CN104606191A - Application of carbohydrazide in preparing brain cancer preventing medicine - Google Patents
Application of carbohydrazide in preparing brain cancer preventing medicine Download PDFInfo
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Abstract
The invention discloses application of a compound (E)-N-furan methylene-1-(3-(6-chloropyridine) methyl)3-phenyl-1H-pyrazol-5-carbohydrazide in preparing a brain cancer preventing medicine, wherein the brain cancer is glioma. Experiments verify that the compound disclosed by the invention has an obvious effect in inhibiting brain cancer cell proliferation and inducing apoptosis and lays a foundation for developing novel brain cancer preventing medicines.
Description
Technical field
The present invention relates to the application of a kind of pyrazoles acyl hydrazone derivative in the anti-brain cancer medicine of preparation, particularly relate to the application of one (E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide in the anti-brain cancer medicine of preparation.
Background technology
The brain cancer compares the one of refractory in cancer, the large percentage that in the brain cancer, glioma is occupied, and glioma is called for short glioma, occurs in neural ectoderm, originate from neural Interstitial cell.In various glioma, the most common with astroglioma, be secondly glioblastoma multiforme etc.
The method of the current treatment brain cancer mainly comprises surgical excision, radiotherapy and chemotherapy, these therapies to the life of patient less than 15 months.Common drug is temozolomide (TMZ) clinically, its external IC
50value is 100 μMs, and clinical trial display temozolomide combines radiotherapy and patient's life span can be extended to 14 months, and the survival rate of 2 years reaches 26.5%.
Acylhydrazone shows the pharmacologically actives such as good antiinflammatory, sterilization, convulsion, antitumor, anti-diabetic, tuberculosis pathogenic bacteria because of its special chemical constitution-CONHN=CH-.The acyl hydrazone derivative described in the patent JP52027775 reported for work, US3513165, US3972905, US5122368, EP0398305 has antiinflammatory, sterilization, convulsion, antitumor, antiviral pharmacologically active; Benzal benzoyl hydazone derivative involved by patent WO02/070464 has antibacterial activity.But, in acylhydrazone chemical constitution is introduced, pyrazole compound forms (E)-N-fural-1-(3-(6-chloropyridine) the methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide compound of new synthesis, and studies the application of this compound in the anti-brain cancer medicine of preparation and have not been reported.
Summary of the invention
For clinical in brain cancer Treatment need at present, the object of the present invention is to provide the application of one (E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide in the anti-brain cancer medicine of preparation.
The chemical structural formula of (E) of the present invention-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide is:
The application of (E) of the present invention-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide in the anti-brain cancer medicine of preparation; Wherein, the described brain cancer refers to glioma.Described glioma is human glioma cell U87MG specifically.
Above-claimed cpd can effectively suppress brain cancer cell (human glioma cell U87MG) to grow, and causes apoptotic concentration to be preferably 20 μMs.
Experiment confirms: (E) of the present invention-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide is suppressing brain cancer cell propagation and causing in apoptosis to have obvious effect, for novel anti-brain cancer drug development provides the foundation.
The effect of essence for a better understanding of the present invention and compound of the present invention, below in conjunction with pharmacological evaluation and the result of (E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide, set forth it further in the growth of suppression brain tumor cell, the effect caused in apoptosis.
The preparation of neuroglial cytoma: cultivate human body brain glioblastoma cell U87MG in conventional manner, collect growth conditions good and be in the cell of logarithmic (log) phase, for subsequent use.
Celluar and Molecular Biology method is adopted to test as follows, to observe (E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide to the impact of human body brain glioblastoma cell U87MG apoptosis.
1. inverted microscope observation of cell form, the i.e. formation of apoptotic body
Collect logarithmic (log) phase human body brain glioblastoma cell U87MG and normal cell, respectively add (E)-N-fural-1-(3-(6-chloropyridine) the methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide of 10 μMs or 20 μMs, process 24h, 72h and 96h, the formation of basis of microscopic observation human body brain glioblastoma cell U87MG morphological change and apoptotic body, found that the cell after (E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide process 24h can find the formation of apoptotic body and obvious morphological change (see Fig. 1) compared with cellular control unit.
2.Annexin-V staining detection compound effect brain cancer cell is to apoptosis-inducing situation
Collect logarithmic (log) phase human body brain glioblastoma cell U87MG, add (E)-N-fural-1-(3-(6-chloropyridine) the methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide of 10 μMs or 20 μMs, Annexin-V dyeing is carried out after acting on 12h, 24h, 48h, 72h respectively, by flow cytometry Annexin-V fluorescence intensity, found that the effect of (E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide to human body brain glioblastoma cell U87MG has concentration and time dependence (see Fig. 2).
