CN116082145A - Fibrate derivative with antioxidant activity, synthesis method and application thereof - Google Patents
Fibrate derivative with antioxidant activity, synthesis method and application thereof Download PDFInfo
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- CN116082145A CN116082145A CN202310072437.5A CN202310072437A CN116082145A CN 116082145 A CN116082145 A CN 116082145A CN 202310072437 A CN202310072437 A CN 202310072437A CN 116082145 A CN116082145 A CN 116082145A
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- 230000003078 antioxidant effect Effects 0.000 title claims abstract description 35
- 229940125753 fibrate Drugs 0.000 title claims abstract description 35
- 238000001308 synthesis method Methods 0.000 title claims abstract description 11
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 239000003814 drug Substances 0.000 claims abstract description 14
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 13
- 229940079593 drug Drugs 0.000 claims abstract description 13
- 235000013376 functional food Nutrition 0.000 claims abstract description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 54
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 18
- 238000004440 column chromatography Methods 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- 230000015572 biosynthetic process Effects 0.000 claims description 16
- 238000003786 synthesis reaction Methods 0.000 claims description 16
- NXXYKOUNUYWIHA-UHFFFAOYSA-N 2,6-Dimethylphenol Chemical compound CC1=CC=CC(C)=C1O NXXYKOUNUYWIHA-UHFFFAOYSA-N 0.000 claims description 14
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- 238000005406 washing Methods 0.000 claims description 11
- 238000006243 chemical reaction Methods 0.000 claims description 10
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- 238000003756 stirring Methods 0.000 claims description 8
- UNZJYKKJZGIFCG-UHFFFAOYSA-N propan-2-yl 2-bromo-2-methylpropanoate Chemical compound CC(C)OC(=O)C(C)(C)Br UNZJYKKJZGIFCG-UHFFFAOYSA-N 0.000 claims description 7
- RKIDDEGICSMIJA-UHFFFAOYSA-N 4-chlorobenzoyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=C1 RKIDDEGICSMIJA-UHFFFAOYSA-N 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
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- 238000000605 extraction Methods 0.000 claims description 5
- 230000002194 synthesizing effect Effects 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract description 4
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 4
- 239000001257 hydrogen Substances 0.000 abstract description 4
- 238000001819 mass spectrum Methods 0.000 abstract description 4
- 238000011160 research Methods 0.000 abstract description 4
- 238000001228 spectrum Methods 0.000 abstract description 4
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- 230000001413 cellular effect Effects 0.000 abstract description 3
- 238000011161 development Methods 0.000 abstract description 3
- 238000000338 in vitro Methods 0.000 abstract description 3
- 238000005481 NMR spectroscopy Methods 0.000 abstract description 2
- 238000004458 analytical method Methods 0.000 abstract 1
- LNTHITQWFMADLM-UHFFFAOYSA-N gallic acid Chemical compound OC(=O)C1=CC(O)=C(O)C(O)=C1 LNTHITQWFMADLM-UHFFFAOYSA-N 0.000 description 10
- 230000003833 cell viability Effects 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
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- 230000004083 survival effect Effects 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 3
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 230000003064 anti-oxidating effect Effects 0.000 description 3
- 239000002274 desiccant Substances 0.000 description 3
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- 101100391174 Dictyostelium discoideum forC gene Proteins 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- WCUXLLCKKVVCTQ-UHFFFAOYSA-M Potassium chloride Chemical compound [Cl-].[K+] WCUXLLCKKVVCTQ-UHFFFAOYSA-M 0.000 description 2
- QTENRWWVYAAPBI-YZTFXSNBSA-N Streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@H]1[C@H](N=C(N)N)[C@@H](O)[C@H](N=C(N)N)[C@@H](O)[C@@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@H]1[C@H](N=C(N)N)[C@@H](O)[C@H](N=C(N)N)[C@@H](O)[C@@H]1O QTENRWWVYAAPBI-YZTFXSNBSA-N 0.000 description 2
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- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
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- 239000006285 cell suspension Substances 0.000 description 1
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- -1 compound 4-Chlorobenzoyl chloride Chemical class 0.000 description 1
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- 238000007405 data analysis Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- DGLRDKLJZLEJCY-UHFFFAOYSA-L disodium hydrogenphosphate dodecahydrate Chemical compound O.O.O.O.O.O.O.O.O.O.O.O.[Na+].[Na+].OP([O-])([O-])=O DGLRDKLJZLEJCY-UHFFFAOYSA-L 0.000 description 1
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- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 231100001083 no cytotoxicity Toxicity 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 230000004792 oxidative damage Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
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- 239000008213 purified water Substances 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C59/125—Saturated compounds having only one carboxyl group and containing ether groups, groups, groups, or groups
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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Abstract
The invention discloses a fibrate derivative with antioxidant activity, a synthesis method and application thereof, wherein the fibrate derivative is a compound ZJX-A376-157, and the structural formula of the compound is as follows:
the synthetic route is as follows:
. The invention uses nuclear magnetic resonance hydrogen spectrum, carbon spectrum and mass spectrum data to divideThe analysis shows that the synthesized fibrate derivative is a new compound, and in-vitro cell activity research proves that the fibrate derivative provided by the invention has strong antioxidant activity on the cellular level, is an excellent antioxidant new compound, and can be applied to the development of antioxidant drugs or functional foods.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry and functional foods, and particularly relates to a fibrate derivative with antioxidant activity, a synthesis method and application thereof.
