CN107827828A - Quinoxaline derivant of the skeleton containing phenylhydrazide and preparation method thereof and the application in antineoplastic is prepared - Google Patents
Quinoxaline derivant of the skeleton containing phenylhydrazide and preparation method thereof and the application in antineoplastic is prepared Download PDFInfo
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- CN107827828A CN107827828A CN201711162513.2A CN201711162513A CN107827828A CN 107827828 A CN107827828 A CN 107827828A CN 201711162513 A CN201711162513 A CN 201711162513A CN 107827828 A CN107827828 A CN 107827828A
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- phenylhydrazide
- quinoxaline derivant
- quinoxaline
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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
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Abstract
Application the invention provides quinoxaline derivant of a kind of skeleton containing phenylhydrazide and preparation method thereof and in antineoplastic is prepared.The quinoxaline derivant of the skeleton containing phenylhydrazide, its structural formula is represented by a formula X：
Description
Technical field
The invention belongs to field of pharmaceutical chemistry technology, and in particular to the quinoxaline derivant of the skeleton containing phenylhydrazide and its preparation
Method and the application in antineoplastic is prepared.
Background technology
The compound of the unit containing hydrazide structure is a kind of nitrogen heteroatom compound being widely used, and has biology well
Performance, it is often used as the synthesis precursor or intermediate of many important drugs, dyestuff and material.Hydrazide structure skeleton is not only weight
The synthesis unit wanted, and it also contains great potential as potential medicine, and this analog derivative has antiviral, anti-swollen
The extensive biology such as knurl, anti-malarial, desinsection, sterilization and physiologically active.
Quinoxaline is the nitrogen-containing heterocycle compound being put together by phenyl ring and pyrazine, and the derivative of such compound, which has, to be resisted
The multiple biological activities such as tumour and antibacterial.Three in quinoxaline ring carry out structure of modification, are advantageous to improve its bioactivity.
The content of the invention
The technical problem of solution：The purpose of the present invention is to construct phenylhydrazide and quinoxaline in same molecule, meanwhile, draw
Enter substituent, design has synthesized a series of quinoxaline derivant of skeletons containing phenylhydrazide, therefore desirable for it is living to obtain preferably biology
Property, higher selectivity, lower toxicity.
Technical scheme：The quinoxaline derivant of the skeleton containing phenylhydrazide, its structural formula is represented by a formula X：
Wherein, R is selected from hydrogen, halogen, alkyl, nitro, alkoxy, haloalkyl.The quinoxaline of the above-mentioned skeleton containing phenylhydrazide
The synthetic method of derivative, including：
Preferably, in the step of 1 prepare compound 2 of compound, reaction dissolvent is ethanol.
Preferably, in the step of 3 prepare compound 4 of compound, reaction dissolvent is water.
Preferably, in the step of 4 prepare compound 5 of compound, reaction dissolvent is dimethylformamide.
Preferably, in the step of 5 prepare compound 6 of compound, reaction dissolvent is ethanol.
Application of the quinoxaline derivant of the above-mentioned skeleton containing phenylhydrazide in antineoplastic is prepared.
Beneficial effect：The present invention has effectively integrated pharmacophoric group quinoxaline and phenylhydrazide, obtains the quinoline of the skeleton containing phenylhydrazide
Quinoline derivant, the series derivates are noval chemical compounds.Synthetic method repeatability is strong, and stability is good, and reaction condition is simple, and
Experimental situation is gentle, and yield is preferable, can largely be produced in the case of smaller input.
The present invention the skeleton containing phenylhydrazide quinoxaline derivant to cervical cancer cell (Hela), lung carcinoma cell (A549),
Melanoma cells (F10) and liver cancer cells (HepG2) have obvious inhibitory action, its action effect and positive control drug angstrom
Sieve is roughly the same for Buddhist nun (Erlotinib), and the part quinoxaline derivant performance for containing phenylhydrazide skeleton is better than positive control drug.
