CN103467497B - The two part copper complex being part with salicylidene taurine and imidazoles and synthetic method thereof and its purposes - Google Patents
The two part copper complex being part with salicylidene taurine and imidazoles and synthetic method thereof and its purposes Download PDFInfo
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- CN103467497B CN103467497B CN201310395131.XA CN201310395131A CN103467497B CN 103467497 B CN103467497 B CN 103467497B CN 201310395131 A CN201310395131 A CN 201310395131A CN 103467497 B CN103467497 B CN 103467497B
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Abstract
The invention discloses a kind of with salicylidene taurine and imidazoles two part copper complex that is part and synthetic method thereof and its purposes, the chemical formula of copper complex of the present invention is C
24h
26cu
2n
6o
8s
2.The present invention with salicylidene taurine and imidazoles for part and copper salt have synthesized this pair of part copper (II) metal complexes, and this title complex of gained is then better general to tumour cell external activity by experiment, particularly gastric carcinoma cells MGC-803, human liver cancer cell BEL-7404, Be very effective; And to normal cell HL-7702 cytotoxicity, comparatively cis-platinum is low, is applicable to preparation efficient, the antitumor drug of low toxicity.
Description
Technical field
The present invention relates to metal coordination chemistry, particularly with the copper metal complexes that salicylidene taurine and imidazoles are part, and the preparation method and use of this metal complexes.
Background technology
Platinum antineoplastic preparation as cis-platinum, carboplatin, oxaliplatin all achieves great success, but it has intrinsic limitation, as resistance, serious toxicity and other side effect.These shortcomings make inorganic chemist attempt find more effective, toxicity is lower, particular target to, the cancer therapy drug of non covalent bond.Recently, because the important physiologically active of the title complex of ruthenium and copper and oxidizing property cause numerous researchists' interest, be expected to become the cancer therapy drug that alternative cis-platinum becomes a new generation.For taking copper as metal coordination centers, and with coordinate the copper schiff bases of ligands, copper schiff bases shows anti-microbial activity and anti-malignant cell proliferation is active.As everyone knows, some antitumor drugs by binding, to revise and the DNA that splits plays their effect, substantially with three kinds of binding modes: 1, electrostatic interaction 2, groove face bonding action 3, Insertion action.In the past few decades, copper complex and DNA combination are widely studied.The mechanism of action of copper complex is also widely studied, and the cytotoxicity of copper complex may be itself and DNA bonding or cut off DNA and cause cell-cycle arrest and apoptosis or generate active oxygen effect making necrocytosis.
Taurine, as the batching in dietary supplements and functional foodstuff and beverage, causes the attention of chemist.But some taurine presence of Schiff-base complex are in the news, and have antiviral, anticancer and anti-microbial activity.It is reported, the schiff bases based on taurine shows various coordination mode.And the interaction of aromaticring stacking can stablize the stability of Schiff base metal complexes, this aromaticring stacking also can make medicine and DNA stabilization.The copper metal complexes antitumour activity of single part is generally not as two part or multiple ligand synergistic copper metal complexes antitumour activity; Therefore; we have selected salicylidene taurine and imidazoles two kinds of parts two part copper metal complexess that to have synthesized with salicylidene taurine and imidazoles be part, and not yet have disclosed report with the synthesis of salicylidene taurine and imidazoles two part copper metal complexess that are part and pharmacologically active thereof.
At present, for structural modification and the transformation of known compound, synthesizing efficient, the antitumor potent agent of low toxicity is the focus of researching and developing new drug now, particularly bio-inorganic chemistry, subject crossing application between coordination chemistry, many metal complexess with anti-tumor activity are as cis-platinum, and dioiganotin compounds has been synthesized and some are for clinical.In this case, be expected to have remarkable antitumour activity with salicylidene taurine and imidazoles for copper (II) metal complexes of the two part of part is used for clinical trial, this is extremely significant work.
Summary of the invention
The present invention is directed to the deficiencies in the prior art, and a kind of two part copper metal complexess being part with salicylidene taurine and imidazoles are provided, and the synthetic method of this metal complexes and its purposes.
With the copper metal complexes that salicylidene taurine and imidazoles are part, described metal ion is copper (II) ion, and the chemical formula as the salicylidene taurine of the first part is C
9h
9nO
4sK
2, structural formula is:
Structurally, because of containing the N of stronger coordination ability, O and suitable sterie configuration, can as the good chelating ligand of metal ion for salicylidene taurine.