3.WTS-1 method detects the activity of cell dehydrogenase, carries out dosage effect analysis
Human body brain glioblastoma cell U87MG is inoculated in 96 orifice plates, after (E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide process 24h and 48h of variable concentrations (100,50,20,10,5,1,0.1,0.01 μMs), detect the activity of succinate dehydrogenase respectively by WST-1 method, calculate survival rate.
Survival rate=(during experimental group absorbance-dosing 0h absorbance) ÷ (during matched group OD value-dosing 0h absorbance) (with not celliferous culture fluid for absorbance measurement blank background).
Experimental result shows (E), and-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide acts on human body brain glioblastoma cell U87MG, and the concentration IC of effective Developing restraint
50be 18.6 μMs of (R
2=0.9771), experimental group cell survival rate comparatively matched group significantly to reduce and in dose dependent.
4.TUNEL dye marker Apoptosis
Collect logarithmic (log) phase human body brain glioblastoma cell U87MG, use (E)-N-fural-1-(3-(6-chloropyridine) the methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide effect of 10 μMs and 20 μMs after 24 hours respectively, 25min is fixed with 1% paraformaldehyde at 0 DEG C, then after PBS eluting 70% ethanol-20 DEG C of environment under preserve and spend the night, use PBS eluting 5min again, add 5 μ lTdr Incubating Solutions, hatch 1h for 37 DEG C, SCC cessation reaction, with Flow cytometry labelling apoptotic cell, to normal group cell and experimental cell analysis of accounts, calculate its positive rate respectively.
Normal group cell: 3.47 ± 0.54%
10 μ Μ group cells: 6.04 ± 1.12%
20 μ Μ group cells: 7.58 ± 1.36%
Result shows: (E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide can cause apoptosis.
5.GFP-LC3 method detects cell growth status, to judge the impact of compound on autophagy
The GFP labelling U87MG cell being in exponential phase is inoculated in 96 orifice plates, after (E)-N-fural-1-(3-(6-chloropyridine) the methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide effect 48h of 20 μMs, with the change of confocal laser scanning microscope GFP albumen, find (E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide function cells 48h, comparatively matched group fluorescence becomes point-like, and the generation (Fig. 4) of autophagy is described.
Above-mentioned experimental data is through statistical procedures, and experimental data represents with mean+/-standard error, and through t inspection, P<0.05, indicates explicitly difference.
To sum up, compound of the present invention (E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide optionally can kill human body brain glioblastoma cell U87MG, cause apoptosis and autophagy simultaneously, find that it has obvious dose dependent, IC by dose-effect relationship research
50be about 20 μMs, this is compared with the first-line drug of the present clinical treatment brain cancer, and active anticancer is stronger.Experimental result indication (E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide is expected to the potential anticarcinogen becoming selective induction brain cancer apoptosis of tumor cells and autophagy and effective treatment intractable brain cancer, has very large development prospect.
Accompanying drawing explanation
At different temporal induction human body brain glioblastoma cells U87MG metamorphosis situation (× 200) after (E)-N-fural-1-(3-(6-chloropyridine) the methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide function cells of Fig. 1 variable concentrations of the present invention.
Fig. 2 Annexin-V staining detects the relative situation of change of fluorescence that (E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide effect on human body brain glioblastoma cell U87MG causes.
Fig. 3 compound (E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide acts on human body brain glioblastoma cell U87MG 24h, flow cytometry cell cycle stage after TUNEL dyeing.
Display (E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide causes human body brain glioblastoma cell U87MG apoptosis, and by cell cycle arrest at G
2/ M the phase.
(E)-N-fural-1-(3-(6-chloropyridine) the methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide effect U87MG-GFP-LC3 cell of Fig. 4 GFP-LC3 methods analyst 20 μMs inducing cell generation autophagy situation after 48 hours.
Wherein: A is cellular control unit, B is the U87MG cell of GFP labelling, and comparatively matched group fluorescence becomes point-like, and the generation of autophagy is described.
Detailed description of the invention
Embodiment 1
(E) preparation of-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide
1) in the round-bottomed flask of 100 milliliters, add potassium carbonate (0.005 mole), 3-phenyl-1H-pyrazole-5-ethyl formate (0.005 mole), CCMP (0.005 mole) and acetonitrile (25 milliliters), device reflux condenser, top connects drying tube.Reflux 4 hours, reacts to raw material and consumes completely, with TLC detection reaction terminal.Concentrating under reduced pressure, remove solvent, add ethyl acetate (30 milliliters), filter, filtrate concentrates, make eluant silica gel column chromatography with ethyl acetate-light petrol (V/V=1/2) and be separated residue (100 ~ 200 order silica gel), obtain 1-(3-(6-chloropyridine) methyl)-3-Phenylpyrazole-5-carboxylic acid, ethyl ester, productive rate is 87%.
