CN114573517A - Quinoxaline compound and preparation method and application thereof - Google Patents
Quinoxaline compound and preparation method and application thereof Download PDFInfo
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- CN114573517A CN114573517A CN202210233387.XA CN202210233387A CN114573517A CN 114573517 A CN114573517 A CN 114573517A CN 202210233387 A CN202210233387 A CN 202210233387A CN 114573517 A CN114573517 A CN 114573517A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 29
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 title claims abstract description 22
- -1 Quinoxaline compound Chemical class 0.000 title claims abstract description 19
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- 150000003252 quinoxalines Chemical class 0.000 claims abstract description 27
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 13
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 12
- SIKJAQJRHWYJAI-UHFFFAOYSA-N benzopyrrole Natural products C1=CC=C2NC=CC2=C1 SIKJAQJRHWYJAI-UHFFFAOYSA-N 0.000 claims abstract description 12
- 229910052736 halogen Inorganic materials 0.000 claims abstract description 12
- PZOUSPYUWWUPPK-UHFFFAOYSA-N indole Natural products CC1=CC=CC2=C1C=CN2 PZOUSPYUWWUPPK-UHFFFAOYSA-N 0.000 claims abstract description 12
- RKJUIXBNRJVNHR-UHFFFAOYSA-N indolenine Natural products C1=CC=C2CC=NC2=C1 RKJUIXBNRJVNHR-UHFFFAOYSA-N 0.000 claims abstract description 12
- 150000002475 indoles Chemical class 0.000 claims abstract description 12
- GEYOCULIXLDCMW-UHFFFAOYSA-N 1,2-phenylenediamine Chemical compound NC1=CC=CC=C1N GEYOCULIXLDCMW-UHFFFAOYSA-N 0.000 claims abstract description 11
- 150000002367 halogens Chemical group 0.000 claims abstract description 11
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 8
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 8
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims abstract description 8
- 125000002346 iodo group Chemical class I* 0.000 claims abstract description 7
- 239000002253 acid Substances 0.000 claims abstract description 6
- 229940125782 compound 2 Drugs 0.000 claims abstract description 6
- 239000002904 solvent Substances 0.000 claims abstract description 6
- RVWUHFFPEOKYLB-UHFFFAOYSA-N 2,2,6,6-tetramethyl-1-oxidopiperidin-1-ium Chemical group CC1(C)CCCC(C)(C)[NH+]1[O-] RVWUHFFPEOKYLB-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims abstract description 4
- 125000002560 nitrile group Chemical group 0.000 claims abstract description 4
- 125000004076 pyridyl group Chemical group 0.000 claims abstract description 4
- 125000001544 thienyl group Chemical group 0.000 claims abstract description 4
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 105
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 45
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 10
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- KLLLJCACIRKBDT-UHFFFAOYSA-N 2-phenyl-1H-indole Chemical compound N1C2=CC=CC=C2C=C1C1=CC=CC=C1 KLLLJCACIRKBDT-UHFFFAOYSA-N 0.000 claims description 5
- 238000004440 column chromatography Methods 0.000 claims description 5
- 239000003480 eluent Substances 0.000 claims description 5
- 239000012074 organic phase Substances 0.000 claims description 5
- 239000003208 petroleum Substances 0.000 claims description 5
- 239000011541 reaction mixture Substances 0.000 claims description 5
- 238000002390 rotary evaporation Methods 0.000 claims description 5
- 229940126214 compound 3 Drugs 0.000 claims description 3
- JKZOMQGCLXJWFO-UHFFFAOYSA-N 5,5-diiodoimidazolidine-2,4-dione Chemical compound IC1(I)NC(=O)NC1=O JKZOMQGCLXJWFO-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical group II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 9
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 abstract description 8
- 239000003814 drug Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 6
- 230000015572 biosynthetic process Effects 0.000 abstract description 5
- 125000001424 substituent group Chemical group 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 230000002194 synthesizing effect Effects 0.000 abstract description 4
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 19
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- 230000002401 inhibitory effect Effects 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 4
- IOOMXAQUNPWDLL-UHFFFAOYSA-N 2-[6-(diethylamino)-3-(diethyliminiumyl)-3h-xanthen-9-yl]-5-sulfobenzene-1-sulfonate Chemical compound C=12C=CC(=[N+](CC)CC)C=C2OC2=CC(N(CC)CC)=CC=C2C=1C1=CC=C(S(O)(=O)=O)C=C1S([O-])(=O)=O IOOMXAQUNPWDLL-UHFFFAOYSA-N 0.000 description 3