Chemical formula as the imidazoles of Ligands is C
3h
4n
2, structural formula is:
Imidazoles structurally has large π key conjugated system, the nitrogen-atoms of stronger coordination and very little sterically hindered, can be used as the good monodentate of metal ion or bridgingligand.
The chemical formula of copper (II) title complex that the present invention is part with salicylidene taurine and imidazoles is for C
24h
26cu
2n
6o
8s
2,structural formula is:
During synthesis, copper forms pentacoordinate dual-core architecture: each copper atom has salicylic aldehyde to provide an oxygen atom ligand respectively, and taurine provides two bridging Sauerstoffatoms and a nitrogen-atoms coordination, and imidazoles provides a nitrogen coordination; The bridging Sauerstoffatom formation dual-core architecture that two copper atoms are provided by taurine.
The synthetic method of two part copper (II) metal complexess that the present invention is part with salicylidene taurine and imidazoles is for solution method, and concrete quantitatively synthesis step is as follows:
1) by 20mmol (2442.4mg) taurine and 20mmol(1122.0mg) potassium hydroxide is dissolved in the ethanol of 20ml, stirs 15min, obtained solution, the sylvite of solvable taurine more easily and salicylic aldehyde react;
2) above-mentioned dropwise instillation 20ml is added with in the ethanolic soln of 20mmol salicylic aldehyde, yellow mercury oxide is obtained in 45-50 DEG C of return stirring reaction 2-3h, because stirring action can make can there be better collision between molecule or ion, contact, reaction is made to carry out more abundant, more completely; Reflux also makes reaction faster more complete; General thermal creep stress will consider the molten boiling point of solvent, reactant decomposition temperature etc., and this temperature of reaction is 50 DEG C, is determined heat-up time by speed of response speed, general 2 to 48 hours, and this reaction is very fast, 2-3 hour;
3) the above-mentioned gained yellow mercury oxide rear ethanol of filtration and ether are respectively washed 2-3 time, in order to remove unreacted reactant and other by product; After drying, obtaining part is pure yellow salicylidene taurine crystallization;
4) Cu (OAc) is got
2h
2o (1mmol, 199.65mg) is dissolved in 10ml ethanol, is added drop-wise in the 15ml aqueous solution containing 1mmol salicylidene taurine part, in 55-65 DEG C of return stirring 4-5h, add solid ligand imidazoles (1mmol, 68.07mg) again, in 55-65 DEG C of return stirring 7-8h; In this step, salicylidene taurine part first with cupric coordination after, imidazoles will again with cupric coordination relative difficult, by reflux with extend the method in reaction times and make its coordination;
5) after reacting, solution filters, filtrate adds water: ethanol contend is than the mixed solvent 25ml for 3:2, this be due to salicylidene taurine and imidazoles be two part copper metal complex concentration of part excessive time be usually polycrystalline shape, be not suitable for growing monocrystalline, need reaction product to dilute;
6) after mixing, get 10ml in 25ml small beaker, preservative film seals, and volatilizees a few days in 5-6 DEG C in a pinprick 15-20 hole, two part copper (II) metal complexes deep green monocrystalline that to obtain with salicylidene taurine and imidazoles be part; Too fast in normal temperature volatilization, also easily forming polycrystalline, for obtaining monocrystalline, except the above step of needs, also needing product dilution as 4 DEG C of volatilization a few days.The structure of gained metal complexes can by ultimate analysis, infrared spectra, nucleus magnetic resonance, the analyses such as X single crystal diffraction.Finally determining this title complex is the new compound never reported, and is obtained the structure of this compound by X single crystal diffraction.
Another object of the present invention, two part copper complexes that also to provide with salicylidene taurine and imidazoles be part are preparing the utilization in antitumor drug.
Advantage of the present invention: the present invention is with salicylidene taurine and imidazoles for part and copper salt have synthesized this pair of part copper (II) metal complexes, and this synthetic method is simple, and easy to operate, cost is low, and gained title complex productive rate is higher.And this title complex of gained is then better general to tumour cell external activity by experiment, particularly gastric carcinoma cells MGC-803, human liver cancer cell BEL-7404, Be very effective; And to normal cell HL-7702 cytotoxicity, comparatively cis-platinum is low, is applicable to preparation efficient, the antitumor drug of low toxicity.
