CN116836142B - 3-chromone-2-sulfonyl acrylonitrile derivative and preparation method and application thereof - Google Patents
3-chromone-2-sulfonyl acrylonitrile derivative and preparation method and application thereof Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 28
- -1 3-chromone-2-sulfonyl acrylonitrile derivative Chemical class 0.000 title claims abstract description 25
- NULJNFUEBPQUNB-UHFFFAOYSA-N 6-chloro-7-methyl-4-oxochromene-3-carbaldehyde Chemical compound O1C=C(C=O)C(=O)C2=C1C=C(C)C(Cl)=C2 NULJNFUEBPQUNB-UHFFFAOYSA-N 0.000 claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 15
- 239000002904 solvent Substances 0.000 claims abstract description 12
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 11
- 239000003513 alkali Substances 0.000 claims abstract description 9
- PCNAYTOJVHTNKK-UHFFFAOYSA-N 2-sulfonylacetonitrile Chemical class O=S(=O)=CC#N PCNAYTOJVHTNKK-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000006000 Knoevenagel condensation reaction Methods 0.000 claims abstract description 5
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 5
- 239000002994 raw material Substances 0.000 claims abstract description 5
- 238000000926 separation method Methods 0.000 claims abstract description 5
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical group CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 14
- 238000006243 chemical reaction Methods 0.000 claims description 11
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 239000002246 antineoplastic agent Substances 0.000 claims description 7
- 229940041181 antineoplastic drug Drugs 0.000 claims description 7
- 239000003208 petroleum Substances 0.000 claims description 7
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- 210000004881 tumor cell Anatomy 0.000 claims description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 3
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 3
- 239000007850 fluorescent dye Substances 0.000 claims description 3
- 230000002401 inhibitory effect Effects 0.000 claims description 3
- 230000035484 reaction time Effects 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 230000004614 tumor growth Effects 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 125000004076 pyridyl group Chemical group 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims 1
- 229940079593 drug Drugs 0.000 abstract description 9
- 230000000259 anti-tumor effect Effects 0.000 abstract description 8
- 238000000799 fluorescence microscopy Methods 0.000 abstract description 5
- 150000004777 chromones Chemical class 0.000 abstract description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 16
- 150000001875 compounds Chemical class 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 7
- 238000000862 absorption spectrum Methods 0.000 description 5
- 230000006837 decompression Effects 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 3
- 230000001028 anti-proliverative effect Effects 0.000 description 3
- 238000002189 fluorescence spectrum Methods 0.000 description 3
- QKLXBIHSGMPUQS-FGZHOGPDSA-M (3r,5r)-7-[4-(4-fluorophenyl)-2,5-dimethyl-1-phenylpyrrol-3-yl]-3,5-dihydroxyheptanoate Chemical compound CC1=C(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C=2C=CC(F)=CC=2)=C(C)N1C1=CC=CC=C1 QKLXBIHSGMPUQS-FGZHOGPDSA-M 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- OTAFHZMPRISVEM-UHFFFAOYSA-N chromone Chemical group C1=CC=C2C(=O)C=COC2=C1 OTAFHZMPRISVEM-UHFFFAOYSA-N 0.000 description 2
- 231100000135 cytotoxicity Toxicity 0.000 description 2
- 230000003013 cytotoxicity Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 230000007704 transition Effects 0.000 description 2
- FOTRKCAZUSJCQD-UHFFFAOYSA-N (methylsulfonyl)acetonitrile Chemical compound CS(=O)(=O)CC#N FOTRKCAZUSJCQD-UHFFFAOYSA-N 0.000 description 1
- BBNNLJMGPASZPD-UHFFFAOYSA-N 2-(4-methylphenyl)sulfonylacetonitrile Chemical compound CC1=CC=C(S(=O)(=O)CC#N)C=C1 BBNNLJMGPASZPD-UHFFFAOYSA-N 0.000 description 1
- ZFCFFNGBCVAUDE-UHFFFAOYSA-N 2-(benzenesulfonyl)acetonitrile Chemical compound N#CCS(=O)(=O)C1=CC=CC=C1 ZFCFFNGBCVAUDE-UHFFFAOYSA-N 0.000 description 1
- SAKACXZDAJXBCI-UHFFFAOYSA-N 2-pyridin-2-ylsulfonylacetonitrile Chemical compound N#CCS(=O)(=O)C1=CC=CC=N1 SAKACXZDAJXBCI-UHFFFAOYSA-N 0.000 description 1
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 1
