CN117700389A - Synthesis and anti-tumor activity research of novel coumarin structure-containing drug small molecules - Google Patents
Synthesis and anti-tumor activity research of novel coumarin structure-containing drug small molecules Download PDFInfo
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- 125000000332 coumarinyl group Chemical group O1C(=O)C(=CC2=CC=CC=C12)* 0.000 title claims abstract description 12
- 239000003814 drug Substances 0.000 title claims abstract description 11
- 229940079593 drug Drugs 0.000 title claims abstract description 9
- 230000000259 anti-tumor effect Effects 0.000 title claims abstract description 6
- 230000015572 biosynthetic process Effects 0.000 title abstract description 13
- 238000003786 synthesis reaction Methods 0.000 title abstract description 13
- 150000003384 small molecules Chemical class 0.000 title description 6
- 230000000844 anti-bacterial effect Effects 0.000 claims description 2
- 230000004071 biological effect Effects 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 230000000840 anti-viral effect Effects 0.000 claims 1
- 150000001893 coumarin derivatives Chemical class 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 37
- -1 amine compounds Chemical class 0.000 abstract description 20
- 230000005764 inhibitory process Effects 0.000 abstract description 11
- 230000000694 effects Effects 0.000 abstract description 8
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 abstract description 5
- 229960002949 fluorouracil Drugs 0.000 abstract description 5
- 239000002246 antineoplastic agent Substances 0.000 abstract description 4
- 229940041181 antineoplastic drug Drugs 0.000 abstract description 3
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 abstract description 3
- XFVZSRRZZNLWBW-UHFFFAOYSA-N 4-(Diethylamino)salicylaldehyde Chemical compound CCN(CC)C1=CC=C(C=O)C(O)=C1 XFVZSRRZZNLWBW-UHFFFAOYSA-N 0.000 abstract description 2
- 108010087230 Sincalide Proteins 0.000 abstract description 2
- 238000007239 Wittig reaction Methods 0.000 abstract description 2
- 238000005893 bromination reaction Methods 0.000 abstract description 2
- 238000010609 cell counting kit-8 assay Methods 0.000 abstract description 2
- 238000005859 coupling reaction Methods 0.000 abstract description 2
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 abstract 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 abstract 1
- MWDVCHRYCKXEBY-LBPRGKRZSA-N 3-chloro-n-[2-oxo-2-[[(1s)-1-phenylethyl]amino]ethyl]benzamide Chemical compound N([C@@H](C)C=1C=CC=CC=1)C(=O)CNC(=O)C1=CC=CC(Cl)=C1 MWDVCHRYCKXEBY-LBPRGKRZSA-N 0.000 abstract 1
- QXAMGWKESXGGNV-UHFFFAOYSA-N 7-(diethylamino)-1-benzopyran-2-one Chemical compound C1=CC(=O)OC2=CC(N(CC)CC)=CC=C21 QXAMGWKESXGGNV-UHFFFAOYSA-N 0.000 abstract 1
- 238000003547 Friedel-Crafts alkylation reaction Methods 0.000 abstract 1
- 239000002994 raw material Substances 0.000 abstract 1
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 59
- 238000006243 chemical reaction Methods 0.000 description 22
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 21
- 210000004027 cell Anatomy 0.000 description 20
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 16
- 239000000203 mixture Substances 0.000 description 13
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 12
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 11
- 238000011282 treatment Methods 0.000 description 11
- 206010028980 Neoplasm Diseases 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
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- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 7
- 238000004440 column chromatography Methods 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 239000003480 eluent Substances 0.000 description 7
- 238000010828 elution Methods 0.000 description 7
- 239000002904 solvent Substances 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 6
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 5
- 201000011510 cancer Diseases 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 150000004775 coumarins Chemical class 0.000 description 4
- 230000000857 drug effect Effects 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000002512 chemotherapy Methods 0.000 description 3
- 238000013399 early diagnosis Methods 0.000 description 3
- 125000001153 fluoro group Chemical group F* 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 238000001959 radiotherapy Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- YEDUAINPPJYDJZ-UHFFFAOYSA-N 2-hydroxybenzothiazole Chemical compound C1=CC=C2SC(O)=NC2=C1 YEDUAINPPJYDJZ-UHFFFAOYSA-N 0.000 description 1