- 238000002965 ELISA Methods 0.000 description 3
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 3
- 206010028980 Neoplasm Diseases 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 201000005202 lung cancer Diseases 0.000 description 3
- 208000020816 lung neoplasm Diseases 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 239000008399 tap water Substances 0.000 description 3
- 235000020679 tap water Nutrition 0.000 description 3
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical compound OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 3
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 238000004737 colorimetric analysis Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
- C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
- C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
- C07D241/40—Benzopyrazines
- C07D241/42—Benzopyrazines with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention discloses a quinoxaline compound and a preparation method and application thereof, wherein the quinoxaline compound comprises the following steps of S1: substituted indole 1 and alpha position 2,2,6, 6-tetramethyl piperidine oxide substituted 1, 3-dicarbonyl compound 2 are subjected to series reaction in an acid solvent to prepare quinoxaline compounds 3 and S2, wherein R1 is alkyl, alkoxy, halogen, polyfluoroalkyl and nitro; r2 is phenyl, alkyl substituted phenyl, halogen substituted phenyl, thienyl, pyridyl, cyclopropyl; nitro or nitrile group, R3 is alkyl, alkoxy, halogen, trifluoromethyl. According to the invention, o-phenylenediamine, substituted indole and iodo reagent are subjected to multi-step conversion reaction to synthesize a series of quinoxaline derivatives, the synthesis process is simple and easy to control, the structure types of target products are various, and various substituents can be introduced at 2-position, 3-position, 5-position, 6-position and 7-position of a parent nucleus of a quinoxaline structure, so that a foundation is laid for synthesizing a drug molecule containing the quinoxaline structure.
Description
Technical Field
The invention relates to the technical field of synthesis and anti-tumor application of quinoxaline derivatives, in particular to a quinoxaline compound and a preparation method and application thereof.
Background
The existing synthesis method of 2, 3-diaryl mainly comprises condensation cyclization of o-phenylenediamine and 1, 2-dicarbonyl compound, the structure types of R2 and R3 in the synthesized molecular structure are less, the substituent groups on the left benzene ring are generally symmetrical, and the substitution type of the synthesized compound is monotonous.
Disclosure of Invention
Therefore, the invention aims to provide a quinoxaline compound and a preparation method and application thereof, wherein o-phenylenediamine, substituted indole and iodo reagent are subjected to multi-step conversion reaction to synthesize a series of quinoxaline derivatives, the synthesis process is simple and easy to control, the structure types of target products are various, and various substituents can be introduced into 2-position, 3-position, 5-position, 6-position and 7-position of a parent nucleus of a quinoxaline structure, so that a foundation is laid for synthesizing a drug molecule containing the quinoxaline structure.
To solve the above technical problem, according to an aspect of the present invention, the present invention provides the following technical solutions:
a quinoxaline compound and a preparation method and application thereof comprise:
s1: substituted indole 1 and alpha position 2,2,6, 6-tetramethyl piperidine oxide substituted 1, 3-dicarbonyl compound 2 are subjected to series reaction in an acid solvent to prepare a quinoxaline compound 3;
s2: the reaction equation of the reaction process is as follows:
wherein, R1 is alkyl, alkoxy, halogen, polyfluoroalkyl, nitro; r2 is phenyl, alkyl substituted phenyl, halogen substituted phenyl, thienyl, pyridyl, cyclopropyl; nitro or nitrile group, R3 is alkyl, alkoxy, halogen, trifluoromethyl.
As a preferable scheme of the quinoxaline compound and the preparation method and the application thereof, the molar ratio of the substituted indole 1 to the iodo reagent to the o-phenylenediamine compound is 1:1-1.1: 1.
As a preferable scheme of the quinoxaline compound and the preparation method and the application thereof, the iodo reagent is iodine simple substance, diiodohydantoin and N-iodo succinimide.
