CN113321634A - Long-chain primary amide chrysin derivative and preparation method and application thereof - Google Patents
Long-chain primary amide chrysin derivative and preparation method and application thereof Download PDFInfo
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- -1 primary amide chrysin derivative Chemical class 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 238000000034 method Methods 0.000 claims abstract description 20
- RTIXKCRFFJGDFG-UHFFFAOYSA-N chrysin Chemical compound C=1C(O)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=CC=C1 RTIXKCRFFJGDFG-UHFFFAOYSA-N 0.000 claims description 231
- NYCXYKOXLNBYID-UHFFFAOYSA-N 5,7-Dihydroxychromone Natural products O1C=CC(=O)C=2C1=CC(O)=CC=2O NYCXYKOXLNBYID-UHFFFAOYSA-N 0.000 claims description 111
- 235000015838 chrysin Nutrition 0.000 claims description 111
- 229940043370 chrysin Drugs 0.000 claims description 111
- 238000006243 chemical reaction Methods 0.000 claims description 51
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 30
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 26
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 24
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 23
- 238000001035 drying Methods 0.000 claims description 19
- 239000000243 solution Substances 0.000 claims description 16
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 15
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 14
- 238000003786 synthesis reaction Methods 0.000 claims description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 14
- 230000015572 biosynthetic process Effects 0.000 claims description 13
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- 125000004494 ethyl ester group Chemical group 0.000 claims description 12
- 238000004809 thin layer chromatography Methods 0.000 claims description 12
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- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 6
- 238000010534 nucleophilic substitution reaction Methods 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
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- 239000007864 aqueous solution Substances 0.000 claims description 5
- 206010033128 Ovarian cancer Diseases 0.000 claims description 4
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- 238000001816 cooling Methods 0.000 claims description 4
- 239000000463 material Substances 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 3
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- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
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- 238000004519 manufacturing process Methods 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 11
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- 238000002474 experimental method Methods 0.000 abstract description 2
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- 150000001875 compounds Chemical class 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 6
- 238000012544 monitoring process Methods 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 5
- 238000001228 spectrum Methods 0.000 description 5
- OBNCKNCVKJNDBV-UHFFFAOYSA-N butanoic acid ethyl ester Natural products CCCC(=O)OCC OBNCKNCVKJNDBV-UHFFFAOYSA-N 0.000 description 4
- 238000001819 mass spectrum Methods 0.000 description 4
- 230000004048 modification Effects 0.000 description 4
- 238000012986 modification Methods 0.000 description 4
- 150000003140 primary amides Chemical group 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- DNSISZSEWVHGLH-UHFFFAOYSA-N butanamide Chemical compound CCCC(N)=O DNSISZSEWVHGLH-UHFFFAOYSA-N 0.000 description 3
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- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 241000196324 Embryophyta Species 0.000 description 2
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- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 2
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- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound 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](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- RGHQKFQZGLKBCF-UHFFFAOYSA-N 2-bromoethyl acetate Chemical compound CC(=O)OCCBr RGHQKFQZGLKBCF-UHFFFAOYSA-N 0.000 description 1
- NVRVNSHHLPQGCU-UHFFFAOYSA-M 6-bromohexanoate Chemical compound [O-]C(=O)CCCCCBr NVRVNSHHLPQGCU-UHFFFAOYSA-M 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 239000006144 Dulbecco’s modified Eagle's medium Substances 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 102000004366 Glucosidases Human genes 0.000 description 1
- 108010056771 Glucosidases Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 240000005790 Oroxylum indicum Species 0.000 description 1
- 235000012920 Oroxylum indicum Nutrition 0.000 description 1
- 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
- 241000241413 Propolis Species 0.000 description 1
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 description 1
- 102000004142 Trypsin Human genes 0.000 description 1