The quinoxaline derivant of the skeleton containing phenylhydrazide of the present invention has more preferable bioactivity, higher selectivity and lower poison
Property.
Embodiment
Technical scheme is described further below, but these embodiments not limit embodiments of the present invention.
The present invention has a variety of different embodiments, is not only limited in content described in this specification.Those skilled in the art exists
In the case of the present application spirit, the scheme completed should be within the scope of the invention.
The invention provides the quinoxaline derivant of one kind skeleton containing phenylhydrazide, its structural formula is represented by a formula X：
Wherein, R is selected from hydrogen, halogen, alkyl, nitro, alkoxy, haloalkyl.
Its synthetic method includes：
Specifically comprise the following steps：
The round bottom that 1 (8mmol), absolute ethyl alcohol (20mL), hydrazine hydrate (120mmol) are added to 50mL by step i. successively burns
In bottle, reaction flask is transferred in oil bath pan, back flow reaction 6h, TLC tracking reaction (solvent VAcOEt:VPE=1:2).Reaction
After end, filtering, solid washed successively with 1mol/L hydrochloric acid (3 × 100mL), distilled water (3 × 150mL), cold ethanol (3 ×
50mL) wash, dry, intermediate 2 will be obtained.
Step ii. under agitation, will be dissolved with the aqueous solution and methyl pyruvate of chloro- 1.2 phenylenediamines (10mmol) of 4.5- bis-
(10mmol) is added in 100mL round-bottomed flask.Stop reaction after three hours, filter to obtain solid crude product, ethanol is tied again
It is brilliant to obtain compound 4.
6,7- bis- chloro- 3- methylquinolines 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.
6mL POCl3s are added drop-wise to the reaction flask equipped with 12mL dimethylformamides by step iii. under 0 DEG C of ice bath
In, then the chloro- 3- methylquinolines ketone of 6,7- bis- of dimethylformamide (6mL) will be dissolved in and be added dropwise in above-mentioned solution, allow anti-
Answer liquid to be gradually raised to and 2h is stirred at room temperature, then reaction flask is transferred in 60 DEG C of oil bath pans and reacts 6h.Reaction will be anti-after terminating
Answer liquid to pour into frozen water, pH=7 be neutralized to sodium carbonate, filter, solid successively with cold ethanol (3 × 50mL), distilled water (3 ×
200mL) wash, dry raw material 5.
6, the 7- bis- chloro- chloroquinoline copper of 3- methyl -4,1H-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。
Compound 5 (3mmol) and compound 2 (3mmol) under agitation, are added to containing ethanol by step iv. successively
In 100mL round-bottomed flask, reaction is stirred at reflux, filters to obtain solid crude product, ethyl alcohol recrystallization obtains compound target compound
6。
Embodiment 1
The preparation of N'- (the chloro- 3- methyl-quinoxalines of 6,7- bis-) phenylhydrazide
Under agitation, successively by 2,6,7- tri- chloro- 3- methyl-quinoxalines of compound phenylhydrazide (1.5mmol) and compound
(1.5mmol) is added in 25mL ethanol solution.Reaction is stirred at reflux, solid separates out, and filtering, ethyl alcohol recrystallization obtains compound
Target compound
Yield：54.6%.
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).
Embodiment 2
The preparation of the chloro- N'- of 3- (the chloro- 3- methyl-quinoxalines of 6,7- bis-) phenylhydrazide
Preparation method reference implementation example 1.
Yield：62.1%.
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).
Embodiment 3
The preparation of N'- (the chloro- 3- methyl-quinoxalines of 6,7- bis-) -3- methyl phenylhydrazides
Preparation method reference implementation example 1.
Yield：50.2%.
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).
Embodiment 4
The preparation of N'- (the chloro- 3- methyl-quinoxalines of 6,7- bis-) -3- methoxybenzene hydrazides
Preparation method reference implementation example 1.
Yield：55.0%.
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).
Embodiment 5
The preparation of N'- (the chloro- 3- methyl-quinoxalines of 6,7- bis-) -3- trifluoromethyl phenylhydrazides
Preparation method reference implementation example 1.