- HWQSZPUCHJKWLS-UHFFFAOYSA-N 7-(diethylamino)-2-oxochromene-3-carbaldehyde Chemical compound C1=C(C=O)C(=O)OC2=CC(N(CC)CC)=CC=C21 HWQSZPUCHJKWLS-UHFFFAOYSA-N 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 238000005727 Friedel-Crafts reaction Methods 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- BAPJBEWLBFYGME-UHFFFAOYSA-N acrylic acid methyl ester Natural products COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000003288 anthiarrhythmic effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000036436 anti-hiv Effects 0.000 description 1
- 230000003262 anti-osteoporosis Effects 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 230000001028 anti-proliverative effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 210000001185 bone marrow Anatomy 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 229940125898 compound 5 Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 210000002950 fibroblast Anatomy 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 238000002329 infrared spectrum Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
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- 230000007246 mechanism Effects 0.000 description 1
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- 238000003541 multi-stage reaction Methods 0.000 description 1
- VMPITZXILSNTON-UHFFFAOYSA-N o-anisidine Chemical compound COC1=CC=CC=C1N VMPITZXILSNTON-UHFFFAOYSA-N 0.000 description 1
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- 239000000047 product Substances 0.000 description 1
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- 239000007858 starting material Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
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- 230000004083 survival effect Effects 0.000 description 1
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- 231100000331 toxic Toxicity 0.000 description 1
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- 210000004881 tumor cell Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
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Abstract
The invention discloses synthesis of a novel coumarin structure-containing drug of a small molecular formula (1) and anti-tumor activity research.Wherein R is
Description
Technical Field
The invention relates to synthesis of novel coumarin structure-containing drug small molecules and anti-tumor activity research
Background
Early diagnosis and treatment of malignant tumors is a major problem in the medical community, and if an effective and accurate diagnosis can be adopted for a tumor patient in early stage of onset, the patient can be subjected to early treatment. However, due to the immaturity of the diagnosis technology, the early diagnosis effect is not ideal, so that the 5-year survival rate of tumor patients is not high. Early diagnosis and treatment of malignant tumors has become a research hotspot in the medical and chemical fields of today.
Traditional tumor treatment methods include surgical treatment, radiation treatment, chemotherapy, traditional Chinese medicine treatment, endocrine treatment and the like, and are generally used for comprehensive treatment by a plurality of means clinically, and the drug treatment is one of main therapies of tumors, plays a great role in cancer treatment, and is particularly important for patients suffering from tumor metastasis. Conventional radiotherapy and chemotherapy use radiation, cytotoxic drugs to kill or inhibit the hyperproliferation of tumor cells. It goes without saying that these treatments, due to their poor selectivity, are necessarily toxic to normal cells of the body, especially to those tissues which proliferate vigorously. Thus, radiation therapy is affected by the tolerance of normal tissues at the irradiated site, and important viscera such as bone marrow, liver and kidney, heart function and digestive tract mucosa tolerance have certain limitations on the dosages of chemotherapy and radiation therapy.
Firstly, coumarin derivatives have various biological activities such as antiarrhythmic, anti-osteoporosis, anticoagulation, antioxidation, anti-HIV, anti-tumor, antibacterial and the like, and have potential medicinal values. Coumarin compounds are useful as potential anticancer agents, their anticancer mechanism involves multiple aspects of cancer pathways, are effective against most cancers, and have fewer adverse effects. At present, based on urgent needs for high-efficiency low-toxicity antitumor drugs, and the coumarin compounds have simpler structures and are easy to chemically synthesize and modify, some coumarin compounds are being developed and screened as antitumor drugs.
Disclosure of Invention
1. The invention discloses a preparation method of a drug small molecule containing a coumarin structure, which uses a CCK8 method to carry out toxicity experiments on cells and evaluates the antiproliferative effect of compounds on A549, HELA, MCF7 and normal mouse fibroblast L929.
