CN107827828B - Quinoxaline derivative containing phenylhydrazide skeleton, preparation method thereof and application thereof in preparation of antitumor drugs - Google Patents
Quinoxaline derivative containing phenylhydrazide skeleton, preparation method thereof and application thereof in preparation of antitumor drugs Download PDFInfo
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- CN107827828B CN107827828B CN201711162513.2A CN201711162513A CN107827828B CN 107827828 B CN107827828 B CN 107827828B CN 201711162513 A CN201711162513 A CN 201711162513A CN 107827828 B CN107827828 B CN 107827828B
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- 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
- C07D241/44—Benzopyrazines with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
Abstract
The invention provides a quinoxaline derivative containing a phenylhydrazide skeleton, a preparation method thereof and application thereof in preparing an antitumor drug. The structural formula of the quinoxaline derivative containing the phenylhydrazide skeleton is shown as a formula X:
Description
Technical Field
The invention belongs to the technical field of medicinal chemistry, and particularly relates to a quinoxaline derivative containing a phenylhydrazide skeleton, a preparation method thereof and application thereof in preparing an antitumor medicament.
Background
The compound containing the hydrazide structural unit is a nitrogen heteroatom compound which is widely applied, has good biological performance, and is often used as a synthetic precursor or intermediate of a plurality of important medicines, dyes and materials. The hydrazide structural skeleton is not only an important synthetic unit, but also has great potential as a potential therapeutic drug, and the derivatives have wide biological and physiological activities of resisting virus, tumor, malaria, insect killing, sterilization and the like.
Quinoxaline is a nitrogen-containing heterocyclic compound spliced by benzene ring and pyrazine, and the derivatives of the compound have various biological activities such as anti-tumor activity, antibacterial activity and the like. The structure of the quinoxaline ring is modified at three positions, which is beneficial to improving the biological activity of the quinoxaline ring.
Disclosure of Invention
The technical problem to be solved is as follows: the invention aims to construct phenylhydrazide and quinoxaline in the same molecule, and simultaneously introduce substituent groups to design and synthesize a series of quinoxaline derivatives containing phenylhydrazide frameworks, so that better biological activity, higher selectivity and lower toxicity are expected to be obtained.
The technical scheme is as follows: the structural formula of the quinoxaline derivative containing the phenylhydrazide skeleton is shown as the formula X:
wherein R is selected from hydrogen, halogen, alkyl, nitro, alkoxy and halogenated alkyl. The synthesis method of the quinoxaline derivative containing the phenylhydrazide skeleton comprises the following steps:
preferably, in the step of preparing the compound 2 from the compound 1, the reaction solvent is ethanol.
Preferably, in the step of preparing the compound 4 from the compound 3, the reaction solvent is water.
Preferably, in the step of preparing the compound 5 from the compound 4, the reaction solvent is dimethylformamide.
Preferably, in the step of preparing the compound 6 from the compound 5, the reaction solvent is ethanol.
The quinoxaline derivative containing the phenylhydrazide skeleton is applied to the preparation of antitumor drugs.
Has the advantages that: the quinoxaline derivative containing the phenylhydrazide skeleton is obtained by effectively integrating the pharmacodynamic groups of quinoxaline and phenylhydrazide, and the series of derivatives are new compounds. The synthesis method has the advantages of strong repeatability, good stability, simple reaction conditions, mild experimental environment and good yield, and can be used for mass production under the condition of small investment.
The quinoxaline derivative containing the phenylhydrazide skeleton has obvious inhibition effect on cervical cancer cells (Hela), lung cancer cells (A549), melanoma cells (F10) and liver cancer cells (HepG2), the action effect of the quinoxaline derivative is approximately equivalent to that of a positive control drug Erlotinib, and part of the quinoxaline derivative containing the phenylhydrazide skeleton is superior to that of the positive control drug in expression. The quinoxaline derivative containing the phenylhydrazide skeleton has better biological activity, higher selectivity and lower toxicity.