As a preferable scheme of the quinoxaline compound, the preparation method and the application thereof, the reaction temperature in the step S1 is 20-100 ℃.
As a preferable scheme of the quinoxaline compounds, the preparation method and the application thereof, 43 quinoxaline compounds are prepared in the step S1.
As a preferable scheme of the quinoxaline compound, the preparation method and the application thereof, the preparation method of the compound 3-1 in 43 quinoxaline compounds comprises the following steps: dissolving 0.2mmol of 2-phenylindole and 0.2mmol of NIS in 20mL of dimethyl sulfoxide, stirring at room temperature for reacting for 2 hours, then adding 0.2mmol of o-phenylenediamine into the reaction mixture, stirring at room temperature for 6 hours, adding 20mL of water into the reaction solution after the reaction is completed, extracting the reaction solution with ethyl acetate for 3 times, combining organic phases, removing the ethyl acetate by rotary evaporation, performing column chromatography, and eluting with an eluent: petroleum ether: ethyl acetate 10:1, and separating to obtain 3-1, 83% of quinoxaline derivative.
Compared with the prior art, the invention has the beneficial effects that: the method is characterized in that o-phenylenediamine, substituted indole and iodo reagent are subjected to multi-step conversion reaction to synthesize a series of quinoxaline derivatives, the synthesis process is simple and easy to control, the structure types of target products are various, various substituents can be introduced at 2-position, 3-position, 5-position, 6-position and 7-position of a parent nucleus of a quinoxaline structure, the foundation is laid for synthesizing medicament molecules containing the quinoxaline structure, when the quinoxaline derivative is used specifically, substituted indole 1 and alpha-position 2,2,6, 6-tetramethylpiperidine oxide substituted 1, 3-dicarbonyl compound 2 are subjected to series reaction in an acid solvent to prepare quinoxaline compounds 3, the total number of the prepared quinoxaline compounds is 43, and the compounds 3-1, 3-2, 3-3, 3-4, 3-4, 2, 3-1, 3-3, 3-4, 3-O-methyl-isoxaline are sequentially adopted, 3-6 of a compound, 3-7 of a compound, 3-8 of a compound, 3-9 of a compound, 3-10 of a compound, 3-11 of a compound, 3-12 of a compound, 3-13 of a compound, 3-14 of a compound, 3-15 of a compound, 3-16 of a compound, 3-17 of a compound, 3-18 of a compound, 3-19 of a compound, 3-20 of a compound, 3-21 of a compound, 3-22 of a compound, 3-23 of a compound, 3-24 of a compound, 3-25 of a compound, 3-26 of a compound, 3-27 of a compound, 3-28 of a compound, 3-29 of a compound, 3-30 of a compound, 3-31 of a compound, 3-32 of a compound, 3-33 of a compound, 3-34 of a compound, 3-9 of a compound, 3-20 of a compound, the compound 3-35, the compound 3-36, the compound 3-37, the compound 3-38, the compound 3-39, the compound 3-40, the compound 3-41, the compound 3-42 and the compound 3-43, wherein the preparation method of the compound 3-1 comprises the following steps: dissolving 0.2mmol of 2-phenylindole and 0.2mmol of NIS in 20mL of dimethyl sulfoxide, stirring at room temperature for reacting for 2 hours, then adding 0.2mmol of o-phenylenediamine into the reaction mixture, stirring at room temperature for 6 hours, adding 20mL of water into the reaction solution after the reaction is completed, extracting the reaction solution with ethyl acetate for 3 times, combining organic phases, removing the ethyl acetate by rotary evaporation, performing column chromatography, and eluting with an eluent: petroleum ether: separating to obtain 3-1, 83% quinoxaline derivative with ethyl acetate of 10:1, carrying out application test detection on the prepared quinoxaline derivative by using the same preparation method as the compound 3-1 for other compounds, collecting logarithmic phase cells, inoculating the cells onto a 96-hole cell culture plate, and adding drug solutions to be detected with different concentrations. After 72 hours of cultivation, 10% trichloroacetic acid was added, and the mixture was cultivated at 4 ℃ for 1 hour, washed 5 times with tap water and air-dried, and the surviving cells were stained with 0.4% (w/v) sulforhodamine B for 20min at room temperature, washed 5 times with 1% acetic acid, and the solution was dissolved with 10mM Tris solution, the absorbance of each well was measured at 540nm in an enzyme-linked immunosorbent assay, and calculated from the inhibition (%) (mean value of a drug-free cell control well a-mean value of a drug-free cell control well)/mean value of a drug-free cell control well a × 100%, compounds 3-6, 3-7, 3-17, 3-21, 3-22, 3-34, and 3-38 had significant cancer cell inhibitory activity, and the half inhibitory concentrations of compounds 3-7 and 3-17 to human lung cancer cells were 1.2 μ M and 2.4 μ M, respectively.