2. The invention adopts the following technical scheme that the medicine small molecule containing coumarin structure has the structural formula of
3. In the invention, R is，R 1 ,R 2 ,R 3 Are each independently H, OCH 3 F or CH 3 。
4. The invention takes 4- (diethylamino) salicylaldehyde as a starting material, and synthesizes 3- (7- (diethylamino) -2-oxo-2H-benzopyran-3-yl) acrylic acid through typical Friedel-crafts reaction, NBS bromination reaction and Wittig reaction and multi-step reaction such as hydrolysis reaction, and the structural formula is as follows:
5. in the invention, 3- (7- (diethylamino) -2-oxo-2H-benzopyran-3-yl) acrylic acid and different amine compounds are subjected to coupling reaction to obtain a coumarin structure-containing drug small molecule: formula (1).
6. The invention is characterized by nuclear magnetic resonance, high resolution mass spectrum, infrared spectrum and the like, and the result fully proves the synthesis of the compound.
Drawings
FIG. 1 is a synthetic route;
FIG. 2 is a target product of the synthetic route;
FIG. 3 is a hydrogen and carbon spectrum of intermediate compound 5;
FIG. 4 is a hydrogen and carbon spectrum of intermediate compound 6;
FIGS. 5-10 are hydrogen and carbon spectra of target compounds 7a-7 f;
FIG. 11 shows the inhibition of different cancer cells by target compounds 7a-7f and 5-fluorouracil at 20 micromolar concentrations.
FIG. 12 is a graph showing IC50 values of target compounds 7a-7f
Description of the embodiments
(1) Synthesis of methyl (E) -3- (7- (diethylamino) -2-oxo-2H-benzopyran-3-yl) acrylate (intermediate Compound 6)
Taking a 100ml single-port bottle, sequentially adding 0.1g of 7- (diethylamino) -2-oxo-2H-benzopyran-3-formaldehyde at normal temperature, adding 0.26g of triphenylphosphine alkenyl methyl acetate, adding quantitative methylene dichloride to dissolve the mixture, transferring the whole reaction system into a 40 ℃ oil pan, connecting a straight condensing tube, introducing nitrogen, and timing to react for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, concentrated, eluted by column chromatography using an eluent (V dichloromethane: V ethyl acetate=40:1), and after the elution, the solvent was spun off by a rotary evaporator, and the residue was dried in a vacuum oven to obtain a yellow solid. Yield: 80%.1H NMR (400 MHz, chloride-d) delta 7.70 (s, 1H), 7.54 (d, j=15.8 Hz, 1H), 7.30 (d, j=8.9 Hz, 1H), 6.95 (d, j=15.8 Hz, 1H), 6.60 (dd, j=8.9, 2.0 Hz, 1H), 6.51-6.45 (m, 1H), 3.78 (s, 1H), 3.44 (q, j=7.1 Hz, 4H), 1.22 (t, j=7.1 Hz, 6H).
(2) Synthesis of (E) -3- (7- (diethylamino) -2-oxo-2H-benzopyran-3-yl) acrylic acid (intermediate Compound 7)
Taking a 100ml single-port bottle, sequentially adding 0.1g of (E) -3- (7- (diethylamino) -2-oxo-2H-benzopyran-3-yl) methyl acrylate, 1.47g of sodium hydroxide, 10ml of water and quantitative absolute ethyl alcohol as a reaction solvent at normal temperature, transferring the whole reaction system into an oil pot at 80 ℃, connecting a condenser tube, protecting with nitrogen, and refluxing for 4 hours. And cooling the reaction product to room temperature after the reaction is finished, taking out the rotor, removing ethanol, adding diluted concentrated hydrochloric acid to enable the pH value to be acidic, separating out flocculent precipitate, filtering, and drying a filter cake in a vacuum drying oven for one night to obtain yellow solid. Yield: 58%.1H NMR (400 MHz, DMSO-d 6) δ12.23 (s, 1H), 8.26 (s, 1H), 7.49-7.41 (m, 1H), 6.74 (dd, J=24.2, 13.3 Hz, 1H), 6.57 (s, 1H), 3.47 (q, J=6.9 Hz, 4H), 1.13 (t, J=6.9 Hz, 6H).