Detailed Description
The technical solutions of the present invention are further described below, but these examples do not limit the embodiments of the present invention. The invention is capable of many different embodiments and is not limited to only those described in this specification. Those skilled in the art should implement the invention within the scope of the present invention without departing from the spirit of the invention of the present application.
The invention provides a quinoxaline derivative containing a phenylhydrazide skeleton, which has a structural formula shown as a formula X:
wherein R is selected from hydrogen, halogen, alkyl, nitro, alkoxy and halogenated alkyl.
The synthesis method comprises the following steps:
the method specifically comprises the following steps:
step i.1 (8mmol), absolute ethanol (20mL) and hydrazine hydrate (120mmol) are added into a 50mL round-bottom flask in sequence, the reaction flask is transferred into an oil bath, reflux reaction is carried out for 6h, and TLC tracing reaction (developing agent V)AcOEt:VPE1: 2). After completion of the reaction, the reaction mixture was filtered, and the solid was washed with 1mol/L hydrochloric acid (3X 100mL), distilled water (3X 150mL) and cold ethanol (3X 50mL) in this order and dried to obtain intermediate 2.
Step ii. an aqueous solution of 4, 5-dichloro-1, 2-phenylenediamine (10mmol) and methyl pyruvate (10mmol) were added to a 100mL round-bottom flask with stirring. The reaction is stopped after three hours, a solid crude product is obtained by filtration, and the compound 4 is obtained by ethanol recrystallization.
6, 7-dichloro-3-methylquinolinecarboxylic acid copper,1H-NMR(300MHz,CDCl3):7.64(s,1H)；7.20(s,1H)；1.53(s,3H).13C-NMR(75MHz,DMSO-d6):164.4；154.4；139.5；131.1；129.7；127.9；122.1；19.9。
step iii, dropwise adding 6mL of phosphorus oxychloride into a reaction flask containing 12mL of dimethylformamide at the temperature of 0 ℃ in an ice bath, dropwise adding 6, 7-dichloro-3-methylquinolinone dissolved in dimethylformamide (6mL) into the solution, gradually raising the temperature of the reaction solution to room temperature, stirring for 2 hours, and then transferring the reaction flask into a 60 ℃ oil bath for reaction for 6 hours. After the reaction, the reaction mixture was poured into ice water, neutralized with sodium carbonate to pH 7, filtered, and the solid was washed with cold ethanol (3 × 50mL) and distilled water (3 × 200mL) in this order and dried to obtain starting material 5.
6, 7-dichloro-3-methyl-4-chloroquinolinecarbon,1H-NMR(300MHz,CDCl3):7.65(s,1H)；7.20(s,1H)；1.53(s,3H).13C-NMR(75MHz,DMSO-d6):164.4；153.1；139.5；131.1；129.7；127.9；122.1；19.9。
step iv, adding the compound 5(3mmol) and the compound 2(3mmol) into a 100mL round-bottom flask containing ethanol in sequence under stirring, stirring and refluxing for reaction, filtering to obtain a solid crude product, and recrystallizing with ethanol to obtain the target compound 6.
Example 1
Preparation of N' - (6, 7-dichloro-3-methylquinoxaline) phenylhydrazide
The compound phenylhydrazide (1.5mmol) and the compound 2,6, 7-trichloro-3-methylquinoxaline (1.5mmol) were added successively to a 25mL ethanol solution with stirring. Stirring and refluxing for reaction, separating out solid, filtering, and recrystallizing with ethanol to obtain the target compound.
Yield: 54.6 percent.
1H-NMR(600MHz,DMSO-d6):8.35(s,ArH,1H)；7.93-7.75(m,ArH,5H)；7.44(s,ArH,1H)；2.94(s,3H).
Example 2
Preparation of 3-chloro-N' - (6, 7-dichloro-3-methylquinoxaline) phenylhydrazide
The preparation process is referred to example 1.