2) in methanol (5 milliliters) solution of 0.341 gram of (0.001 mole) 1-(3-(6-chloropyridine) methyl)-3-Phenylpyrazole-5-carboxylic acid, ethyl ester, add the hydrazine hydrate of 1.2 milliliter 80%, stirring and refluxing reacts 1 hour, reaction to raw material consumes, completely with TLC detection reaction terminal.Hold over night, separates out solid, and filter, decompress filter obtains crude product; Obtain high-purity 1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide with 8 milliliters of ethyl alcohol recrystallizations, productive rate is 86%.
3) obtain 0.328 gram of (0.001 mole) 1-benzyl-3-(4-chlorphenyl)-1H-pyrazoles-5-carbohydrazide and 0.096 gram of (0.001 mole) furtural are joined in 10 milliliters of ethanol, back flow reaction 8 hours, reaction to raw material consumes, completely with TLC detection reaction terminal; Hold over night, separates out white solid, and filter, decompress filter obtains crude product; Obtain high-purity (E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide with 12 milliliters of ethyl alcohol recrystallizations, productive rate is 98%.
Structural formula is as follows:
Molecular formula: C
21h
16clN
5o
2
Molecular weight: 405.84
Character: white solid
Fusing point: 210-212 DEG C
Nuclear magnetic resonance data is as follows:
1H-NMR(300MHz,CDCl
3+DMSO)δ:5.86(s,2H,CH
2),6.51(s,1H,FuH),6.87(s,1H,FuH),7.24(s,1H,4-H),7.27-7.43(m,5H,ArH,PyH,FuH),7.55-7.83(m,3H,ArH,PyH),8.31(s,1H,＝CH),8.50(s,1H,PyH),11.57(s,1H,NH).
Ir data is as follows:
IR(KBr)ν:3204-3049(NH),1649(C＝O)cm
–1.
Mass spectrometric data is as follows:
MS(EI):m/z 406.6(M+H)
+。
Embodiment 2
Selectivity Anticancer Activity Analysis
Two kinds of cell lines (human body brain glioblastoma cell U87MG, the HegG2 cell that form is similar to human normal cell) are adopted to carry out active anticancer screening to the compound that the present invention synthesizes in conventional manner.
At 37 DEG C containing 5%CO
2environment under, with DMEM culture medium culturing human body brain glioblastoma cell U87MG, 1640 culture medium culturing HepG2 cells, collect U87MG and the HepG2 cell of logarithmic (log) phase, to be inoculated in 96 orifice plates (2 × 10
4individual/hole), the compounds of this invention through variable concentrations (100,50,20,10,5,1,0.1,0.01 μMs) is added after hatching 24h, after effect 24h, every hole adds 10 μ lWST-1, after continue to hatch 2h, the method being detected its absorbance by euzymelinked immunosorbent assay (ELISA) detects cell survival rate, carries out dose-effect relationship research.
Survival rate=(during experimental group absorbance-dosing 0h absorbance) ÷ (during matched group OD value-dosing 0h absorbance) (with not celliferous culture fluid for absorbance measurement blank background).
Through SigmaPlot software analysis the compounds of this invention (E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide to the half lethal dose (IC of brain cancer cell
50) be 18.6 μMs of (IC
50value is lower than 20 μMs), 100 μMs are then higher than to HepG2.
Embodiment 3
(E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide affects the Time-effect relationship of cell proliferation and cellular morphology
Collect U87MG and the HepG2 cell of logarithmic (log) phase, be inoculated in 96 orifice plates, 37 DEG C also containing 5%CO
2environment under hatch 24h after, add compound of the present invention (E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide with the variable concentrations of 0,10,20 μM, after effect 24h, 72h and 96h, observe the impact (the results are shown in Figure 1) of compound on U87MG cell proliferation and form respectively.Result sees that action time is longer, the effect of compound on intracellular is stronger, and the effect of (E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide to U87MG cell has time dependence.
Embodiment 4
(E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide is to the apoptosis induction of brain cancer cell
Anticarcinogen plays its effect by inducing apoptosis of tumour cell usually.In order to the ability of preliminary assessment compound inducing apoptosis of tumour cell of the present invention, with Annexin-V staining and this compound effects of flow cytometry after cell to the apoptosis induction situation of cell.