- 108090000631 Trypsin Proteins 0.000 description 1
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- 150000001298 alcohols Chemical class 0.000 description 1
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- 238000005804 alkylation reaction Methods 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
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- 150000002170 ethers Chemical class 0.000 description 1
- PQJJJMRNHATNKG-UHFFFAOYSA-N ethyl bromoacetate Chemical compound CCOC(=O)CBr PQJJJMRNHATNKG-UHFFFAOYSA-N 0.000 description 1
- 239000012091 fetal bovine serum Substances 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- 150000002212 flavone derivatives Chemical class 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 229930003935 flavonoid Natural products 0.000 description 1
- 235000017173 flavonoids Nutrition 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
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- 238000007254 oxidation reaction Methods 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
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- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 229940069949 propolis Drugs 0.000 description 1
- CQRYARSYNCAZFO-UHFFFAOYSA-N salicyl alcohol Chemical compound OCC1=CC=CC=C1O CQRYARSYNCAZFO-UHFFFAOYSA-N 0.000 description 1
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- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
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- 239000012588 trypsin Substances 0.000 description 1
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
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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
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- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of medicines, and relates to a long-chain primary amide chrysin derivative, and a preparation method and application thereof. The long-chain primary amide chrysin derivative has a structure shown in a formula I, wherein n is an integer of 1-3. The method for preparing the long-chain primary amide chrysin derivative has the advantages of high reaction speed, mild conditions, simple and convenient purification and high yield, and cell experiments prove that the long-chain primary amide chrysin derivative has better antitumor cell activity.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a long-chain primamide chrysin derivative, a preparation method of the long-chain primamide chrysin derivative, and application of the long-chain primamide chrysin derivative.
Background
In recent years, the incidence of cancers is increasing day by day, and the side effects and drug resistance of chemotherapeutic drugs and targeted drugs are generated, so that researchers aim at traditional Chinese medicines and traditional Chinese medicine monomers with small toxic and side effects. Chrysin is a flavonoid compound. Chrysin (5, 7-dihydroxyflavone) is a traditional Chinese medicine monomer existing in various medicinal plants, is used as a natural flavone (shown in a structural formula I) widely distributed in propolis and oroxylum indicum, and has various biological activities, such as pharmacological activities of resisting tumors, inflammation, bacteria, anxiety and oxidation and the like. In the in vivo metabolism process, the water solubility and the fat solubility are poor, and the C-5 or C-7 hydroxyl of chrysin is rapidly glycosylated to cause the activity reduction, thereby limiting the clinical application. Therefore, structural modification of C-5 or C-7 of chrysin is an effective method for improving chrysin activity.
The structural modification of chrysin mainly comprises the following aspects: (1) hydrophilic and lipophilic groups are introduced on chrysin to achieve the purpose of increasing hydrophilicity and lipophilicity. (2) Some specific pharmacodynamic groups are introduced to enhance some pharmacological activity. (3) Condensing with amino acid and other bioactive substances to increase the cell intake and thus to enhance its pharmacological activity.
Because of the hydrogen bonding of the hydroxyl group of C5, nucleophilic substitution is easier to occur at the C7 position, and the C7 modified chrysin derivative has more glucosidase inhibition activity. Therefore, modification of chrysin C7 position can effectively improve chrysin activity and stability, mainly alkylation of 7 position and paraffin substitution, and the like, and no report related to synthesis of 7-position primary amide substituted chrysin derivatives is available.
Disclosure of Invention
The invention aims to transform the hydroxyl at the position 7 with the strongest metabolic activity to obtain the derivative of long-chain primary amide chrysin which the metabolic inactivation is not easy and the anti-tumor activity is better.
In order to achieve the above object, the present invention provides a long-chain primary amide chrysin derivative, which has a structure shown in formula I,
in the formula I, n is an integer of 1-3.