Yield：62.3%.
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).
Embodiment 6
The quinoxaline derivant anti tumor activity in vitro research of the skeleton containing phenylhydrazide
Phenylhydrazide bone is determined using MTT [3- (4,5)-bis- methyl -2- thiazoles-(2,5)-phenyl bromination tetrazole is blue] methods
The quinoxaline derivant of frame is thin to cervical cancer cell (Hela), lung carcinoma cell (A549), melanoma cells (F10) and liver cancer
Half-inhibition concentration (the IC of born of the same parents (HepG2)50)。
(1) preparation of nutrient solution (every liter)：1. suspension cell：RPMI-1640 culture powder one bag (10.4g), newborn ox blood
Clear 100mL, penicillin solution (200,000 U/mL) 0.5mL, Streptomycin Solution (200,000 U/mL) 0.5mL, after adding tri-distilled water to dissolve, use
5.6% NaHCO3Solution adjusts pH value to be finally settled to 1000mL to 7.2-7.4.Filtration sterilization.2. attached cell：Ibid, then
Add NaHCO3 2.00g、HEPES 2.38g。
(2) preparation of D-Hanks buffer solutions (every liter)：NaCl 8.00g, KCl 0.40g, Na2HPO4·12H2O
0.06g, KH2PO40.06g, NaHCO30.35g.Autoclaving.
(3) preparation of trypsin solution：It is 0.5% trypsin solution to be made into concentration using D-Hanks buffer solutions.Cross and filter out
Bacterium.
(4) preparation of decoction is tested：Test sample is made into storing solution with a small amount of tri-distilled water dissolving, typically empirically most
10 times of preparation storing solutions of high concentration.It is different according to compound dissolubility, can directly it be dissolved with tri-distilled water, or helped with a small amount of DMSO
It is molten, then add tri-distilled water dissolving.Concentration of the DMSO in nutrient solution unsuitable excessive, DMSO end in every hole cell suspension after dosing
Concentration is usually no more than 0.05%-0.1%.Storing solution is stored in standby in -20 DEG C of refrigerators.
(5) cervical cancer cell (Hela), lung carcinoma cell (A549), melanoma cells (F10) and liver cancer cells
(HepG2) culture：For suspension growth cell, cellar culture in RPMI-1640 nutrient solutions (containing 10% calf serum, 100U/
ML streptomysins), it is placed in 37 DEG C, 5%CO2Cultivated in incubator, every passage in 3-4 days once.By nutrient solution in former bottle during passage
It is transferred in centrifuge tube, 1000rpm centrifugation 5min, discards original fluid, add equivalent fresh medium, piping and druming is uniform, pipettes
In right amount into fresh cultured bottle, it is supplemented fresh medium to original volume (nutrient solution volume is about the 1/10 of blake bottle capacity).
(6) cell incubation：Take the logarithm the tumour cell in growth period, tune concentration of cell suspension is 1-1.5 × 105Individual mL-1.
Add the μ L of cell suspension 100 per hole in 96 well culture plates, put 37 DEG C, 5%CO224h is cultivated in incubator.After cultivating 24h, press respectively
Design adds decoction.
(8) dosing：Test decoction is added separately in each hole according to the concentration gradient of ultimate density, each concentration is set
6 parallel holes.Experiment is divided into drug test group (the test medicine for being separately added into various concentrations), quinoxaline group, positive drug group (angstrom sieve
For Buddhist nun), negative control group (only plus nutrient solution and cell, be not added with test medicine) and blank group (only add nutrient solution, be not added with cell and survey
Reagent).96 orifice plates after dosing are placed in 37 DEG C, 5%CO248h is cultivated in incubator.Quinoxaline group and positive control medicine
Activity determines according to the method for test sample；Inhibiting rate=(1- medicine groups/negative group) * 100%.
