached 80%. According to the instructions, a certain amount of reporter gene blank plasmid or reporter gene plasmid containing Nogo-B promoter is mixed with internal reference plasmid (pGL 4.70) and transfection reagent, and left for 30min to form a transfection complex, and the transfection complex is uniformly dripped onto the corresponding cell sap surface on the well plate. Cells were cultured in an incubator at 37 ℃. After about 6-8 hours of transfection, the medium containing the transfection complex was discarded, and the cells were treated with 10. Mu.M of flavonoids and isoflavonoids for about 24 hours, changing to fresh serum-free medium. Cells were lysed using cell lysates provided by the luciferase reporter assay kit, and the lysate supernatant was used for luciferase activity detection. The cellular protein extract is diluted by a certain amount and then added into a 96-well plate, then the 96-well plate is placed into a chemiluminescent instrument, a program is set, and the activity of luciferase is measured. The relative fluorescence intensities were calculated and compared to an empty control and the effect of each drug on Nogo-B transcriptional activity of Huh7 cells was calculated.
First, 24 flavonoids in total were screened for FLM_1-24, and then the effect of FLM_25-48 on Nogo-B transcriptional activity of Huh7 cells was determined again by the dual-luciferase reporter system based on the results of the dual-luciferase reporter system (FIG. 1). As shown in FIG. 2, compounds FLM_33 and FLM_34 also have significant inhibitory effects on Nogo-B transcriptional activity of Huh7 cells. As can be seen from FIG. 1, flavonoids FLM_5, FLM_6, FLM_9 and FLM_18 have different degrees of inhibition effects on Nogo-B transcriptional activity of Huh7 cells. It can also be seen from FIG. 2 that the compounds FLM_33 and FLM_34 also have good inhibitory effect on Nogo-B transcriptional activity at an action concentration of 10. Mu.M, and thus these compounds can be used as Nogo-B inhibitors for developing drugs for treating related liver diseases.

Claims (1)

1. The application of flavonoid compounds is characterized in that:
the flavonoid compounds are used for preparing a regulator with a regulating effect on Nogo-B expression of human liver cancer cell line Huh7 cells;
the flavonoid compound is selected from 5-methoxyflavone FLM_5, 6-methoxyflavone FLM_6, 6-methylflavone FLM_9, 3', 7-dimethoxyisoflavone FLM_18, 6-ethoxy-2-phenyl-4H-chromen-4-one FLM_33, 6-butoxy-2-phenyl-4H-chromen-4-one FLM_34;
the flavonoid compound has a remarkable inhibiting effect on the expression of Nogo-B of Huh7 cells.
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