Background
In recent years, with the rapid development of economy and society in China, the living standard of people is rapidly improved, so that the life of people in China is greatly prolonged. However, the older the age, the more free radicals are accumulated in the human body, the more injury is caused by oxidation, and finally the aging and death of the human body are caused. In addition, excessive oxidation can cause other diseases such as liver injury, cardiovascular disease, cancer, stroke, myocardial infarction, alzheimer's disease, parkinson's disease, etc. At present, antioxidant medicines are rarely marketed, and have limited categories and low efficacy. Therefore, research and development of novel high-efficiency antioxidant drugs are necessary.
Fibrates are a common and efficient hypolipidemic agent, but research has been carried out in recent years to find that fibrates also have non-hypolipidemic effects, such as antioxidant, anti-inflammatory, antitumor effects, etc. However, there are few fibrates currently available for practical use in clinical therapy for antioxidant activity, due to the relatively low antioxidant activity of fibrates. Based on the above, the fibrate compound is derivatized, so that the fibrate derivative ZJX-A376-157 with novel structure is obtained, and the fibrate derivative has good antioxidant capacity at the cellular level.
By searching, no patent publication related to the present patent application has been found.
Disclosure of Invention
The invention aims to overcome the defects of the prior art, and provides a synthesis method of a beta derivative and application of the beta derivative in an antioxidant drug or functional food by derivatizing a fibrate compound.
The technical scheme adopted for solving the technical problems is as follows:
a fibrate derivative with antioxidant activity, which is a compound ZJX-A376-157, and has the structural formula:
the synthesis method of the fibrate derivative comprises the following synthesis routes:
further, the synthesis method comprises the following steps:
(1) Synthesis of Compound ZJX-A376-88:
dissolving 4-chlorobenzoyl chloride in anhydrous dichloromethane, and adding anhydrous AlCl 3 Stirring and refluxing 2, 6-dimethylphenol at 60deg.C for 30min, TLC tracking reaction, quenching with distilled water, adjusting pH to acidity with 1.0mol/L hydrochloric acid, extracting with ethyl acetate for 3 times, mixing organic phases, washing with saturated saline solution, and anhydrous Na 2 SO 4 Drying, vacuum concentrating under reduced pressure to obtain crude product, and purifying by column chromatography to obtain compound ZJX-A376-88;
wherein, 4-chlorobenzoyl chloride: anhydrous AlCl 3 : ratio eq of 2, 6-dimethylphenol: eq: eq is 1:1:1, the volume ratio of the eluent system in the column chromatography purification is 15-30: petroleum ether of 1: ethyl acetate;
(2) Synthesis of Compound ZJX-A376-89:
dissolving compound ZJX-A376-88 in acetonitrile, adding anhydrous K 2 CO 3 Isopropyl 2-bromoisobutyrate, stirred at 82 ℃ under reflux overnight, TLC followed by completion of the reaction, distilled water quenching, extraction 3 times with ethyl acetate, combined organic phases, washing with saturated brine, anhydrous Na 2 SO 4 Drying, vacuum concentrating under reduced pressure to obtain crude product, and purifying by column chromatography to obtain compound ZJX-A376-89;
wherein, the compound ZJX-A376-88: anhydrous K 2 CO 3 : ratio eq of isopropyl 2-bromoisobutyrate: eq: eq is 1:2.5:2.5, the volume ratio of the eluent system in the column chromatography purification is 30-50: petroleum ether of 1: ethyl acetate;
(3) Synthesis of Compound ZJX-A376-157:
dissolving compound ZJX-A376-89 in isopropanol, adding NaOH, stirring and refluxing at 83 deg.C for 2h, tracking the completion of TLC, quenching with distilled water, adjusting pH to acidity with 1.0mol/L hydrochloric acid, extracting with ethyl acetate for 3 times, mixing organic phases, washing with saturated saline solution, and anhydrous Na 2 SO 4 Drying, vacuum concentrating under reduced pressure to obtain crude product, and purifying by column chromatography to obtain compound ZJX-A376-157;
wherein, the compound ZJX-A376-89: ratio eq of NaOH: eq is 1:3, the volume ratio of the eluent system in the column chromatography purification is 3-5: petroleum ether of 1: ethyl acetate.