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- YLEIFZAVNWDOBM-ZTNXSLBXSA-N ac1l9hc7 Chemical compound C([C@H]12)C[C@@H](C([C@@H](O)CC3)(C)C)[C@@]43C[C@@]14CC[C@@]1(C)[C@@]2(C)C[C@@H]2O[C@]3(O)[C@H](O)C(C)(C)O[C@@H]3[C@@H](C)[C@H]12 YLEIFZAVNWDOBM-ZTNXSLBXSA-N 0.000 description 1
- SRVFFFJZQVENJC-IHRRRGAJSA-N aloxistatin Chemical compound CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)NCCC(C)C SRVFFFJZQVENJC-IHRRRGAJSA-N 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 230000005670 electromagnetic radiation Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000001678 irradiating effect Effects 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- QAPTWHXHEYAIKG-RCOXNQKVSA-N n-[(1r,2s,5r)-5-(tert-butylamino)-2-[(3s)-2-oxo-3-[[6-(trifluoromethyl)quinazolin-4-yl]amino]pyrrolidin-1-yl]cyclohexyl]acetamide Chemical compound CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1C(=O)[C@@H](NC=2C3=CC(=CC=C3N=CN=2)C(F)(F)F)CC1 QAPTWHXHEYAIKG-RCOXNQKVSA-N 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 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 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000004565 tumor cell growth Effects 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 238000002371 ultraviolet--visible spectrum Methods 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
Classifications
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- 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
-
- 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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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C09K11/00—Luminescent, e.g. electroluminescent, chemiluminescent materials
- C09K11/06—Luminescent, e.g. electroluminescent, chemiluminescent materials containing organic luminescent materials
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N21/00—Investigating or analysing materials by the use of optical means, i.e. using sub-millimetre waves, infrared, visible or ultraviolet light
- G01N21/62—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light
- G01N21/63—Systems in which the material investigated is excited whereby it emits light or causes a change in wavelength of the incident light optically excited
- G01N21/64—Fluorescence; Phosphorescence
- G01N21/6428—Measuring fluorescence of fluorescent products of reactions or of fluorochrome labelled reactive substances, e.g. measuring quenching effects, using measuring "optrodes"
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- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
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- C09K2211/00—Chemical nature of organic luminescent or tenebrescent compounds
- C09K2211/10—Non-macromolecular compounds
- C09K2211/1018—Heterocyclic compounds
- C09K2211/1025—Heterocyclic compounds characterised by ligands
- C09K2211/1088—Heterocyclic compounds characterised by ligands containing oxygen as the only heteroatom
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Abstract
The invention relates to the technical field of medicines, in particular to a 3-chromone-2-sulfonyl acrylonitrile derivative and a preparation method and application thereof. The specific technical scheme is as follows: according to the invention, 6-chloro-3-formyl-7-methyl chromone and substituted sulfonyl acetonitrile are used as raw materials, under the catalysis of alkali, a Knoevenagel condensation reaction is carried out, a solvent is removed, and a silica gel column chromatography separation is carried out to obtain the 3-chromone-2-sulfonyl acrylonitrile derivative, so that an important reference is provided for developing the chromone derivative with anti-tumor activity and fluorescence imaging.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a 3-chromone-2-sulfonyl acrylonitrile derivative and a preparation method and application thereof.
Background
The chromone derivatives are derivatives containing a benzo-six-membered oxygen heterocyclic skeleton, and have remarkable biological activity in the aspects of anti-tumor, antibacterial, antiviral and the like. Has been considered as a novel pharmacophore with important anti-tumor, antibacterial and antiviral effects. In recent years, researchers have modified the structure of the chromone skeleton to synthesize a plurality of lead compounds such as candidate drugs and enzyme inhibitors with obvious antitumor activity.