Detailed Description
The present invention will be described in detail with reference to the following embodiments in order to make the aforementioned objects, features and advantages of the invention more comprehensible.
In the following description, numerous specific details are set forth in order to provide a thorough understanding of the present invention, but the present invention may be practiced in other ways than those specifically described herein, and it will be apparent to those of ordinary skill in the art that the present invention may be practiced without departing from the spirit and scope of the present invention, and therefore the present invention is not limited to the specific embodiments disclosed below.
In order to make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention are described in further detail below.
The invention provides a quinoxaline compound and a preparation method and application thereof, a series of quinoxaline derivatives are synthesized by multi-step conversion reaction of o-phenylenediamine, substituted indole and iodo reagent, the synthesis process is simple and easy to control, the structure types of target products are various, and various substituents can be introduced into 2-position, 3-position, 5-position, 6-position and 7-position of a parent nucleus of a quinoxaline structure, so that a foundation is laid for synthesizing a drug molecule containing the quinoxaline structure.
A quinoxaline compound and a preparation method and application thereof comprise:
s1: substituted indole 1 and alpha position 2,2,6, 6-tetramethyl piperidine oxide substituted 1, 3-dicarbonyl compound 2 are subjected to series reaction in an acid solvent to prepare quinoxaline compounds 3, wherein the prepared quinoxaline compounds have 43 types, and the specific molecular formula is as follows:
s2: the reaction equation of the reaction process is as follows:
wherein R1 is alkyl, alkoxy, halogen, polyfluoroalkyl or nitro; r2 is phenyl, alkyl substituted phenyl, halogen substituted phenyl, thienyl, pyridyl, cyclopropyl; nitro or nitrile group, R3 is alkyl, alkoxy, halogen, trifluoromethyl.
Preparation of Compound 3-1
Dissolving 0.2mmol of 2-phenylindole and 0.2mmol of NIS in 20mL of dimethyl sulfoxide, stirring at room temperature for reaction for 2 hours, then adding 0.2mmol of o-phenylenediamine into the reaction mixture, stirring at room temperature for 6 hours, adding 20mL of water into the reaction solution after the reaction is completed, extracting the reaction solution with ethyl acetate for 3 times, combining organic phases, removing ethyl acetate by rotary evaporation, and separating by column chromatography (eluent: petroleum ether: ethyl acetate 10:1) to obtain the quinoxaline derivative 3-1 (83%).
1H NMR(400MHz,CDCl3)δ8.24–8.15(m,1H),8.15–8.06(m, 1H),7.84–7.72(m,2H),7.65–7.52(m,2H),7.42–7.29(m,3H), 7.20–7.08(m,1H),6.91–6.78(m,2H),6.55(t,J＝7.5Hz,1H), 4.62(s,2H)；
Preparation of Compound 3-2
Compound 3-2 was prepared in the same manner as in the preparation of compound 3-1, except that 3, 4-dimethylphthaldiamine was used instead of o-phenylenediamine.