The application of the fibrate derivative in preparing antioxidant medicines.
The use of a fibrate derivative as described above in the preparation of a functional food.
The invention has the advantages and positive effects that:
1. the invention synthesizes a new fibrate derivative with antioxidant activity, and spectrum and mass spectrum data analysis show that the synthesized fibrate derivative is a new compound, and in-vitro cell activity research proves that the fibrate derivative provided by the invention has strong antioxidant activity on the cellular level, is a new compound with excellent antioxidant activity, and is expected to be developed into a new antioxidant drug or functional food.
2. According to the invention, the fibrate drug is structurally derivatized, so that the fibrate drug has excellent antioxidant activity, and the derivative with excellent antioxidant activity is obtained by in-vitro activity test of the derivative. The invention opens up the research direction of a new type of antioxidant drugs and functional foods.
Drawings
FIG. 1 shows the present invention of the compound ZJX-A376-88 in deuterated CHCl 3 Nuclear magnetic hydrogen spectrogram of (a);
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum of the compound ZJX-A376-89 in deuterated DMSO;
FIG. 3 shows the compound ZJX-A376-89 in deuterated CHCl according to the invention 3 Nuclear magnetic carbon spectrogram of (a);
FIG. 4 is a high resolution mass spectrum of the compound ZJX-A376-89 of the present invention;
FIG. 5 shows the present invention of the compound ZJX-A376-157 in deuterated CHCl 3 Nuclear magnetic hydrogen spectrogram of (a);
FIG. 6 shows the compound ZJX-A376-157 of the present invention in deuterated CHCl 3 Nuclear magnetic carbon spectrogram of (a);
FIG. 7 is a high resolution mass spectrum of the compound ZJX-A376-157 of the present invention;
FIG. 8 is a graph showing the effect of gallic acid on PC-12 cell viability in the present invention;
FIG. 9 is a graph showing the effect of the compound ZJX-A376-89 of the present invention on PC-12 cell viability;
FIG. 10 is a graph showing the effect of the compound ZJX-A376-157 on PC-12 cell viability.
Detailed Description
The invention will now be further illustrated by reference to the following examples, which are intended to be illustrative, not limiting, and are not intended to limit the scope of the invention.
The various experimental operations involved in the specific embodiments are conventional in the art, and are not specifically noted herein, and may be implemented by those skilled in the art with reference to various general specifications, technical literature or related specifications, manuals, etc. before the filing date of the present invention.
A fibrate derivative with antioxidant activity, which is a compound ZJX-A376-157, and has the structural formula:
the synthesis method of the fibrate derivative comprises the following synthesis routes:
preferably, the synthesis method comprises the following steps:
(1) Synthesis of Compound ZJX-A376-88:
dissolving 4-chlorobenzoyl chloride in anhydrous dichloromethane, and adding anhydrous AlCl 3 Stirring and refluxing 2, 6-dimethylphenol at 60deg.C for 30min, TLC tracking reaction, quenching with distilled water, adjusting pH to acidity with 1.0mol/L hydrochloric acid, extracting with ethyl acetate for 3 times, mixing organic phases, washing with saturated saline solution, and anhydrous Na 2 SO 4 Drying, vacuum concentrating under reduced pressure to obtain crude product, and purifying by column chromatography to obtain compound ZJX-A376-88;
wherein, 4-chlorobenzoyl chloride: anhydrous AlCl 3 : ratio eq of 2, 6-dimethylphenol: eq: eq is 1:1:1, the volume ratio of the eluent system in the column chromatography purification is 15-30: petroleum ether of 1: ethyl acetate;
(2) Synthesis of Compound ZJX-A376-89:
dissolving compound ZJX-A376-88 in acetonitrile, adding anhydrous K 2 CO 3 Isopropyl 2-bromoisobutyrate, stirred at 82 ℃ under reflux overnight, TLC followed by completion of the reaction, distilled water quenching, extraction 3 times with ethyl acetate, combined organic phases, washing with saturated brine, anhydrous Na 2 SO 4 Drying, vacuum concentrating under reduced pressure to obtain crude product, and purifying by column chromatography to obtain compound ZJX-A376-89;
wherein, the compound ZJX-A376-88: anhydrous K 2 CO 3 : ratio eq of isopropyl 2-bromoisobutyrate: eq: eq is 1:2.5:2.5, the volume ratio of the eluent system in the column chromatography purification is 30-50: petroleum ether of 1: ethyl acetate;
(3) Synthesis of Compound ZJX-A376-157:
dissolving compound ZJX-A376-89 in isopropanol, adding NaOH, stirring and refluxing at 83 deg.C for 2h, tracking the completion of TLC, quenching with distilled water, adjusting pH to acidity with 1.0mol/L hydrochloric acid, extracting with ethyl acetate for 3 times, mixing organic phases, washing with saturated saline solution, and anhydrous Na 2 SO 4 Drying, vacuum concentrating under reduced pressure to obtain crude product, and purifying by column chromatography to obtain compound ZJX-A376-157;
wherein, the compound ZJX-A376-89: ratio eq of NaOH: eq is 1:3, the volume ratio of the eluent system in the column chromatography purification is 3-5: petroleum ether of 1: ethyl acetate.
The application of the fibrate derivative in preparing antioxidant medicines.
The use of a fibrate derivative as described above in the preparation of a functional food.
The preparation and detection are as follows:
a fibrate derivative with antioxidant activity, which is a compound ZJX-A376-157, and has the structural formula:
the synthesis method of the fibrate derivative comprises the following synthesis routes:
preferably, the specific steps of the synthetic route are as follows:
(1) Synthesis of Compound ZJX-A376-88:
weighing compound 4-Chlorobenzoyl chloride (150 mg,0.857mmol,1 eq) was placed in a 25mL round bottom flask and dissolved completely with 2mL anhydrous DCM and anhydrous AlCl added at room temperature 3 (114.284 mg,0.857mmol,1 eq) and 2, 6-dimethylphenol (104.691 mg,0.857mmol,1 eq), stirring reflux for 30min at 60 ℃, tlc followed by completion of the reaction, distilled water quenching the reaction, 1.0mol/L hydrochloric acid to adjust pH to acidity, EA extraction (30 ml×3), combining the organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, filtering off the drying agent, evaporating off the solvent under reduced pressure, and purifying the residue by silica gel column chromatography (PE: ea=20:1, 15:1, v/v) to give the product: 110mg, yellow solid, yield 49.23%.
HNMR(400MHz,CDCl 3 ) Delta 7.70 (d, j=8.4 hz, 2H), 7.46 (t, j=8.4 hz, 4H), 2.29 (s, 6H) as
Shown in fig. 1.
(2) Synthesis of Compound ZJX-A376-89:
compound ZJX-A376-88 (100 mg,0.384mmol,1 eq) was weighed into a 25mL round bottom flask and dissolved completely with the addition of 2mL acetonitrile, and anhydrous K was added at room temperature 2 CO 3 (104.691 mg,0.857mmol,2.5 eq) was added dropwise isopropyl 2-bromoisobutyrate (179.18 mg,0.857mmol,2.5 eq) at 82 ℃ with stirring and refluxing overnight, TLC followed by completion of the reaction, distilled water quenching, EA extraction (30 ml×3), combined organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, filtration of the drying agent, evaporation of the solvent under reduced pressure, purification of the residue by silica gel column chromatography (PE: ea=50:1, 30:1, v/v) gave the product: 70mg, white solid, 46.93% yield.
HNMR (400 mhz, dmso) δ7.71 (d, j=8.4 hz, 2H), 7.61 (d, j=8.4 hz, 2H), 7.42 (s, 2H), 4.94-5.03 (m, 1H), 2.20 (s, 6H), 1.41 (s, 6H), 1.25 (d, j=6.4 hz, 6H).
13 CNMR(100MHz,CDCl 3 ) Delta 195.06,173.52,157.34,138.64,136.36,133.37,132.95,131.39,130.86,128.65,81.42,69.18,25.59,21.77,18.29 as shown in figure 3.
HRMS(ESI-TOF)m/zcalcd.forC 22 H 25 ClO 4 [M+H] + 389.1514, found389.1514. As shown in FIG. 4.