In addition, the chromone compound generally shows different fluorescence performances due to a certain conjugated system, but the emission wavelength of the general fluorescence is shorter, which is unfavorable for fluorescence imaging. If the structure conjugated system can be increased, the fluorescence emission wavelength can be further increased, and the obtained fluorescent molecule can be used for living cell fluorescence imaging and other purposes. Most of traditional antitumor drugs lack luminophores, which is unfavorable for tracking the release of the drugs in vivo and imaging living cells. Therefore, the structural modification of the chromone is carried out, and the development of novel chromone derivatives with anti-tumor activity and fluorescence imaging function has important significance for realizing the multifunction of the medicine.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides a 3-chromone-2-sulfonyl acrylonitrile derivative, and a preparation method and application thereof.
In order to achieve the above purpose, the invention is realized by the following technical scheme:
the invention discloses a 3-chromone-2-sulfonyl acrylonitrile derivative, the structural formula is shown as the following formula (I),
wherein R is one of alkyl and aryl pyridyl.
Correspondingly, the preparation method of the 3-chromone-2-sulfonyl acrylonitrile derivative takes 6-chloro-3-formyl-7-methyl chromone and substituted sulfonyl acetonitrile as raw materials, and the 3-chromone-2-sulfonyl acrylonitrile derivative is obtained after removing a solvent and separating by silica gel column chromatography after Knoevenagel condensation reaction under the catalysis of alkali.
Preferably, the mass ratio of the 6-chloro-3-formyl-7-methylchromone to the substituted sulfonyl acetonitrile is 1:1.
preferably, the base is one of triethylamine, diethylamine and N, N-diisopropylethylamine, and the amount of the base is 1-2 times that of 6-chloro-3-formyl-7-methylchromone; the solvent for the reaction is one of methanol, ethanol, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran and dioxane.
Preferably, the reaction time is 12-24 hours, and the reaction temperature is 25-100 ℃.
Preferably, the mobile phase of the silica gel column chromatography is ethyl acetate:petroleum ether=1:3-2, v/v.
Correspondingly, the derivatives prepared according to the derivatives or the preparation method are applied to the preparation of antitumor drugs.
Preferably, the 3-chromonyl-2-sulfonyl acrylonitrile derivative is used for preparing a medicament for inhibiting the growth of tumor cells MDA-MB-231.
Correspondingly, the derivatives prepared according to the derivatives or the preparation method are applied to the preparation of fluorescent probes.
Correspondingly, the active ingredient of the antitumor drug is the derivative or the derivative prepared by the preparation method, or the pharmaceutically acceptable salt thereof.
The invention has the following beneficial effects:
1. the invention uses 6-chloro-3-formyl-7-methyl chromone and sulfonyl acrylonitrile compound to carry out Knoevenagel condensation reaction under the catalysis of alkali to synthesize a series of novel 3-chromone-2-sulfonyl acrylonitrile. Provides an important reference for developing chromone derivatives with anti-tumor activity and fluorescence imaging. Meanwhile, cytotoxicity experiments prove that the compounds have anti-tumor activity and have strong inhibition capability on tumor cell growth. The fluorescence spectrophotometer detects that the emission wavelength of the medicine reaches 467nm.
2. The present invention provides a novel, predominantly pharmaceutically acceptable compound; the preparation method of the novel compound has the advantages of few operation steps, few side reactions, readily available raw materials, environment-friendly solvent and easy separation and purification of products. The medicine has good anti-tumor activity and fluorescence.
Drawings
FIG. 1 shows the cytotoxicity test results of compounds 2a, 2b, 2c and 2d against MDA-MB-231;
FIG. 2 is an ultraviolet absorption spectrum and a fluorescence emission spectrum of the compounds 2a, 2b, 2c and 2d.
Detailed Description
The following description of the embodiments of the present invention will be made clearly and completely with reference to the accompanying drawings, in which it is apparent that the embodiments described are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The technical means used in the examples are conventional means well known to those skilled in the art unless otherwise indicated.
1. The invention discloses a 3-chromone-2-sulfonyl acrylonitrile derivative, the structural formula is shown as the following formula (I),
wherein R is one of alkyl and aryl pyridyl.