(1) Synthesis of (E) -3- (7- (diethylamino) -2-oxo-2H-benzopyran-3-yl) -N-phenylacrylamide (Compound 7 a)
A100 ml single-necked flask was taken, 0.1g of (E) -3- (7- (diethylamino) -2-oxo-2H-benzopyran-3-yl) acrylic acid was successively added at room temperature, 0.13g of 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDC) was added, 0.09g of 1-hydroxybenzotriazole (HoBt) and N, N-Diisopropylethylamine (DIPEA). Mu.l were dissolved by adding a fixed amount of methylene chloride and ultra-dry tetrahydrofuran, and the whole reaction system was transferred to a magnetic stirrer and reacted at room temperature under nitrogen protection for 1 hour. After 1 hour 80. Mu.l of aniline was added and the reaction was continued for 12 hours. After the reaction, the mixture was washed with saturated NaCl solution and dichloromethane several times, dried over anhydrous magnesium sulfate for one hour, suction-filtered after the drying was completed, the filtrate was concentrated, eluted by column chromatography using an eluent (V dichloromethane: V ethyl acetate=30:1), the solvent was removed after elution, and the residue was dried in a vacuum oven overnight to give a yellow solid. Yield: 32%.1H NMR (400 MHz, DMSO-d 6) δ10.23 (s, 1H), 8.17 (s, 1H), 7.71 (d, j=7.8 Hz, 1H), 7.49 (d, j=9.0 Hz, 1H), 7.41 (d, j=15.3 Hz, 1H), 7.31 (t, j=7.9 Hz, 1H), 7.23 (d, j=15.4 Hz, 1H), 7.04 (t, j=7.3 Hz, 1H), 6.77 (d, j=11.0 Hz, 1H), 6.56 (s, 1H), 3.46 (q, j=6.9 Hz, 4H), 1.14 (t, j=7.0 Hz, 6H).
(2) Synthesis of (E) -3- (7- (diethylamino) -2-oxo-2H-benzopyran-3-yl) -N- (p-tolyl) acrylamide (Compound 7 b)
A100 ml single-necked flask was taken, 0.1g of (E) -3- (7- (diethylamino) -2-oxo-2H-benzopyran-3-yl) acrylic acid was sequentially added at room temperature, 0.13g,HOBT 0.09g,DIPEA 120. Mu.l of EDC was added, and a fixed amount of methylene chloride and ultra-dry tetrahydrofuran were added to dissolve the mixture, and the whole reaction system was transferred to a magnetic stirrer under nitrogen protection and reacted at room temperature for 1 hour. After 1 hour, 80. Mu.l of para-aminoanisole was added thereto and the reaction was continued for 12 hours. After the reaction, the mixture was extracted with saturated NaCl solution and dichloromethane, then dried over anhydrous magnesium sulfate for one hour, after the drying was completed, suction filtration was performed, the filtrate was concentrated, eluted by column chromatography using an eluent (V dichloromethane: V ethyl acetate=30:1), the solvent was removed after elution, and the residue was dried in a vacuum oven overnight to give a yellow solid. Yield: 75%.1H NMR (400 MHz, DMSO-d 6) δ10.22 (s, 1H), 8.17 (s, 1H), 7.49 (d, J=8.9 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.38 (s, 1H), 7.25-7.19 (m, 2H), 6.77 (d, J=9.0 Hz, 1H), 6.63 (d, J=8.1 Hz, 1H), 6.57 (s, 1H), 3.73 (s, 3H), 3.47 (q, J=6.7 Hz, 4H), 1.14 (t, J=6.9 Hz, 6H).
(3) Synthesis of (E) -3- (7- (diethylamino) -2-oxo-2H-benzopyran-3-yl) -N- (2-methoxyphenyl) acrylamide (Compound 7 c)
A100 ml single-necked flask was taken, 0.1g of (E) -3- (7- (diethylamino) -2-oxo-2H-benzopyran-3-yl) acrylic acid was sequentially added at room temperature, 0.13g,HoBt 0.09g,DIPEA 120. Mu.l of EDC was added, and a fixed amount of methylene chloride and ultra-dry tetrahydrofuran were added to dissolve the mixture, and the whole reaction system was transferred to a magnetic stirrer, and then, nitrogen was introduced to react at room temperature for 1 hour. 80 μl of o-aminoanisole was added after 1 hour, and the reaction was continued for 12 hours. After the reaction, the mixture was extracted with saturated NaCl solution and dichloromethane, dried over anhydrous magnesium sulfate for one hour, suction-filtered after the drying was completed, the filtrate was concentrated, eluted by column chromatography using an eluent (V dichloromethane: V ethyl acetate=30:1), the solvent was removed after elution, and the residue was dried in a vacuum oven to obtain a white solid. Yield: 45%.1H NMR (400 MHz, DMSO-d 6) δ10.22 (s, 1H), 8.17 (s, 1H), 7.49 (d, J=8.9 Hz, 1H), 7.43 (d, J=8.1 Hz, 1H), 7.38 (s, 1H), 7.25-7.19 (m, 2H), 6.77 (d, J=9.0 Hz, 1H), 6.63 (d, J=8.1 Hz, 1H), 6.57 (s, 1H), 3.73 (s, 3H), 3.47 (q, J=6.7 Hz, 4H), 1.14 (t, J=6.9 Hz, 6H).