Accompanying drawing explanation
Fig. 1 is the molecular structure of embodiment gained copper (II) metal complexes;
Fig. 2 is that embodiment gained copper (II) metal complexes is by the axial structure cell accumulation graph of a;
Fig. 3 is embodiment gained copper (II) metal complexes induction gastric carcinoma cells MGC-803 apoptosis figure;
Fig. 4 is that embodiment gained copper (II) metal complexes affects gastric carcinoma cells MGC-803 periodogram.
Embodiment:
Embodiment:
Two part copper (II) metal complexess that synthesis is part with salicylidene taurine and imidazoles.
By the taurine of 20mmol (2442.4mg) and 20mmol(1122.0mg) potassium hydroxide be dissolved in the ethanol of 20ml, stir 15min, obtained solution; Be added with in the ethanolic soln of 20mmol salicylic aldehyde by above-mentioned dropwise instillation 20ml, obtain yellow mercury oxide in 50 DEG C of return stirring reaction 2h, gained yellow mercury oxide is respectively washed 3 times, after drying with ethanol and ether, is obtained part salicylidene taurine after filtering; Get Cu (OAc)
2h
2o (1mmol, 199.65mg) is dissolved in 10ml ethanol, is added drop-wise in the 15ml aqueous solution containing 1mmol salicylidene taurine part, in 60 DEG C of return stirring 4h, then adds solid ligand imidazoles (1mmol, 68.07mg) in 60 DEG C of return stirring 8h; After reacting, solution filters, and filtrate adds water: ethanol contend is than the mixed solvent 25ml for 3:2; After mixing, get 10ml in 25ml small beaker, preservative film seals, pinprick 20 holes in 4 DEG C of volatilization a few days, two part copper (II) metal complexes green crystals that to obtain with salicylidene taurine and imidazoles be part.
Experimental example: salicylidene taurine and imidazoles are the anti-tumor activity experiment of two part copper (II) metal complexess of part.
1) cell strain and cell cultures
Tumor cell line MGC-803, BEL-7404, A549, SK-OV-3 and normal cell strain HL-7702, all come from theAmericanTypeCultureCollection (Rockville, MD, USA), cell is in 5% incubator 37 DEG C of volumetric concentrations, with being added with 10% foetal calf serum and 100 μ gmL
-1streptomycin sulphate, the DMEM culture medium culturing of 100 units per ml penicillin.
2) cell growth inhibition test (mtt assay)
Note: MTT full name is 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide, Chinese chemistry 3-(4 by name, 5-mtt.html'target='_blank'> dimethylthiazole-2)-2,5-diphenyltetrazolium bromide bromine salt, trade(brand)name: mtt.html'target='_blank'> tetrazolium bromide.It is a kind of dyestuff of yellow color.
Be that two part copper (II) metal complexess of part are with after DMSO hydrotropy by salicylidene taurine and imidazoles; perfect medium is used to be diluted to five gradients successively; 20 times to the working fluid of final concentration, between each gradient except drug level difference, solubility promoter DMSO equal size is all consistent.Being that the filtering with microporous membrane of 0.22um is degerming with diameter is again placed in 4 DEG C of preservations.By the tumor cell line MGC-803 of logarithmic phase, BEL-7404, A549, SK-OV-3 and normal cell HL-7702, be inoculated in 96 orifice plates respectively with every hole 0.18ml, cell concn is about 0.4-0.5 × 10
4/ hole, cultivate 12h after cell attachment, add the test-compound of different concns respectively, every hole 20ul, final concentration is made to be respectively 0 μM, 20 μMs, 40 μMs, 80 μMs of each gradients establish 4 multiple holes, wherein DMSO final concentration is less than 0.5%, corresponding negative control group is set simultaneously and (in nutrient solution, only has cell and equivalent DMSO, without medicine), often organize and 4 multiple holes are also set, after drug effect 48h, incline nutrient solution, add 100 μ lDMSO, plate shaker concussion 10min, crystallisate is fully dissolved, blank group returns to zero, absorbancy (A) value after removing end absorbance value is measured with 550nm/655nm dual wavelength by microplate reader, with Bliss method difference computerized compound to tumor cell line MGC-803, BEL-7404, A549, the IC of SK-OV-3 and normal cell HL-7702
50value, all experiment repetitions 3 times.Experimental result in table 1, can find out this salicylidene taurine and imidazoles be two part copper metal complexess of part to the cytotoxicity of normal people's quasi-liver cell HL-7702 lower than cis-platinum; And to the cytotoxicity of tumour cell MGC-803, BEL-7404 apparently higher than cis-platinum.