2. The invention discloses a preparation method of a 3-chromone-2-sulfonyl acrylonitrile derivative, which takes 6-chloro-3-formyl-7-methyl chromone and substituted sulfonyl acetonitrile as raw materials, and the 3-chromone-2-sulfonyl acrylonitrile derivative is obtained after the solvent is removed by decompression concentration and silica gel column chromatography separation after Knoevenagel condensation reaction under the catalysis of alkali.
The reaction equation is as follows:
wherein, R group in the substituted sulfonyl acetonitrile is one of a hydrocarbon group and a pyridyl group of an aryl group.
Further, the mass ratio of the 6-chloro-3-formyl-7-methylchromone to the substituted sulfonyl acetonitrile is 1:1. the used alkali is one of triethylamine, diethylamine and N, N-diisopropylethylamine, and the mass of the alkali is 1-2 times of that of 6-chloro-3-formyl-7-methyl chromone; the solvent for the reaction is one of methanol, ethanol, N-Dimethylformamide (DMF), N-Dimethylacetamide (DMA), tetrahydrofuran (THF) and dioxane. The reaction time is 12-24 h, and the reaction temperature is 25-100 ℃. The mobile phase of the silica gel column chromatography is ethyl acetate, petroleum ether=1:3-2, v/v.
3. The invention discloses application of the derivative or the derivative prepared by the preparation method in preparation of antitumor drugs.
In particular, the 3-chromonyl-2-sulfonyl acrylonitrile derivative is used for preparing a drug for inhibiting the growth of tumor cells MDA-MB-231.
4. The invention discloses application of the derivative or the derivative prepared by the preparation method in preparation of fluorescent probes.
5. The invention discloses an anti-tumor drug, the active ingredient of the drug is the derivative or the derivative prepared by the preparation method, or the pharmaceutically acceptable salt thereof.
The invention is further illustrated below in conjunction with specific examples.
Example 1
(E) -synthesis of 3- (6-chloro-7-methyl-4-oxo-4H-chromen-3-yl) -2- (methylsulfonyl) acrylonitrile (2 a):
6-chloro-3-formyl-7-methylchromone (1 mmol), methylsulfonyl acetonitrile (1 mmol) and triethylamine (1 mmol) are added into 20mL of ethanol, stirred at room temperature for reaction for 24h, the solvent is removed by decompression concentration, and the mobile phase is ethyl acetate:petroleum ether=1:3-2, v/v by silica gel column chromatography separation, thus obtaining the compound 2a.
The obtained product is measured on a nuclear magnetic resonance instrument, and the obtained nuclear magnetic resonance data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ:9.20(s,1H,C＝CH),8.13(s,1H,CH-O),8.06(s,1H,Ar-H),7.87(s,1H,Ar-H),3.40(s,3H,CH 3 ),2.50(s,3H,CH 3 ). 13 C NMR(100MHz,DMSO-d 6 )δ:172.87,162.54,154.30,144.77,144.75,132.70,125.36,122.74,121.66,116.69,115.53,113.15,42.24,20.72.HRMS(ESI)calcd for C 14 H 11 ClNO 4 S[M+H] + 324.0097,found 324.0099。
example 2
(E) -synthesis of 3- (6-chloro-7-methyl-4-oxo-4H-chromen-3-yl) -2- (phenylsulfonyl) acrylonitrile (2 b):
6-chloro-3-formyl-7-methylchromone (1 mmol), benzenesulfonylacetonitrile (1 mmol) and triethylamine (1 mmol) were added to 20mL of ethanol, stirred at room temperature for reaction for 24h, concentrated under reduced pressure to remove the solvent, and separated by silica gel column chromatography with ethyl acetate as mobile phase and petroleum ether=1:3-2, v/v to obtain compound 2b.