1H NMR(400MHz,CDCl3)δ7.92(s,1H),7.85(s,1H),7.58–7.51 (m,2H),7.34–7.27(m,3H),7.10(td,J＝8.1,1.5Hz,1H),6.84 (dd,J＝7.7,1.4Hz,1H),6.79(d,J＝7.6Hz,1H),6.54(td,J＝7.6, 1.0Hz,1H),4.57(s,2H),2.52(s,3H),2.51(s,3H)。
3-3, 3-4, 3-6, 3-7, 3-8, 3-9, 3-10, 3-11, 3-12, 3-13, 3-14, 3-15, 3-16, 3-17, 3-18, 3-19, 3-20, 3-21, 3-22, 3-23, 3-24, 3-25, 3-26, 3-27, 3-28, 3-29, 3-30, 3-31, 3-32, 3-9, 3-10, 3-14, 3-15, 3-16, 3-17, 3-18, 3-19, 3-20, 3-21, 3-22, 3-23, 3-24, 3-25, 3-26, 3-27, 3-28, 3-29, 3-30, 3-31, 3-32, or, The preparation methods of the compounds 3-33, 3-34, 3-35, 3-36, 3-37, 3-38, 3-39, 3-40, 3-41, 3-42 and 3-43 are the same as those of the compound 3-1.
Experimental test examples:
the test principle is as follows: a sulforhodamine colorimetric method is mainly used for detecting the cell proliferation condition. SRB is a pink anionic dye, is easily soluble in water, and can be specifically combined with basic amino acids which form proteins in cells under an acidic condition; an absorption peak is generated under the wavelength of 540nm, and the light absorption value is in positive linear correlation with the cell quantity, so that the method can be used for quantitative detection of the cell quantity.
The test method comprises the following steps:
sample preparation: dissolving a test sample in DMSO (dimethylsulfoxide), and ultrasonically dissolving the test sample at the concentration of 100mM/L to obtain a medicinal solution which can be stored at the temperature of-20 ℃;
log phase cells were collected, seeded onto 96 well cell culture plates, and different concentrations of test drug solutions were added. After 72 hours of incubation, 10% trichloroacetic acid was added, incubation was carried out at 4 ℃ for 1 hour, washed 5 times with tap water and air-dried, and the surviving cells were stained with 0.4% (w/v) sulforhodamine B at room temperature for 20min, washed 5 times with 1% acetic acid, and the solution was dissolved with 10mM Tris solution, and the absorbance of each well was measured at 540nm in an ELISA detector.
The test data calculation method comprises the following steps:
inhibition (%) - (average value of a value in drug-free cell control well-average value of a value in drug-free cell control well)/average value of a value in drug-free cell control well × 100%.
From the experimental results, data on all ICs 50 that are quite close to the normal method were calculated according to the principles of the oblique dot method.
The basic formula:
1.IC50:IC50＝Log-1[Xm-i×(∑p–0.5)+i/4×(1-Pm-Pn)]
2. LD50 with 0% and 100% mortality:
IC50＝Log-1[Xm-i×(∑p–0.5)]
where Xm is the log dose value of the highest mortality Pm group, i is the group distance, Pm is the highest mortality, Pn is the lowest mortality, and n is the number of animals in each group.
The activity results are given in the following table:
as can be seen from the results of the antitumor activity, the compounds 3-6, 3-7, 3-17, 3-21, 3-22, 3-34 and 3-38 of the invention have significant cancer cell inhibitory activity, and the half inhibitory concentrations of the compounds 3-7 and 3-17 to human lung cancer cells are 1.2 and 2.4. mu.M, respectively.