The cytotoxicity of table 1 title complex
Note: MGC-803 is gastric carcinoma cells, and BEL-7404 is human liver cancer cell, and A549 is human lung carcinoma cell, and SK-OV-3 is Proliferation of Human Ovarian Cell, and HL-7702 is normal liver cell.
3) cell apoptosis assay analysis
With the monolayer cell that tryptic digestion converges, by cell harvesting in the substratum containing serum, in each hole of flat 6 orifice plates, add 2ml cell suspension with sample injector, every hole adds 5 × 10
3-100 × 10
3individual cell, puts culture plate to CO
2in incubator; incubation in 37 DEG C of moist environments; treat cell attachment; after adding copper (II) the metal complexes process for the two part of part with salicylidene taurine and imidazoles of the same concentration of above-mentioned preparation in tumour cell; combine with acridine orange and ethidium bromide and cell is dyeed; utilize fluorescence inverted microscope, the apoptosis situation that qualitative detection is copper (II) the metal complexes inducing tumor cell of the two part of part with salicylidene taurine and imidazoles.As shown in Figure 3, control group is green, and be yellow-green colour after apoptosis, have apoptotic body to occur, result shows, title complex can induce the apoptosis of human tumor cells MGC-803.
4) cell cycle experimental analysis
Flow cytometry test concentration is 0,5 μMs, 10 μMs, and 20 μMs of salicylidene taurines and imidazoles are after two part copper metal complexes effect MGC-80348h of part, the cell of PI dyeing; Result shows, as shown in Figure 4, the concentration of title complex increases, S issue amount is increased to 63.19% from 48.08%, and G1 and the G2 phase obviously reduces, illustrate that this copper complex can affect the cell cycle by the S phase, postpone or T suppression cell cycle progression, the ratio of apoptotic cell, from 5 to 20 μMs, presents dose-dependently.
Body outer suppressioning experiment shows, the title complex of gained is then better general to tested tumour cell external activity, particularly gastric carcinoma cells MGC-803, human liver cancer cell BEL-7404, Be very effective; And to human normal cell line HL-7702 cytotoxicity, comparatively cis-platinum is low, is applicable to preparation efficient, the antitumor drug of low toxicity.
Claims (2)
1. the two part copper complexes being part with salicylidene taurine and imidazoles are preparing the application in antitumor drug, it is characterized in that: the chemical formula of described title complex is C
24h
26cu
2n
6o
8s
2, structural formula is:
It is as follows that the synthetic method of described title complex comprises step:
1) by 20mmol (2442.4mg) taurine and 20mmol(1122.0mg) potassium hydroxide is dissolved in the ethanol of 20ml, stirs 15min, obtained solution;
2) above-mentioned dropwise instillation 20ml is added with in the ethanolic soln of 20mmol salicylic aldehyde, obtains yellow mercury oxide in 45-50 DEG C of return stirring reaction 2-3h;
3) the above-mentioned gained yellow mercury oxide rear ethanol of filtration and ether are respectively washed 2-3 time, after drying, obtain part salicylidene taurine;
4) 1mmol (199.65mg) Cu (OAc) is got
2h
2o is dissolved in 10ml ethanol, is added drop-wise in the 15ml aqueous solution containing 1mmol salicylidene taurine part, in 55-65 DEG C of return stirring 4-5h, then adds 1mmol(68.07mg) solid ligand imidazoles is in 55-65 DEG C of return stirring 7-8h;
5) after reacting, solution filters, and filtrate adds water: ethanol contend is than the mixed solvent 25ml for 3:2;
6) after mixing, get 10ml in 25ml small beaker, preservative film seals, and volatilizees a few days in 5-6 DEG C in a pinprick 15-20 hole, two part copper (II) metal complexes green crystals that to obtain with salicylidene taurine and imidazoles be part.
2. application according to claim 1, is characterized in that: described chemical formula C
24h
26cu
2n
6o
8s
2middle metal ion is copper (II) ion, and the chemical formula as the salicylidene taurine of the first part is C
9h
9nO
4sK
2, structural formula is:
Chemical formula as the imidazoles of Ligands is C
3h
4n
2, structural formula is:
。
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