(4) Synthesis of (E) -3- (7- (diethylamino) -2-oxo-2H-benzopyran-3-yl) -N- (3-methoxyphenyl) acrylamide (Compound 7 d)
A100 ml single-necked flask was taken, 0.1g of (E) -3- (7- (diethylamino) -2-oxo-2H-benzopyran-3-yl) acrylic acid was sequentially added at room temperature, 0.13g,HoBt 0.09g,DIPEA 120. Mu.l of EDC was added, and a fixed amount of methylene chloride and ultra-dry tetrahydrofuran were added to dissolve the mixture, and the whole reaction system was transferred to a magnetic stirrer, and then, nitrogen was introduced to react at room temperature for 1 hour. After 1 hour, 80. Mu.l of meta-aminoanisole was added thereto, and the reaction was continued for 12 hours. After the reaction, the mixture was washed with saturated NaCl solution and dichloromethane several times, dried over anhydrous magnesium sulfate for one hour, suction-filtered after the drying was completed, the filtrate was concentrated, eluted by column chromatography using an eluent (V dichloromethane: V ethyl acetate=30:1), the solvent was removed after elution, and the residue was dried in a vacuum oven overnight to give a pale yellow solid. Yield: 61%.1H NMR (400 MHz, DMSO-d 6) δ9.38 (s, 1H), 8.16 (s, 1H), 8.06 (d, j=7.8 Hz, 1H), 7.48 (d, j=8.9 Hz, 1H), 7.38 (d, j=10.7 Hz, 1H), 7.12-7.01 (m, 2H), 6.92 (t, j=7.4 Hz, 1H), 6.77 (d, j=10.7 Hz, 1H), 6.58 (s, 1H), 3.85 (s, 3H), 3.47 (q, j=6.7 Hz, 4H), 1.14 (t, j=6.9 Hz, 6H).
(5) Synthesis of (E) -3- (7- (diethylamino) -2-oxo-2H-benzopyran-3-yl) -N- (4-methoxyphenyl) acrylamide (Compound 8 d)
A100 ml single-necked flask was taken, 0.1g of (E) -3- (7- (diethylamino) -2-oxo-2H-benzopyran-3-yl) acrylic acid was sequentially added at room temperature, 0.13g,HoBt 0.09g,DIPEA 120. Mu.l of EDC was added, and a fixed amount of methylene chloride and ultra-dry tetrahydrofuran were added to dissolve the mixture, and the whole reaction system was transferred to a magnetic stirrer, and then, nitrogen was introduced to react at room temperature for 1 hour. 80 μl of para-aminoanisole was added after 1 hour, and the reaction was continued for 12 hours. After the reaction, the mixture was washed with saturated NaCl solution and dichloromethane several times, dried over anhydrous magnesium sulfate for one hour, suction-filtered after the drying was completed, the filtrate was concentrated, eluted by column chromatography using an eluent (V dichloromethane: V ethyl acetate=30:1), the solvent was removed after elution, and the residue was dried in a vacuum oven overnight to give a pale yellow solid. Yield: 71%.1H NMR (400 MHz, DMSO-d 6) δ10.11 (s, 1H), 8.15 (s, 1H), 7.63 (d, j=8.5 Hz, 2H), 7.49 (d, j=8.8 Hz, 1H), 7.38 (d, j=15.2 Hz, 1H), 7.20 (d, j=15.4 Hz, 1H), 6.89 (d, j=8.5 Hz, 1H), 6.76 (d, j=8.7 Hz, 1H), 6.56 (s, 1H), 3.72 (s, 3H), 3.50-3.42 (m, 4H), 1.14 (t, j=6.5 Hz, 6H).