(3) Synthesis of Compound ZJX-A376-157:
compound ZJX-a376-89 (105 mg,0.27mmol,1 eq) was weighed into a 50mL round bottom flask, added with 2mL of isopropanol to dissolve completely, naOH (32.4 mg,0.81mmol,3 eq) was added at room temperature, stirred and refluxed for 2h at 83 ℃, tlc followed by completion of the reaction, distilled water quenched, 1.0mol/L hydrochloric acid adjusted to pH acidic, EA extracted (30 ml×3), the organic phases combined, washed with saturated brine, dried over anhydrous sodium sulfate, the drying agent filtered off, the solvent evaporated under reduced pressure, and the residue purified by silica gel column chromatography (PE: ea=5:1, 3:1, v/v) to give the product: 90mg, white solid, 98.89% yield.
HNMR(400MHz,CDCl 3 )δ7.70(d,J＝7.6Hz,2H),7.43(s,4H),2.27(s,6H),1.54(s,6H).
As shown in fig. 5.
13 CNMR(100MHz,CDCl 3 ) Delta 195.08,177.27,138.88,136.19,133.29,131.45,131.13,128.77,81.92,25.44,18.42 as shown in figure 6.
HRMS(ESI-TOF)m/zcalcd.forC 19 H 19 ClO 4 [M+H] + 347.1056, found347.1055. As shown in fig. 7.
The compounds of the present invention and their antioxidant activity were measured as follows:
1) Preparing a solution:
preparation of RPMI1640 culture solution: 5mL of penicillin, streptomycin solution and 50mL of fetal bovine serum are added into 500mL of RPMI1640 cell culture solution, a culture medium containing 10% of fetal bovine serum and 1% of green streptomycin solution is finally prepared, the preparation of the culture medium is carried out in an ultra-clean workbench, and then the culture medium is placed in a refrigerator for storage at 4 ℃.
Preparation of PBS buffer: in a 1000mL conical flask, 8g of sodium chloride, 0.2g of potassium chloride, 2.9g of disodium hydrogen phosphate dodecahydrate and 0.2g of potassium dihydrogen phosphate are weighed, 800mL of purified water is added, the mixture is fully stirred and dissolved, the volume is fixed to 1000mL, and the mixture is placed in a refrigerator for 4 ℃ for storage after high-pressure sterilization.
Preparation of MTT solution: 0.5g of MTT dry powder was weighed and dissolved in 100mLPBS buffer, and after filtration sterilization with a 0.22. Mu.M filter membrane, the solution was stored in a refrigerator at-12 ℃.
2) The method for measuring the antioxidant activity comprises the following specific steps:
cells used in the measurement of antioxidant Activity test of the present invention: adrenal pheochromocytoma PC-12.
The culture solution used for PC-12 cells is RPMI1640 cell culture solution containing 1% penicillin-streptomycin solution and 10% fetal bovine serum, and the culture conditions are 37 ℃ and 5% CO 2 Is a constant temperature incubator.
The method comprises the following specific steps:
(1) After counting the cells with a hemocytometer, they were diluted to 5X 10 with culture medium 5 individual/mL;
(2) 100. Mu.L of the cell suspension was added to each well of the 96-well plate, and PC-12 cells were cultured in an incubator at 37℃for 16 hours;
(3) Dissolving a required test compound in dimethyl sulfoxide, sequentially adding 0.5 mu L/hole according to the concentration, and incubating for 0.5h in an incubator at 37 ℃ with the final concentration of the drug of 5, 10, 20, 40 and 80 mu M;
(4) Added to a final concentration of 100 mu M H 2 O 2 Incubation in incubator at 37 ℃ for 4h;
(5) MTT with the concentration of 20 mu L and 5mg/mL is added, and the mixture is incubated for 4 hours at 37 ℃ in an incubator;
(6) The medium was discarded, 100. Mu.L of DMSO was added to lyse the cells, incubated at 37℃for 10 minutes, and OD values at 492 and 630nm were measured with a microplate reader;
(7) Data were processed and survival was calculated from OD values.
3) The experimental results show that:
the invention adopts hydrogen peroxide for modeling, hydrogen peroxide is added into cells, and the cell survival rate is reduced from 100% to about 30%. As shown in fig. 8, the present invention uses gallic acid as a positive control, and uses gallic acid pre-protection at different concentrations in the model group, and the cell survival rate gradually increases with increasing concentration, exhibiting dose dependency. At 5 μm, the cell viability was 59%, more than 50% indicating that gallic acid can exert significant antioxidant effect at 5 μm; the cell viability was 106% with 80. Mu.M gallic acid pre-protection, comparable to the blank.