The second aspect of the present invention provides a method for preparing the long-chain primary amide chrysin derivative, which comprises the following steps:
performing nucleophilic substitution by using chrysin and bromoalkanoic acid ethyl ester shown as a formula II, using potassium carbonate as a catalyst and DMF as a solvent; then hydrolyzing the mixture into long-chain carboxylic acid by using sodium hydroxide and DMSO; finally, chloroform is used as a solvent, thionyl chloride and ammonia gas are used for chlorination and ammoniation to obtain a target product, namely the long-chain primary amide chrysin derivative;
further, the preparation method comprises the following steps:
synthesis of S1, 7-O-long-chain alkanoic acid ethyl ester chrysin
Dissolving chrysin and potassium carbonate with dry DMF (dimethyl formamide) for preliminary reaction, then adding bromo-long-chain ethyl alkanoate, heating for reaction, filtering to remove potassium carbonate after the reaction is finished, washing with water to discharge materials, drying, and recrystallizing with ethyl acetate to obtain 7-O-long-chain ethyl alkanoate chrysin;
synthesis of S2.7-O-long-chain alkanoic acid chrysin
Dissolving 7-O-long-chain alkanoic acid ethyl ester chrysin and DMSO, dripping sodium hydroxide aqueous solution at 55-65 ℃ for reaction, introducing the reaction solution into dilute hydrochloric acid solution after the reaction is finished, filtering, and drying to obtain a pure product of the 7-O-long-chain alkanoic acid chrysin;
synthesis of S3.7-O-long-chain alkylamide chrysin
Dissolving 7-O-long-chain alkanoic acid chrysin by using dry chloroform, adding thionyl chloride, reacting at 50-55 ℃, cooling to 0-10 ℃ after complete reaction, introducing ammonia gas for reaction, spin-drying after the reaction is finished, adding water to wash out ammonium chloride, drying, and carrying out column chromatography to obtain the 7-O-long-chain alkylamide chrysin.
Specifically, step S1 includes:
dissolving chrysin and potassium carbonate by using a small amount of dry DMF (dimethyl formamide), reacting for 10-30 min at 55-65 ℃, adding bromo-long-chain ethyl alkanoate, heating to 75-85 ℃ for reaction, detecting the reaction by using thin-layer chromatography, filtering to remove potassium carbonate after the reaction is finished, washing with water, discharging, drying, and recrystallizing by using ethyl acetate to obtain the 7-O-long-chain ethyl alkanoate chrysin.
Specifically, step S2 includes:
dissolving 7-O-long-chain alkanoic acid ethyl ester chrysin in DMSO, dripping 2-3% sodium hydroxide aqueous solution at 55-65 ℃, reacting for 20-40 min, detecting the completion of the reaction by thin-layer chromatography, introducing a dilute hydrochloric acid solution into the reaction solution after the reaction is completed, filtering, and drying to obtain the 7-O-long-chain alkanoic acid chrysin.
According to the present invention, in step S1, the 7-O-long-chain alkanoic acid ethyl ester chrysin may be 7-O-ethyl acetate chrysin or 7-O-ethyl butyrate chrysin.
According to the present invention, in step S2, the 7-O-long-chain alkanoic acid chrysin may be 7-O-acetic acid chrysin or 7-O-butyric acid chrysin.
According to the present invention, in step S3, the 7-O-long-chain alkylamide chrysin can be 7-O-acetamide chrysin or 7-O-butyramide chrysin.
The third aspect of the invention provides the application of the long-chain primary amide chrysin derivative in preparing an anti-tumor preparation.
In particular, the anti-tumor agent can be an anti-ovarian cancer agent.
The 7-position hydroxyl of chrysin is modified by a chemical synthesis means, and the 7-position modified long-chain primary amide chrysin derivative is obtained by nucleophilic substitution, hydrolysis, chlorination and ammoniation. The method for preparing the long-chain primary amide chrysin derivative has the advantages of high reaction speed, mild condition, simple and convenient purification and high yield, and cell experiments prove that the derivative has better antitumor cell activity, thereby providing an idea for developing the chrysin and the derivative thereof into anticancer drugs.
Additional features and advantages of the invention will be set forth in the detailed description which follows.
Drawings
The above and other objects, features and advantages of the present invention will become more apparent by describing in more detail exemplary embodiments thereof with reference to the attached drawings.
FIG. 1 is a scheme showing the synthesis of long-chain alkylamide chrysin according to the present invention.
FIG. 2 shows the hydrogen spectrum of 7-O-acetamide chrysin.
FIG. 3 is a mass spectrum of 7-O-acetamide chrysin.
FIG. 4 is a hydrogen spectrum of 7-O-butanamide chrysin.
FIG. 5 is a mass spectrum of 7-O-butyramide chrysin.