The obtained product is measured on a nuclear magnetic resonance instrument, and the obtained nuclear magnetic resonance data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ:9.20(s,1H,C＝CH),8.34(s,1H,CH-O),8.04(s,1H,Ar-H),8.00(dd,J＝7.25,1.41Hz,2H,Ar-H),7.89～7.86(overlapped,2H,Ar-H),7.77(dd,2H,J＝7.25,1.41Hz,2H,Ar-H),2.49(s,3H,CH 3 ). 13 C NMR(100MHz,DMSO-d 6 )δ:172.55,163.16,153.99,144.64,144.55,137.52,135.95,132.89,130.65,128.72,125.28,122.63,121.56,117.19,115.70,112.70,20.32.HRMS(ESI)calcd for C 19 H 13 ClNO 4 S[M+H] + 386.0254,found 386.0257。
example 3
(E) -synthesis of 3- (6-chloro-7-methyl-4-oxo-4H-chromen-3-yl) -2-tolylacrylonitrile (2 c):
6-chloro-3-formyl-7-methylchromone (1 mmol), 4-toluenesulfonyl acetonitrile (1 mmol) and triethylamine (1 mmol) are added into 20mL of ethanol, the mixture is stirred at room temperature for reaction for 24h, the solvent is removed by decompression concentration, and the mixture is separated by silica gel column chromatography, wherein the mobile phase is ethyl acetate, petroleum ether=1:3-2, v/v, and the compound 2c is obtained.
The obtained product is measured on a nuclear magnetic resonance instrument, and the obtained nuclear magnetic resonance data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ:9.18(s,1H,C＝CH),8.30(s,1H,CH-O),8.04(s,1H,Ar-H),7.89～7.86(overlapped,3H,Ar-H),7.56(d,J＝8.38Hz,2H,Ar-H),2.49(s,3H,CH 3 ),2.45(s,3H,CH 3 ). 13 C NMR(100MHz,DMSO-d 6 )δ:172.79,163.02,154.24,146.73,144.70,144.08,134.82,132.67,131.15,128.86,125.35,122.75,121.63,116.67,116.13,112.89,21.73,20.71.HRMS(ESI)calcd for C 20 H 15 ClNO 4 S[M+H] + 400.0410,found 400.0412。
example 4
(E) -synthesis of 3- (6-chloro-7-methyl-4-oxo-4H-chromen-3-yl) -2- (pyridin-2-ylsulfonyl) acrylonitrile (2 d):
6-chloro-3-formyl-7-methylchromone (1 mmol), 2-pyridine sulfonyl acetonitrile (1 mmol) and triethylamine (1 mmol) are added into 20mL of ethanol, the mixture is stirred at room temperature for reaction for 24h, the solvent is removed by decompression concentration, and the mixture is separated by silica gel column chromatography, wherein the mobile phase is ethyl acetate, petroleum ether=1:3-2, v/v, and the compound 2d is obtained.
The obtained product is measured on a nuclear magnetic resonance instrument, and the obtained nuclear magnetic resonance data are as follows:
1 H NMR(400MHz,DMSO-d 6 )δ:9.27(s,1H,C＝CH),8.86(dt,J＝4.66,1.28Hz,1H,pyridine-H),8.35(s,1H,CH-O),8.26(dd,J＝4.66,0.79Hz,2H,Ar-H),8.05(s,1H,Ar-H),7.87～7.84(overlapped,2H,Ar-H,pyridine-H),2.50(s,3H,CH 3 ). 13 C NMR(100MHz,DMSO-d 6 )δ:172.83,163.72,155.51,154.25,151.66,146.63,144.75,140.22,132.72,129.63,125.41,123.82,122.80,121.66,116.71,113.28,112.76,20.72.HRMS(ESI)calcd for C 18 H 12 ClN 2 O 4 S[M+H] + 387.0206,found 387.0205。
example 5 Effect verification
1. About 2X 10 cells were seeded in 96-well dishes while tumor cells (MDA-MB-231) were in the logarithmic growth phase 3 After 24h of cell attachment, 100. Mu.M of drugs of different concentrations diluted in 10% FBS-containing medium were added to each well, and the cells were again placed in a 37℃incubator. After cells were cultured for 72h with drug, medium in 96-well plates was discarded, 100 μl CCK8 reagent was added per well and incubation in incubator was continued for 2h. Reading OD of each well with an ELISA reader 450 Values were calculated to calculate the change in activity of cells after treatment with different concentrations of drug.