Yield: 62.1 percent.
1H-NMR(600MHz,DMSO-d6):8.36(s,ArH,1H)；7.93-7.74(m,ArH,4H)；7.44(s,ArH,1H)；2.94(s,3H).
Example 3
Preparation of N' - (6, 7-dichloro-3-methylquinoxaline) -3-methylbenzhydrazide
The preparation process is referred to example 1.
Yield: 50.2 percent.
1H-NMR(600MHz,DMSO-d6):8.34(s,ArH,1H)；7.93-7.73(m,ArH,4H)；7.44(s,ArH,1H)；2.94(s,3H)；2.36(s,3H,CH3).
Example 4
Preparation of N' - (6, 7-dichloro-3-methylquinoxaline) -3-methoxybenzenehydrazide
The preparation process is referred to example 1.
Yield: 55.0 percent.
1H-NMR(600MHz,DMSO-d6):8.34(s,ArH,1H)；7.93-7.73(m,ArH,4H)；7.44(s,ArH,1H)；3.78(s,3H,OCH3)；2.94(s,3H).
Example 5
Preparation of N' - (6, 7-dichloro-3-methylquinoxaline) -3-trifluoromethylphenylhydrazide
The preparation process is referred to example 1.
Yield: 62.3 percent.
1H-NMR(600MHz,DMSO-d6):8.34(s,ArH,1H)；8.02-7.72(m,ArH,4H)；7.44(s,ArH,1H)；2.94(s,3H).
Example 6
In vitro anti-tumor activity research of quinoxaline derivative containing phenylhydrazide skeleton
MTT [3- (4,5) -dimethyl-2-thiazole- (2,5) -phenyl bromide tetrazolium blue is adopted]The method is used for determining the half Inhibition Concentration (IC) of quinoxaline derivatives of the phenylhydrazide skeleton on cervical cancer cells (Hela), lung cancer cells (A549), melanoma cells (F10) and liver cancer cells (HepG2)50)。
(1) Preparation of culture solution (per liter): suspension of cells: RPMI-1640 culture powder one bag (10.4g), newborn bovine serum 100mL, penicillin solution (20 ten thousand U/mL)0.5mL, streptomycin solution (20 ten thousand U/mL)0.5mL, dissolving with distilled water, and dissolving with 5.6% NaHCO3Adjusting the pH value of the solution to 7.2-7.4, and finally metering to 1000 mL. And (5) filtering and sterilizing. Adherent cells: as above, NaHCO is added3 2.00g、HEPES 2.38g。
(2) Preparation of D-Hanks buffer (per liter): NaCl 8.00g, KCl 0.40g, Na2HPO4·12H2O 0.06g，KH2PO4 0.06g，NaHCO30.35 g. And (5) autoclaving.
(3) Preparation of a trypsin solution: D-Hanks buffer solution is used to prepare 0.5% trypsin solution. And (5) filtering and sterilizing.
(4) Preparing an experimental liquid medicine: dissolving a test sample with a small amount of triple distilled water to prepare a stock solution, and generally preparing the stock solution according to 10 times of the highest concentration of an experiment. According to different solubility of the compound, the compound can be directly dissolved by using triple distilled water, or a small amount of DMSO is used for assisting dissolution, and then the triple distilled water is added for dissolution. The concentration of DMSO in the culture solution is not too high, and the final concentration of DMSO in each cell suspension after dosing is generally not more than 0.05% -0.1%. The stock solution was stored in a refrigerator at-20 ℃ for further use.