Detailed Description
Preferred embodiments of the present invention will be described in more detail below. While the following describes preferred embodiments of the present invention, it should be understood that the present invention may be embodied in various forms and should not be limited by the embodiments set forth herein.
Examples
Synthesis of long-chain primary amide chrysin derivative
1. Material
1.1 drugs and reagents
Chrysin (purity > 98%), shanghai-sourced leaf biology ltd; tetramethylsilane (TMS), Adamas-beta, USA; silica gel GF254 board, Qingdao oceanic chemical plant; ethyl 2-bromoacetate, ethyl 4-bromoacetate, deuterated dimethyl sulfoxide, potassium carbonate (analytically pure), shanghai alatin biochemistry science and technology, ltd; n, N-dimethylformamide, methanol, ethyl acetate, dichloromethane, chloroform (analytical grade) and purchased from Chemicals, Inc., national pharmaceutical group.
1.2 Experimental instruments
An AL204 electronic analytical balance; WRS-1C melting point apparatus, Shanghai Shenguan apparatus Instrument Co., Ltd; AVANCE III HD 400 Nuclear Magnetic Resonance (NMR) Bopomometer, Bruker; ELAN DRC-e mass spectrometer, PerkinElmer, USA; DF-101S heat collection type constant temperature heating magnetic stirrer, Consumer of Instrument Limited responsibility in City; RE-52AA rotary evaporator, Shanghai Yanglong Biochemical apparatus factory; SHZ-D (III) desk-top circulating water vacuum pump, Consumer of Zyguyghua instruments, Inc.
2 method
The synthetic route is shown in figure 1, wherein compound 1 is chrysin, compound 2 is chrysin of 7-O-long chain alkanoic acid ethyl ester, compound 3 is chrysin of 7-O-long chain alkanoic acid, and compound 4 is chrysin of 7-O-long chain alkylamide.
2.1 Synthesis of Chemicals 1-2
Synthesis of 7-O-long-chain alkanoic acid ethyl ester chrysin general rule: dissolving 1 equivalent of chrysin and 2 times equivalent of potassium carbonate with a small amount of dry DMF (dimethyl formamide), reacting at 60 ℃ for 20min, adding 2 times equivalent of bromo long-chain alkyl alkanoate, heating to 80 ℃ for reaction, detecting the reaction by thin-layer chromatography, filtering to remove potassium carbonate, washing with water, discharging, drying, and recrystallizing with ethyl acetate to obtain the pure 7-O-long-chain alkyl alkanoate chrysin.
Using 7-O-ethyl acetate (ethyl butyrate) chrysin as an example: taking 0.27g (1.05mmol) of chrysin and 0.29g (2.10mmol) of potassium carbonate to put in a three-neck flask, adding 15ml of DMF to dissolve, stirring for 20min at 60 ℃ under the protection of nitrogen, slowly dropwise adding a DMF solution containing 0.38g of 2-bromoethyl acetate or 0.41g of 4-bromoethyl butyrate (2.10mol), heating to 80 ℃, reacting for 1-2 h, and monitoring the completion of the reaction by thin-layer chromatography. After the reaction is finished, filtering to remove potassium carbonate, pouring the reaction liquid into ice water with the amount of 20 times that of the reaction liquid to separate out a product, and drying to obtain a 7-O-ethyl acetate (ethyl butyrate) chrysin crude product. Then, the solid was recrystallized from ethyl acetate to obtain pure 7-O-ethyl acetate (ethyl butyrate) chrysin 0.33g (0.32g) with a yield of 91.0% (84.2%).
2.2 Synthesis of Compounds 2 to 3
General rule for synthesizing 7-O-long-chain alkanoic acid chrysin: dissolving 7-O-long-chain alkanoic acid ethyl ester chrysin with 1 time equivalent by using a small amount of DMSO (dimethyl sulfoxide), dripping 2.5% of sodium hydroxide aqueous solution at the temperature of 60 ℃, reacting for 30min, detecting the completion of the reaction by using thin-layer chromatography, introducing a dilute hydrochloric acid solution into the reaction solution after the reaction is completed, filtering and drying to obtain the pure 7-O-long-chain alkanoic acid chrysin.