In the specific use, substituted indole 1 and alpha-2, 2,6, 6-tetramethylpiperidine oxide substituted 1, 3-dicarbonyl compound 2 are subjected to a series reaction in an acid solvent to prepare quinoxaline compound 3, wherein the prepared quinoxaline compounds are 43 in total, and the compounds are sequentially compound 3-1, compound 3-2, compound 3-3, compound 3-4, compound 3-6, compound 3-7, compound 3-8, compound 3-9, compound 3-10, compound 3-11, compound 3-12, compound 3-13, compound 3-14, compound 3-15, compound 3-16, compound 3-17, Compound 3-18, compound 3-19, compound 3-20, compound 3-21, compound 3-22, compound 3-23, compound 3-24, compound 3-25, compound 3-26, compound 3-27, compound 3-28, compound 3-29, compound 3-30, compound 3-31, compound 3-32, compound 3-33, compound 3-34, compound 3-35, compound 3-36, compound 3-37, compound 3-38, compound 3-39, compound 3-40, compound 3-41, compound 3-42, compound 3-43, wherein the method of preparing compound 3-1 is: dissolving 0.2mmol of 2-phenylindole and 0.2mmol of NIS in 20mL of dimethyl sulfoxide, stirring at room temperature for reacting for 2 hours, then adding 0.2mmol of o-phenylenediamine into the reaction mixture, stirring at room temperature for 6 hours, adding 20mL of water into the reaction solution after the reaction is completed, extracting the reaction solution with ethyl acetate for 3 times, combining organic phases, removing the ethyl acetate by rotary evaporation, performing column chromatography, and eluting with an eluent: petroleum ether: separating to obtain 3-1, 83% quinoxaline derivative with ethyl acetate of 10:1, carrying out application test detection on the prepared quinoxaline derivative by using the same preparation method as the compound 3-1 for other compounds, collecting logarithmic phase cells, inoculating the cells onto a 96-hole cell culture plate, and adding drug solutions to be detected with different concentrations. After 72 hours of cultivation, 10% trichloroacetic acid was added, and the mixture was cultivated at 4 ℃ for 1 hour, washed 5 times with tap water and air-dried, and the surviving cells were stained with 0.4% (w/v) sulforhodamine B for 20min at room temperature, washed 5 times with 1% acetic acid, solubilized with 10mM Tris solution, the absorbance of each well was measured at 540nm in an enzyme-linked immunosorbent assay, and calculated from the inhibition (%) (mean value of a drug-free cell control well a-mean value of a drug-free cell control well)/mean value of a drug-free cell control well a × 100%, compounds 3-6, 3-7, 3-17, 3-21, 3-22, 3-34, and 3-38 had significant cancer cell inhibitory activity, and the half inhibitory concentrations of compounds 3-7 and 3-17 to human lung cancer cells were 1.2 μ M and 2.4 μ M, respectively.
While the invention has been described with reference to an embodiment, various modifications may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In particular, the various features of the disclosed embodiments of the invention may be used in any combination, provided that no structural conflict exists, and the combinations are not exhaustively described in this specification merely for the sake of brevity and resource conservation. Therefore, it is intended that the invention not be limited to the particular embodiments disclosed, but that the invention will include all embodiments falling within the scope of the appended claims.
Claims (6)
1. A quinoxaline compound and a preparation method and application thereof are characterized by comprising the following steps:
s1: substituted indole 1 and alpha position 2,2,6, 6-tetramethyl piperidine oxide substituted 1, 3-dicarbonyl compound 2 are subjected to series reaction in an acid solvent to prepare a quinoxaline compound 3;
s2: the reaction equation of the reaction process is as follows:
wherein R1 is alkyl, alkoxy, halogen, polyfluoroalkyl or nitro; r2 is phenyl, alkyl substituted phenyl, halogen substituted phenyl, thienyl, pyridyl, cyclopropyl; nitro or nitrile group, R3 is alkyl, alkoxy, halogen, trifluoromethyl.
2. The quinoxaline compound as claimed in claim 1, and the preparation method and application thereof, wherein the molar ratio of the substituted indole 1 to the iodo reagent to the o-phenylenediamine compound is 1:1 to 1.1: 1.
3. The quinoxaline compound and the preparation method and application thereof according to claim 2, wherein the iodine reagent is iodine, diiodohydantoin or N-iodosuccinimide.
4. The quinoxaline compounds according to claim 3, the preparation method and the application thereof, wherein in the step S1, the reaction temperature is 20-100 ℃.
5. The quinoxaline compounds and the preparation method and application thereof according to claim 4, wherein the total number of the quinoxaline compounds prepared in the step S1 is 43.
6. The quinoxaline compounds and the preparation method and the application thereof according to claim 5, wherein the preparation method of the compound 3-1 in the 43 quinoxaline compounds is as follows: dissolving 0.2mmol of 2-phenylindole and 0.2mmol of NIS in 20mL of dimethyl sulfoxide, stirring at room temperature for reacting for 2 hours, then adding 0.2mmol of o-phenylenediamine into the reaction mixture, stirring at room temperature for 6 hours, adding 20mL of water into the reaction solution after the reaction is completed, extracting the reaction solution with ethyl acetate for 3 times, combining organic phases, removing the ethyl acetate by rotary evaporation, performing column chromatography, and eluting with an eluent: petroleum ether: ethyl acetate 10:1, and separating to obtain 3-1, 83% of quinoxaline derivative.
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