The cytotoxicity results of compounds 2a, 2b, 2c and 2d against MDA-MB-231 are shown in FIG. 1. From the experimental results, the semi-inhibitory concentrations of the compounds on MDA-MB-231 are shown in Table 1. As can be seen from Table 1, the antiproliferative activity of four compounds was shown to be good, with the antiproliferative activity of compound 2c being slightly stronger than that of the other three compounds, 11.5. Mu. Mol/L, and the antiproliferative activities of 2a, 2b and 2d being closer.
semi-Inhibitory Concentration (IC) of the compounds of Table 1 on MDA-MB-231 50 ,μmol/L)
| Compounds of formula (I) | 2a | 2b | 2c | 2d |
| IC 50 | 16.6 | 17.8 | 11.5 | 15.7 |
2. Ultraviolet absorption spectrum and fluorescence emission spectrum
Ultraviolet spectrum generation the ultraviolet absorption spectrum is generated by the transition of valence electrons in the molecule. When the valence electrons in the molecule are irradiated by ultraviolet light or visible light, the electrons absorb light with corresponding wavelength to transition from a low energy level to a high energy level, and the corresponding generated absorption spectrum is called ultraviolet-visible spectrum. Fluorescence is the radiation from a substance that is excited after absorption of electromagnetic radiation, the excited atoms or molecules re-emitting at the same or different wavelength from the excitation radiation during de-excitation. When the excitation light source stops irradiating the sample, the re-emission process is stopped immediately, and this re-emitted light is called fluorescence. The absorption wavelength of the compounds is 406 to 416nm. The fluorescence emission wavelength thus produced was 459 to 467nm. The ultraviolet absorption spectrum and fluorescence emission spectrum of the compound are shown in fig. 2, and the results are shown in the following table 2.
The maximum absorption wavelength and the maximum emission wavelength (nm) of the compounds of Table 2
| Compounds of formula (I) | 2a | 2b | 2c | 2d |
| λ max (nm) | 406 | 414 | 416 | 411 |
| λ em (nm) | 460 | 459 | 467 | 462 |
The above embodiments are only illustrative of the preferred embodiments of the present invention and are not intended to limit the scope of the present invention, and various modifications and improvements made by those skilled in the art to the technical solutions of the present invention should fall within the protection scope defined by the claims of the present invention without departing from the design spirit of the present invention.
Claims (10)
1. A 3-chromonyl-2-sulfonylacrylonitrile derivative characterized by: the structural formula is shown as the following formula (I),
wherein R is one of methyl, phenyl, 4-tolyl or pyridyl.
2. A process for the preparation of a 3-chromonyl-2-sulfonylacrylonitrile derivative according to claim 1, characterized in that: 6-chloro-3-formyl-7-methyl chromone and substituted sulfonyl acetonitrile are used as raw materials, under the catalysis of alkali, knoevenagel condensation reaction is carried out, solvent is removed, and silica gel column chromatography separation is carried out, thus obtaining the 3-chromone-2-sulfonyl acrylonitrile derivative.
3. The preparation method according to claim 2, characterized in that: the mass ratio of the 6-chloro-3-formyl-7-methylchromone to the substituted sulfonyl acetonitrile is 1:1.
4. the preparation method according to claim 2, characterized in that: the used alkali is one of triethylamine, diethylamine and N, N-diisopropylethylamine, and the mass of the alkali is 1-2 times of that of 6-chloro-3-formyl-7-methyl chromone; the solvent for the reaction is one of methanol, ethanol, N-dimethylformamide, N-dimethylacetamide, tetrahydrofuran and dioxane.
5. The preparation method according to claim 2, characterized in that: the reaction time is 12-24 h, and the reaction temperature is 25-100 ℃.
6. The preparation method according to claim 2, characterized in that: the mobile phase of the silica gel column chromatography is ethyl acetate, petroleum ether=1:3-2, v/v.
7. Use of a derivative according to claim 1 or a derivative prepared by a preparation method according to any one of claims 2 to 6 in the preparation of an antitumor drug.
8. The use according to claim 7, characterized in that: the 3-chromone-2-sulfonyl acrylonitrile derivative is used for preparing a medicament for inhibiting the growth of tumor cells MDA-MB-231.
9. Use of a derivative according to claim 1 or a derivative prepared by a preparation method according to any one of claims 2 to 6 in the preparation of a fluorescent probe.
10. An antitumor drug, characterized in that: the active ingredient of the medicine is the derivative as defined in claim 1 or the derivative prepared by the preparation method as defined in any one of claims 2 to 6, or pharmaceutically acceptable salt thereof.
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