(6) Synthesis of (E) -3- (7- (diethylamino) -2-oxo-2H-benzopyran-3-yl) -N- (4-fluorophenyl) acrylamide (Compound 8 d)
A100 ml single-necked flask was taken, 0.1g of (E) -3- (7- (diethylamino) -2-oxo-2H-benzopyran-3-yl) acrylic acid was sequentially added at room temperature, 0.13g,HoBt 0.09g,DIPEA 120. Mu.l of EDC was added, and a fixed amount of methylene chloride and ultra-dry tetrahydrofuran were added to dissolve the mixture, and the whole reaction system was transferred to a magnetic stirrer, and then, nitrogen was introduced to react at room temperature for 1 hour. After 1 hour, 80. Mu.l of para-aminoanisole was added thereto, and the reaction was continued for 12 hours. After the reaction, the mixture was washed with saturated NaCl solution and dichloromethane several times, dried over anhydrous magnesium sulfate for one hour, suction-filtered after the drying was completed, the filtrate was concentrated, eluted by column chromatography using an eluent (V dichloromethane: V ethyl acetate=30:1), the solvent was removed after elution, and the residue was dried in a vacuum oven overnight to give a pale yellow solid. Yield: 46%.1H NMR (400 MHz, DMSO-d 6) δ10.11 (s, 1H), 8.15 (s, 1H), 7.63 (d, j=8.5 Hz, 2H), 7.49 (d, j=8.8 Hz, 1H), 7.38 (d, j=15.2 Hz, 1H), 7.20 (d, j=15.4 Hz, 1H), 6.89 (d, j=8.5 Hz, 1H), 6.76 (d, j=8.7 Hz, 1H), 6.56 (s, 1H), 3.72 (s, 3H), 3.50-3.42 (m, 4H), 1.14 (t, j=6.5 Hz, 6H).
1. The invention carries out CCK-8 experimental test on target compounds 8a-8f, expresses HELA, A549, MCF-7 and L929, and tests the target compounds 8a-8f and 5-fluorouracil at the concentration of 20 mu M. As can be seen from FIG. 12, the 7c containing the structure of the amine compound with the coumarin structure and the methoxy substituent grafted at the tail end of the benzene ring has the best inhibition effect on HELA cells, MCF-7 cells and A549 cells, the inhibition rates are respectively 60.9%, 70.47% and 75.80%, and the inhibition rates of 5-fluorouracil on HELA cells, MCF-7 cells and A549 cells are respectively 74.43%, 52.79% and 46.87%. The structure 7a of the compound containing the coumarin structure and the benzene ring end without the branch amide has the secondary inhibition effect on MCF-7 cells and A549 cells, the inhibition rate is 65.82 percent and 74.12 percent, and the inhibition rate of 5-fluorouracil on MCF-7 cells is 52.79 percent and 46.87 percent.
2. The present invention calculates IC50 values for compounds 8a-8f at concentrations of 40. Mu.M, 20. Mu.M, 10. Mu.M, 5. Mu.M for HELA, A549, MCF-7 cells, wherein the IC50 values for compounds 7a, 7c for MCF-7 cells and A549 cells are lower, and the IC50 values for 7a for HELA cells are lower. For amine compounds with benzene ring terminal connected with different groups at the 4 th position, the drug effect of the compound containing methoxy and no substituent in MCF-7 cells and A549 cells is obviously better than that of the compound containing F atom, and the drug effect of the compound containing F atom is better than that of the compound containing methyl. Unlike the compound containing F atom in MCF-7 cells at position 4, the drug effect is better than that of the compound containing methyl, while the drug effect of the compound containing methoxy is still optimal. FIG. 12 shows the IC50 values of the target compounds 7a-7f for different cells.
Claims (5)
1. A novel drug micromolecule (1) containing coumarin structure is characterized in that the molecular chemical structure is as follows,
r is，R 1 ,R 2 ,R 3 H, OCH for corresponding position 3 F or CH 3 。
3. The coumarin structure derivative formula (1) as claimed in claim 1, wherein the target product is:
4. the coumarin structure derivative formula (1) as claimed in claim 1, wherein the synthetic route is as follows:
5. the use of coumarin derivatives of formula (1) as claimed in claim 1, having various biological activities such as antiviral, antibacterial and antitumor.
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