Taking 7-O-acetic acid (butyric acid) chrysin as an example: taking 0.68g (0.74g) of 7-O-ethyl acetate (ethyl butyrate) chrysin of 2mmol, adding 40ml of DMSO to dissolve the chrysin, slowly dropwise adding 10ml of 2.5% sodium hydroxide to dissolve the chrysin at 60 ℃, reacting for 30min, monitoring the completion of the reaction by thin layer chromatography, pouring the reaction solution into 1000ml of 5% hydrochloric acid solution to precipitate after the reaction is completed, standing overnight, filtering, and drying in vacuum to obtain light yellow solid, namely 7-O-acetic acid (butyric acid) chrysin, wherein 0.58g (0.63) of the chrysin is obtained respectively, and the yield is 93.5% (92.6%).
2.3 Synthesis of Compounds 3 to 4
General rule for synthesizing 7-O-long-chain alkylamide chrysin: dissolving 1 equivalent of 7-O-long-chain alkanoic acid chrysin by using a little of dry chloroform, adding 4 times of equivalent of thionyl chloride, reacting at 50-55 ℃, monitoring the reaction by using thin-layer chromatography, cooling to 0-10 ℃ after the reaction is completed, introducing ammonia gas, monitoring the reaction by using the thin-layer chromatography, after the reaction is completed, spin-drying, adding water to wash away ammonium chloride, drying, and carrying out column chromatography to obtain the target compound.
Taking 7-O-acetamide (butanamide) chrysin as an example: taking 0.62g (0.68g) of 2mmol 7-O-acetic acid (butyric acid) chrysin and a three-neck flask, adding 50ml of dry chloroform for dissolving, dripping 0.95g 8mmol thionyl chloride at the temperature of 50-55 ℃, reacting for 4-8 h, monitoring the reaction by thin-layer chromatography, cooling to 0-10 ℃ in an ice bath after the reaction is finished, introducing ammonia gas, reacting for 0.5h, monitoring the reaction by thin-layer chromatography, spin-drying the reaction solution after the reaction is finished, adding water for washing, and filtering to obtain a crude product of the 7-O-acetamide (butyramide) chrysin. Then silica gel with 200-300 meshes is used for preparing a sand accompanying sample, and dichloromethane is used for: methanol (v: v) ═ 50: 1, to obtain a light yellow solid, i.e. 7-O-acetamide (butyramide) chrysin 0.52(0.58) with a yield of 85.2% (86.6%).
2.4 identification of the target Compound Structure
(1) The melting point of the target compound is measured. (2) The target compound was dissolved using deuterated DMSO and tested for hydrogen spectra using 400MHZ nuclear magnetization. (3) The molecular weight of the target compound was determined using ESI ion source. The characterization results are shown in FIGS. 2 to 5.
FIG. 2 shows the hydrogen spectrum of 7-O-acetamide chrysin. FIG. 3 is a mass spectrum of 7-O-acetamide chrysin.
7-O-acetamide chrysin: m.p.279-281 ℃, ESI-MS: 310.3M/z [ M + H ]]—，1H NMR(400MHz,DMSO)δ12.82(s,1H，5-OH),8.11(d,J＝6.7Hz,2H,Ar-2H),7.72–7.55(m,4H,Ar-3H,NH),7.49(s,1H,Ar-1H),7.08(s,1H,NH),6.83(d,J＝2.2Hz,1H,Ar-1H),6.45(d,J＝2.2Hz,1H,Ar-1H),4.60(s,2H,CH2).
FIG. 4 is a hydrogen spectrum of 7-O-butanamide chrysin. FIG. 5 is a mass spectrum of 7-O-butyramide chrysin.
7-O-butyramide chrysin: m.p.231-232 ℃, ESI-MS: 338.4M/z [ M + H ]]—，1H NMR(400MHz,DMSO)δ12.80(s,1H，5-OH),8.11(dd,J＝8.1,1.4Hz,2H,Ar-2H),7.78–7.50(m,3H,Ar-3H),7.35(s,1H,Ar-1H),7.05(s,1H,NH),6.84(d,J＝2.2Hz,2H,Ar-1H,NH),6.40(d,J＝2.2Hz,1H,Ar-1H),4.11(t,J＝6.5Hz,2H,CH2),2.24(t,J＝7.4Hz,2H,CH2-2H),1.96(p,J＝6.8Hz,2H,CH2-2H).