(5) Culturing of cervical cancer cell (Hela), lung cancer cell (A549), melanoma cell (F10) and liver cancer cell (HepG 2): for suspension growth of cells, the cells were cultured in RPMI-1640 medium (containing 10% calf serum and 100U/mL streptomycin) at 37 ℃ in 5% CO2Culturing in an incubator, and subculturing every 3-4 days. Transferring the culture solution in the original bottle to a centrifuge tube during passage, centrifuging at 1000rpm for 5min, discarding the original culture solution, adding an equal amount of fresh culture solution, uniformly blowing, transferring an appropriate amount of fresh culture solution to the fresh culture bottle, and supplementing the fresh culture solution to the original volume (the volume of the culture solution is about 1/10 of the volume of the culture bottle).
(6) Cell incubation: taking tumor cells in logarithmic growth phase, adjusting cell suspension concentration to 1-1.5 × 105Each mL-1. Adding 100 μ L of cell suspension into each well of 96-well culture plate, standing at 37 deg.C and 5% CO2Culturing in an incubator for 24 h. After culturing for 24h, adding the liquid medicines according to the design.
(8) Adding medicine: and respectively adding the test liquid medicine into each hole according to the concentration gradient of the final concentration, wherein each concentration is provided with 6 parallel holes. The experiment is divided into a drug test group (respectively adding test drugs with different concentrations), a quinoxaline group, a positive drug group (erlotinib), a negative control group (only adding culture solution and cells and not adding test drugs) and a blank group (only adding culture solution and not adding cells and test drugs). The dosed 96-well plate was placed at 37 ℃ in 5% CO2Culturing in an incubator for 48 h. The activity of the quinoxaline group and the positive control drug is determined according to the method of the test sample; inhibition rate (1-drug/negative) 100%.
(9) Determination of surviving cells: after 48h incubation, 40. mu.L of MTT (4 mg/mL using D-Hanks buffer) was added to each well of a 96-well plate. After standing at 37 ℃ for 4h, the supernatant was removed. Add 150. mu.L DMSO/well, shake for 5min, dissolve formazan crystals. Finally, the optical density (OD value) of each well was measured at a wavelength of 570nm using an automatic microplate reader.
Median Inhibitory Concentration (IC)50) Defined as the drug concentration when 50% of the tumor cells survived. A standard curve of the cell growth inhibition rate was prepared from the measured optical density (OD value), and the drug concentration corresponding to the standard curve was determined.
Measured IC50See table 1.
TABLE 1 inhibition of tumor cells by quinoxaline derivatives containing a hydrazide skeleton IC50Value (μ M)
a3 times of parallel tests, the experimental results are averaged, and the error is between 5 and 10 percent
From the above experiments, quinoxaline does not inhibit tumor activity, the derivative thereof has anti-tumor activity, and meanwhile, the phenylhydrazide unit is used as an intermediate, and the current literature reports that the derivative thereof has wide biological and physiological activities such as antivirus, anti-tumor, anti-malaria, insecticidal, bactericidal and the like. From this example, a series of compounds synthesized by the present invention have better antitumor activity than positive control drugs, and the quinoxaline mother unit thereof does not inhibit tumor activity. The phenylhydrazide is toxic, cannot be directly used as a medicine, and only can be used as an intermediate, so that the experiment does not take the phenylhydrazide as a comparative example.
Although the preferred embodiments of the present invention have been described in detail, the present invention is not limited to the details of the embodiments, and various equivalent modifications can be made within the technical spirit of the present invention, and the scope of the present invention is also within the scope of the present invention. It should be noted that the various features described in the above embodiments may be combined in any suitable manner without departing from the scope of the invention. The invention is not described in detail in order to avoid unnecessary repetition. In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the disclosure of the present invention as long as it does not depart from the spirit of the present invention.
Claims (7)
1. The structural formula of the quinoxaline derivative containing the phenylhydrazide skeleton is shown as the formula X:
wherein R is hydrogen, chlorine, methyl, methoxyl or trifluoromethyl.
2. The method for synthesizing a quinoxaline derivative containing a hydrazide skeleton according to claim 1, wherein: the method comprises the following steps:
wherein R is hydrogen, chlorine, methyl, methoxyl or trifluoromethyl.