By concentration 10 μMs, (E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide of 20 μMs and 37 DEG C, U87MG cell and containing 5%CO
2environment under hatch altogether, 12,24,48,72h gets 1ml cell, 1000rpm respectively, 4 DEG C are centrifugal 10 minutes, abandon supernatant, add the PBS that 1ml is cold, concussion makes cell suspension, 1000rpm gently, 4 DEG C are centrifugal 10 minutes, abandon supernatant, repeat to add PBS, centrifugal twice.Use trypsinization again, then wash with PBS, cell is resuspended in 200ul Binding Buffer, adds 10ul Annexin V-FITC, mixes gently, lucifuge room temperature reaction 15 minutes.Add 300ul Binding Buffer, sampled in 1 hour, dye with fluorescent dye Annexin-V, flow cytometry fluorescence intensity, the dependency (the results are shown in Figure 2) of result display (E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide and concentration free to U87MG cytosis.
Embodiment 5
TUNEL staining examine apoptosis
TUNEL dyeing is used for the degree of apoptosis of detecting and assessing cell, and this analytical method terminal transferase marker DNA end, by representational DNA fragmentation in Flow cytometry apoptosis situation, analyzes the situation of apoptosis.
Collect logarithmic (log) phase human body brain glioblastoma cell U87MG, (E)-N-fural-1-(3-(6-chloropyridine) the methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide of 10 μMs, 20 μMs is contained 5%CO at 37 DEG C
2environment under act on U87MG cell 24h, centrifugal collecting cell, abandon supernatant, 25min is fixed with 1% paraformaldehyde at 0 DEG C, then through PBS eluting, 70% ethanol-4 DEG C of pre-cooling fixedly spends the night, centrifugal collecting cell, PBS eluting 5min, after, add 5 μ lTdr Incubating Solutions, hatch 1h for 37 DEG C, SCC cessation reaction, with Flow cytometry labelling apoptotic cell, result shows, after the compound effects cell 24h of 10 μMs, 20 μMs, apoptosis rate is respectively 6.04 ± 1.12% and 7.58 ± 1.36%, and normal control cells is only 3.47 ± 0.54%.
Embodiment 6
(E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide induction brain cancer cell is arrested in the G2/M phase
Take the logarithm the human body brain glioblastoma cell U87MG of trophophase, and adjustment cell concentration is 1X10
6/ ml, is inoculated in 6 orifice plates with 1ml volume, is adding (E)-N-fural-1-(3-(6-chloropyridine) the methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide 0.5ml that concentration is 20 μMs, at 37 DEG C containing 5%CO
2environment under act on U87MG cell 24h, centrifugal collecting cell, abandons supernatant, washes cell twice with pre-cooling PBS, add pre-cooling 70% ethanol, fixedly spend the night in 4 DEG C, centrifugal collecting cell, washes cell once with the PBS of 1ml, add 500uLPBS containing 50ug/ml ethidium bromide (PI), 100ug/ml RNase A, 0.2%Triton X-100,4 DEG C of lucifuges hatch 30 minutes.With standardization program flow cytomery, result cell cycle fits software ModFit and analyzes.
Result shows: compound (E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide can induce brain cancer cell to be arrested in the G2/M phase (the results are shown in Figure 3).
Embodiment 7
(E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide causes cell autophagy situation analysis
Human body brain glioblastoma cell U87MG LZRS-GFP-LC3B-IRES-ZEO retrovirus is carried out transfection, obtain the U87-GFP-LC3 cell carrying green fluorescence, (E)-N-fural-1-(3-(6-chloropyridine) the methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide of this cell and 20 μMs is contained 5%CO at 37 DEG C
2condition under when acting on 72h after, use confocal microscopy analysis, compared with matched group, the cell green fluorescence of experimental group becomes point-like (the results are shown in Figure 4), and the generation of autophagy is described.
Claims (3)
1. the application of (E)-N-fural-1-(3-(6-chloropyridine) methyl)-3-phenyl-1H-pyrazoles-5-carbohydrazide in the anti-brain cancer medicine of preparation.
2. apply as claimed in claim 1, it is characterized in that: the described brain cancer is glioma.
3. apply as claimed in claim 2, it is characterized in that: described glioma is human glioma cell U87MG.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114057646A (en) * | 2021-12-14 | 2022-02-18 | 常州大学 | Pyrazole derivative and application thereof in preparation of antitumor drugs |
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| CN101121711A (en) * | 2007-09-19 | 2008-02-13 | 山东大学 | Pyrazolcarbazone derivatives and application thereof |
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2015
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101121711A (en) * | 2007-09-19 | 2008-02-13 | 山东大学 | Pyrazolcarbazone derivatives and application thereof |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114057646A (en) * | 2021-12-14 | 2022-02-18 | 常州大学 | Pyrazole derivative and application thereof in preparation of antitumor drugs |
| CN114057646B (en) * | 2021-12-14 | 2023-05-02 | 常州大学 | Pyrazole derivative and application thereof in preparation of antitumor drugs |
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Application publication date: 20150513 |