MTT method for detecting antitumor activity of chrysin derivative
Material
Chrysin (Shanghai-derived leaf biology Co., Ltd., batch No.: X24O6C4947, purity > 98%); 7-O-acetamide chrysin (self-made); 7-O-butyramide chrysin (self-made); DMEM high-glucose cell culture medium (Gibco, USA, batch No. 8118326); penicillin, streptomycin (Hyclone, USA, batch number: 1677648); fetal bovine serum (Gibco, USA, batch No. 42F 0266K); 0.25% trypsin (containing 0.02% EDTA) (Gibco, USA, batch No. 2042337); MTT (Wuhan Chu city Zhengmao science and technology engineering Co., Ltd., batch No.: CC 1110035). The human ovarian cancer SKOV3 cell line is from the type Collection of Chinese university (Wuhan university).
Method and results
Cells were incubated at 37 ℃ with 5% CO2And cultivating under 90% humidity condition. Taking SKOV3 cells in logarithmic growth phase at 5X 103The concentration of each well was inoculated into a 96-well plate. Culturing for 24 hr, discarding culture solution, and adding fresh culture medium prepared with different concentrations of white pigmentThe final concentrations of the saligenin, 7-O-acetamide chrysin and 7-O-butyramide chrysin were 200. mu. mol/L, 100. mu. mol/L, 50. mu. mol/L, 25. mu. mol/L and 12.5. mu. mol/L, respectively, and 100. mu.L of fresh medium without drug was added to the blank wells, 3 wells per group. After further incubation in the incubator for 48h, 20. mu.L of MTT solution (final concentration 0.5mg/mL) was added to each well. After continuing to culture in a carbon dioxide incubator for 4h, the culture medium in the wells was aspirated, 150 μ L of dimethyl sulfoxide (DMSO) was added to each well, shaken and shaken for 10min to completely dissolve the purple crystals at the bottoms of the wells, the absorbance value (OD value) was measured at 490nm on an microplate reader, and the survival rate (%) (experimental OD value/control OD value) × 100 was calculated using the following formula. IC calculation of three Compounds against SKOV3 cells Using GraphPad Prism 6.0 for non-Linear regression50. The results are shown in Table 1.
Antitumor Activity of the Compounds of Table 1 against SKOV3
The invention synthesizes the 7-O-acetamide chrysin and the 7-O-butyramide chrysin for the first time. Different from the previous method for preparing the chrysin derivative, the method uses DMF for nucleophilic substitution, and solves the problems of slow reaction rate and low yield of the previous method using acetone as the nucleophilic substitution. In order to solve the problem of poor solubility of the traditional process using alcohols as solvents, DMSO is used as a solvent for hydrolysis to synthesize 7-O-alkyl chrysin under alkaline conditions; and finally, preparing the primary amide by using dichloromethane as a solvent, thionyl chloride as an acylating agent and ammonia gas as an amino source through a one-pot method. The method has the advantages of simple operation, easily-achieved reaction conditions, high yield and the like, and provides a simple and convenient synthetic route for modifying chrysin or medicaments with phenolic hydroxyl groups into ether compounds. By determining the effect of the two derivatives and chrysin on the activity of SKOV3 cells, it was found that the antitumor activity of the chrysin derivatives had an enhanced trend compared to chrysin.
The invention provides a simple and convenient route for synthesizing the C7-position primary amide derivative of chrysin, avoids the activity reduction caused by the glycosylation of C7-position hydroxyl of chrysin, and the obtained derivative has a tendency of enhancing the antitumor activity. The synthesized 7-O-acetamide chrysin and 7-O-butyramide chrysin have the potential of becoming medicaments for treating ovarian cancer.
Having described embodiments of the present invention, the foregoing description is intended to be exemplary, not exhaustive, and not limited to the embodiments disclosed. Many modifications and variations will be apparent to those of ordinary skill in the art without departing from the scope and spirit of the described embodiments.