(9) measure of survivaling cell：In 96 orifice plates after having cultivated 48h, the μ L of MTT 40 are added (to be delayed with D-Hanks per hole
Fliud flushing is made into 4mg/mL).After 37 DEG C are placed 4h, supernatant is removed.Add 150 μ L DMSO per hole, vibrate 5min, make
Formazan crystallization dissolvings.Finally, the optical density (OD values) in each hole is detected at 570nm wavelength using automatic ELIASA.
Half-inhibition concentration (IC50) it is defined as the drug concentration when 50% tumor cell survival.According to the light of measure
Density (OD values), the standard curve of inhibitory rate of cell growth is made, its corresponding drug concentration is tried to achieve on standard curve.
The IC measured50It is shown in Table 1.
Suppression IC of the quinoxaline derivant of the skeleton containing phenylhydrazide of table 1 to tumour cell50It is worth (μM)
a3 parallel tests, experimental result are averaged, and error is between 5%-10%
Known by above-mentioned experiment, quinoxaline does not suppress tumor promotion, and its derivative has antitumor activity, while benzene
Hydrazyde units, as intermediate, document report is all that its derivative has antiviral, antitumor, anti-malarial, desinsection, killed at present
The extensive biology such as bacterium and physiologically active.In terms of the present embodiment, a series of compounds tool antitumor activity that the present invention synthesizes is excellent
In positive control drug, while its quinoxaline mother unit does not suppress tumor promotion.Phenylhydrazide is poisonous can not be directly as medicine
Using intermediate can only be used as, therefore this experiment is not as comparative example.
The preferred embodiment of the present invention described in detail above, still, the present invention are not limited in above-mentioned embodiment
Detail, in the range of the technology design of the present invention, a variety of equivalents can be carried out to technical scheme, this
A little equivalents belong to protection scope of the present invention.It is further to note that described in above-mentioned embodiment
Each particular technique feature, in the case of reconcilable, can be combined by any suitable means.In order to avoid not
Necessary repetition, the present invention no longer separately illustrate to various combinations of possible ways.In addition, a variety of implementations of the present invention
It can also be combined between mode, as long as it without prejudice to the thought of the present invention, it is public that it should equally be considered as institute of the invention
The content opened.
Claims (7)
1. the quinoxaline derivant of the skeleton containing phenylhydrazide, its structural formula is represented by a formula X：
Wherein, R is hydrogen, halogen, alkyl, nitro, alkoxy, haloalkyl.
2. the synthetic method of the quinoxaline derivant of the skeleton containing phenylhydrazide described in claim 1, it is characterised in that：Including：
,
Wherein, R is hydrogen, halogen, alkyl, nitro, alkoxy, haloalkyl.
3. the synthetic method of the quinoxaline derivant of the skeleton according to claim 1 containing phenylhydrazide, it is characterised in that：Chemical combination
In the step of 1 prepare compound 2 of thing, reaction dissolvent is ethanol.
4. the synthetic method of the quinoxaline derivant of the skeleton according to claim 1 containing phenylhydrazide, it is characterised in that：Chemical combination
In the step of 3 prepare compound 4 of thing, reaction dissolvent is water.
5. the synthetic method of the quinoxaline derivant of the skeleton according to claim 1 containing phenylhydrazide, it is characterised in that：Chemical combination
In the step of 4 prepare compound 5 of thing, reaction dissolvent is dimethylformamide.
6. the synthetic method of the quinoxaline derivant of the skeleton according to claim 1 containing phenylhydrazide, it is characterised in that：Chemical combination
In the step of 5 prepare compound 6 of thing, reaction dissolvent is ethanol.
7. application of the quinoxaline derivant of the skeleton containing phenylhydrazide described in claim 1 in antineoplastic is prepared.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110698418A (en) * | 2019-09-11 | 2020-01-17 | 广西师范大学 | 3-arylamino quinoxaline-2-formamide derivative and preparation method and application thereof |
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| CN110698418B (en) * | 2019-09-11 | 2022-07-01 | 广西师范大学 | 3-arylamino quinoxaline-2-formamide derivative and preparation method and application thereof |
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