3. The method for synthesizing a quinoxaline derivative containing a hydrazide skeleton according to claim 2, wherein: in the step of preparing the compound 2 from the compound 1, the reaction solvent is ethanol.
4. The method for synthesizing a quinoxaline derivative containing a hydrazide skeleton according to claim 2, wherein: compound 3 in the step of preparing compound 4, the reaction solvent is water.
5. The method for synthesizing a quinoxaline derivative containing a hydrazide skeleton according to claim 2, wherein: compound 4 in the step of preparing compound 5, the reaction solvent is dimethylformamide.
6. The method for synthesizing a quinoxaline derivative containing a hydrazide skeleton according to claim 2, wherein: in the step of preparing compound 6 from compound 5, the reaction solvent is ethanol.
7. The use of the quinoxaline derivative containing a hydrazide skeleton according to claim 1 for preparing an antitumor agent.
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Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004004651A2 (en) * | 2002-07-03 | 2004-01-15 | Wayne State University | Therapeutic amides |
| CN101704792A (en) * | 2009-11-02 | 2010-05-12 | 山东大学 | Quinoxalinone derivative with matrix metalloproteinase inhibitory activity and preparation method and application thereof |
| WO2011093365A1 (en) * | 2010-01-27 | 2011-08-04 | 協和発酵キリン株式会社 | Nitrogenated heterocyclic compound |
| CN103124731A (en) * | 2010-09-16 | 2013-05-29 | 和记黄埔医药（上海）有限公司 | Fused heteroaryls and their uses |
| CN103619846A (en) * | 2011-06-27 | 2014-03-05 | 詹森药业有限公司 | 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivatives |
| CN104529915A (en) * | 2015-01-27 | 2015-04-22 | 山东大学 | Quinoxalinone analog with DNA (deoxyribonucleic acid) topoismerase II inhibiting activity, and preparation method and application thereof |
| US20160031890A1 (en) * | 2013-03-14 | 2016-02-04 | Dorre A. Grueneberg | Novel methods, compounds, and compositions for inhibition of ros |
-
2017
- 2017-11-21 CN CN201711162513.2A patent/CN107827828B/en not_active Expired - Fee Related
Patent Citations (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004004651A2 (en) * | 2002-07-03 | 2004-01-15 | Wayne State University | Therapeutic amides |
| CN101704792A (en) * | 2009-11-02 | 2010-05-12 | 山东大学 | Quinoxalinone derivative with matrix metalloproteinase inhibitory activity and preparation method and application thereof |
| WO2011093365A1 (en) * | 2010-01-27 | 2011-08-04 | 協和発酵キリン株式会社 | Nitrogenated heterocyclic compound |
| CN103124731A (en) * | 2010-09-16 | 2013-05-29 | 和记黄埔医药（上海）有限公司 | Fused heteroaryls and their uses |
| CN103619846A (en) * | 2011-06-27 | 2014-03-05 | 詹森药业有限公司 | 1-aryl-4-methyl-[1,2,4]triazolo[4,3-a]quinoxaline derivatives |
| US20160031890A1 (en) * | 2013-03-14 | 2016-02-04 | Dorre A. Grueneberg | Novel methods, compounds, and compositions for inhibition of ros |
| CN104529915A (en) * | 2015-01-27 | 2015-04-22 | 山东大学 | Quinoxalinone analog with DNA (deoxyribonucleic acid) topoismerase II inhibiting activity, and preparation method and application thereof |
Non-Patent Citations (2)
| Title |
|---|
| Identification of novel 2-(1H-indol-1-yl)-benzohydrazides CXCR4 ligands impairing breast cancer growth & motility;Fedora Grande,等;《Future Medicinal Chemistry》;20160125;第08卷(第02期);第93-106页 * |
| 新型喹喔啉衍生物的合成与表征;张春玲,等;《海峡药学》;20130715;第25卷(第07期);第209-211页 * |
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