As shown in FIG. 9, the compound ZJX-A376-89 does not well protect cells from oxidative damage by hydrogen peroxide even at 80. Mu.M, and its survival rate is 54% or more than 50%. This demonstrates that the compound ZJX-A376-89 only exerts a significant antioxidant effect at 80. Mu.M.
As shown in FIG. 10, the compound ZJX-A376-157 still showed no cytotoxicity at 80. Mu.M (cell viability was 95% in the group of 80. Mu.M compound ZJX-A376-157 with medium alone), which suggests that the compound ZJX-A376-157 is non-toxic or low toxic. When 10 mu M of the compound ZJX-A376-157 was pre-protected, the cell viability increased from 31% to 50%, which suggests that the compound ZJX-A376-157 could exert a significant antioxidant effect at 10 mu M.
The experimental results show that the compound ZJX-A376-157 has simple synthesis and purification methods and better antioxidation activity, and has wide prospect in the aspects of development and application of antioxidation medicaments and functional foods. The derivatives of the invention can be applied to the preparation of antioxidant drugs and functional foods, including but not limited to the application to the antioxidation.
Although embodiments of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that: various substitutions, changes and modifications are possible without departing from the spirit and scope of the invention and the appended claims, and therefore the scope of the invention is not limited to the disclosure of the embodiments.
Claims (5)
1. A fibrate derivative having antioxidant activity, characterized in that: the fibrate derivative is a compound ZJX-A376-157, and has the structural formula:
2. the method for synthesizing a fibrate derivative of claim 1, wherein the method comprises the steps of: the synthetic route is as follows:
3. the synthesis method according to claim 2, characterized in that: the method comprises the following steps:
(1) Synthesis of Compound ZJX-A376-88:
dissolving 4-chlorobenzoyl chloride in anhydrous dichloromethane, and adding anhydrous AlCl 3 Stirring and refluxing 2, 6-dimethylphenol at 60deg.C for 30min, TLC tracking reaction, quenching with distilled water, adjusting pH to acidity with 1.0mol/L hydrochloric acid, extracting with ethyl acetate for 3 times, mixing organic phases, washing with saturated saline solution, and anhydrous Na 2 SO 4 Drying, vacuum concentrating under reduced pressure to obtain crude product, and purifying by column chromatography to obtain compound ZJX-A376-88;
wherein, 4-chlorobenzoyl chloride: anhydrous AlCl 3 : ratio eq of 2, 6-dimethylphenol: eq: eq is 1:1:1, the volume ratio of the eluent system in the column chromatography purification is 15-30: petroleum ether of 1: ethyl acetate;
(2) Synthesis of Compound ZJX-A376-89:
dissolving compound ZJX-A376-88 in acetonitrile, adding anhydrous K 2 CO 3 Isopropyl 2-bromoisobutyrate, stirred at 82 ℃ under reflux overnight, TLC followed by completion of the reaction, distilled water quenching, extraction 3 times with ethyl acetate, combined organic phases, washing with saturated brine, anhydrous Na 2 SO 4 Drying, vacuum concentrating under reduced pressure to obtain crude product, and purifying by column chromatography to obtain compound ZJX-A376-89;
wherein, the compound ZJX-A376-88: anhydrous K 2 CO 3 : ratio eq of isopropyl 2-bromoisobutyrate: eq: eq is 1:2.5:2.5, the volume ratio of the eluent system in the column chromatography purification is 30-50: petroleum ether of 1: ethyl acetate;
(3) Synthesis of Compound ZJX-A376-157:
dissolving compound ZJX-A376-89 in isopropanol, adding NaOH, stirring and refluxing at 83 deg.C for 2h, tracking the completion of TLC, quenching with distilled water, adjusting pH to acidity with 1.0mol/L hydrochloric acid, extracting with ethyl acetate for 3 times, mixing organic phases, washing with saturated saline solution, and anhydrous Na 2 SO 4 Drying, vacuum concentrating under reduced pressure to obtain crude product, and purifying by column chromatography to obtain compound ZJX-A376-157;
wherein, the compound ZJX-A376-89: ratio eq of NaOH: eq is 1:3, the volume ratio of the eluent system in the column chromatography purification is 3-5: petroleum ether of 1: ethyl acetate.
4. Use of the fibrate derivative of claim 1 for the preparation of an antioxidant drug.
5. Use of the fibrate derivative of claim 1 for the preparation of a functional food.
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