Claims (10)
1. A long-chain primary amide chrysin derivative has a structure shown in a formula I,
in the formula I, n is an integer of 1-3.
2. The process for preparing long-chain primary amide chrysin derivatives according to claim 1, comprising the steps of:
performing nucleophilic substitution by using chrysin and bromoalkanoic acid ethyl ester shown as a formula II, using potassium carbonate as a catalyst and DMF as a solvent; then hydrolyzing the mixture into long-chain carboxylic acid by using sodium hydroxide and DMSO; finally, chloroform is used as a solvent, thionyl chloride and ammonia gas are used for chlorination and ammoniation to obtain a target product, namely the long-chain primary amide chrysin derivative;
3. the method for preparing long-chain primary amide chrysin derivatives according to claim 2, wherein the method comprises the following steps:
synthesis of S1, 7-O-long-chain alkanoic acid ethyl ester chrysin
Dissolving chrysin and potassium carbonate with dry DMF (dimethyl formamide) for preliminary reaction, then adding bromo-long-chain ethyl alkanoate, heating for reaction, filtering to remove potassium carbonate after the reaction is finished, washing with water to discharge materials, drying, and recrystallizing with ethyl acetate to obtain 7-O-long-chain ethyl alkanoate chrysin;
synthesis of S2.7-O-long-chain alkanoic acid chrysin
Dissolving 7-O-long-chain alkanoic acid ethyl ester chrysin and DMSO, dripping sodium hydroxide aqueous solution at 55-65 ℃ for reaction, introducing the reaction solution into dilute hydrochloric acid solution after the reaction is finished, filtering, and drying to obtain a pure product of the 7-O-long-chain alkanoic acid chrysin;
synthesis of S3.7-O-long-chain alkylamide chrysin
Dissolving 7-O-long-chain alkanoic acid chrysin by using dry chloroform, adding thionyl chloride, reacting at 50-55 ℃, cooling to 0-10 ℃ after complete reaction, introducing ammonia gas for reaction, spin-drying after the reaction is finished, adding water to wash out ammonium chloride, drying, and carrying out column chromatography to obtain the 7-O-long-chain alkylamide chrysin.
4. The method for preparing long-chain primary amide chrysin derivatives according to claim 3, wherein step S1 comprises:
dissolving chrysin and potassium carbonate by using a small amount of dry DMF (dimethyl formamide), reacting for 10-30 min at 55-65 ℃, adding bromo-long-chain ethyl alkanoate, heating to 75-85 ℃ for reaction, detecting the reaction by using thin-layer chromatography, filtering to remove potassium carbonate after the reaction is finished, washing with water, discharging, drying, and recrystallizing by using ethyl acetate to obtain the 7-O-long-chain ethyl alkanoate chrysin.
5. The method for preparing long-chain primary amide chrysin derivatives according to claim 3, wherein step S2 comprises:
dissolving 7-O-long-chain alkanoic acid ethyl ester chrysin in DMSO, dripping 2-3% sodium hydroxide aqueous solution at 55-65 ℃, reacting for 20-40 min, detecting the completion of the reaction by thin-layer chromatography, introducing a dilute hydrochloric acid solution into the reaction solution after the reaction is completed, filtering, and drying to obtain the 7-O-long-chain alkanoic acid chrysin.
6. The method of preparing a long-chain primary amide chrysin derivative according to claim 3, wherein in step S1, the 7-O-long-chain alkyl alkanoate chrysin is 7-O-ethyl acetate chrysin or 7-O-ethyl butyrate chrysin.
7. The method of claim 3, wherein in step S2, the 7-O-long-chain alkanoic acid chrysin is 7-O-acetic acid chrysin or 7-O-butyric acid chrysin.
8. The method for preparing a long-chain primary amide chrysin derivative according to claim 3, wherein in step S3, the 7-O-long-chain alkylamide chrysin is 7-O-acetamide chrysin or 7-O-butyramide chrysin.
9. The use of a long chain primary amide chrysin derivative according to claim 1 in the preparation of an anti-tumor agent.
10. The use according to claim 9, wherein the anti-tumor agent is an anti-ovarian cancer agent.
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