CN100528886C - Metal complex with liriodenine as ligand and its synthesis process and use - Google Patents
Metal complex with liriodenine as ligand and its synthesis process and use Download PDFInfo
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- CN100528886C CN100528886C CNB2006100203196A CN200610020319A CN100528886C CN 100528886 C CN100528886 C CN 100528886C CN B2006100203196 A CNB2006100203196 A CN B2006100203196A CN 200610020319 A CN200610020319 A CN 200610020319A CN 100528886 C CN100528886 C CN 100528886C
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Abstract
The present invention relates to metal complex with lirodenine as ligand and its preparation process. The preparation process of the metal complex includes: dissolving metal salt and lirodenine in the molar ratio of 1 to 1-3 in polar solvent, reaction at 20-100 deg.c, filtering to obtain the precipitate, purifying and drying to obtain the metal complex. Or, the preparation process includes: dissolving metal salt and lirodenine in the molar ratio of 1 to 1-3 in polar solvent, reaction at 60-150 deg.c in vacuum condition, eliminating solvent after reaction, purifying and drying to obtain the metal complex. The metal complex has antitumor activity higher than that of lirodenine and high medicinal value, and may be used in preparing various kinds of antitumor medicine.
Description
(1) technical field:
The present invention relates to metal complex, is the metal complexes of part with the liriodendrin particularly, the invention still further relates to the preparation method and use of this metal complexes.
(2) background technology:
The luxuriant and rich with fragrance isoquinoline alkaloid of A Piao is the series alkaloid that a class has strong pharmacologically active, is analgesic as A Piaofei; O-methylatheroline,noraporphine, liriodendrin then are the alkaloids with remarkable anti-tumor activity, and existence and its anti-tumor activity of the planarity of this quasi-molecule and assorted N atom, methylene-dioxy and ketonic oxygen group have remarkable relation.Liriodendrin (Liriodenine) is a kind of luxuriant and rich with fragrance isoquinoline alkaloid of a kind of A Piao that is present in the Chinese medicinal plant such as Magnoliaceae, Rutaceae, to the alkaloidal research situation of Liriodendron, mainly comprise two aspects from present: on the one hand in the plant of never equal genus (as Magnoliaceae, annonaceae, Rutaceae etc.) it being carried out dose and composition analysis; On the other hand, then be to the particularly research of anti-tumor activity of its pharmacologically active, the investigator has carried out extensive studies and has obtained bigger progress the pharmacological action of liriodendrin, experimental results show that liriodendrin has antitumor significantly, antiviral, bacteriostatic activity, antimycotic and antibacterium breeding effect, recent research then is directed to its antitumous effect and anti-HIV effect more, as find that liriodendrin has significant inhibitory effect to the growth of Human Lung Cancer cell A549, can bring out the apoptosis of cancer cells, and its mechanism of action has been carried out the comparatively discussion of system.But at present, be part and synthetic has the metal complexes of pharmacologically active with natural pharmacological component liriodendrin, and the synthetic method of this type of title complex and pharmacology activity research, disclosed achievement in research and technology report is not arranged as yet.
(3) summary of the invention:
It is the metal complexes of part with the liriodendrin that the present invention will disclose a kind of; The present invention also will disclose the preparation method and use of above-mentioned metal complexes.
From traditional herbal medicine, extract effective pharmacological component, and with various metal ion effects with physiologically active, synthetic have synergistic metal matrix lead compound, is a brand-new direction of the inorganic pharmacochemistry and the modernization of Chinese medicine.The present invention then is, and to be part with the liriodendrin that itself has better antitumous effect synthetic with main group metal or transition metal, particularly exist with occurring in nature, also have many-sided pharmacologically active such as antitumor, antibacterial or the generally acknowledged necessary multiple metallic element of human body and synthesize, obtain a series of metal complexes.
The molecular formula of liriodendrin is C
17H
9NO
3, molecular weight is 275g/mol, structural formula is as follows:
In this molecular structure, heterocycle N atom and carbonyl O atom have stronger coordination ability, can form following coordination mode in coordination reaction: (LA of the following stated is called for short for the liriodendrin part)
N, O bidentate chelating mode: two atoms of N, O and central metal M huge legendary turtle with liriodendrin are closed coordination, form five-ring huge legendary turtle zoarium.With the difference of metal M ligancy, the ratio that ligand L A can form amount of substance with metal M is the title complex of 1: 1,2: 1,3: 1 types.The complex structure formula of gained is suc as formula (I):
Wherein, M represents certain metallic element, is selected from the transition metal or the main group metal of the periodic table of elements.
When selecting transition metal, preferably select for use itself have anti-tumor activity element such as Pt (II), Pt (IV), Ag (I), Au (I), Au (III), Ru (II), Pd (II), Ti (IV), Mo (O), Co (III) etc. synthesize, because these elements itself promptly have certain anti-tumor activity, itself and the liriodendrin with better anti-tumor activity are synthesized, and the anti-tumor activity of the title complex of gained is generally higher; And select for use the necessary element of generally acknowledged human body such as Mn (II), Fe (II), Co (II), Ni (II), Cu (II), Zn (II) etc. synthetic, then because these elements itself are the element of needed by human, liriodendrin is synthetic preferably with itself and anti-tumor activity, also is easier to obtain anti-tumor activity better and can play the title complex of certain beneficial effect to human body.Can preferentially select Pt (II), Pt (IV), Ag (I), Au (III), Ru (II), Pd (II), Ti (IV), Mo (O), Co (II), Mn (II), Fe (II), Zn (II), Cu elements such as (II) and liriodendrin synthetic.And by various anti-tumor activity tests, particularly, kinds of tumor cells such as cancer of the stomach, cervical cancer, nasopharyngeal carcinoma, ovarian cancer there is higher restraining effect by Pt (II), Pt (IV), Ag (I), Au (III), Ti (IV), Mo (O), Zn (II), Cu transition metal and liriodendrin synthetic title complexs such as (II).
When selecting main group metal, preferably select the element such as Ga (III), Sn (II), the Sn (IV) etc. that itself promptly have anti-tumor activity for use, because these elements itself promptly have certain anti-tumor activity, itself and the liriodendrin with better anti-tumor activity are synthesized, and the anti-tumor activity of the title complex of gained is generally higher; And select for use the necessary element of generally acknowledged human body such as Mg (II), Ca (II) etc. to synthesize, then because these elements itself are the element of needed by human, liriodendrin is synthetic preferably with itself and anti-tumor activity, also is easier to obtain anti-tumor activity better and can play the title complex of certain beneficial effect to human body.Particularly, kinds of tumor cells such as cancer of the stomach, cervical cancer, nasopharyngeal carcinoma, ovarian cancer there is higher restraining effect by Sn (IV) element and liriodendrin synthetic title complex.
Can adopt methods such as solution method, solvent-thermal method to synthesize with N, the described title complex of O bidentate chelating mode synthetic formula (I):
Synthetic with solution method, step is as follows:
1), be that 1: 1～3 metal-salt and liriodendrin part are dissolved in the polar solvent with the molar weight ratio according to the ratio of the amount of substance of ligand L A in the metal complexes and metal M expection; The polar solvent consumption can be any amount, and dissolved metal salt being as the criterion, consumption generally can be 10～200ml; Any metal-salt of transition metal or main group metal all can synthesize; And described polar solvent can be polar solvent arbitrarily, as water, methyl alcohol, ethanol, acetone, dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, acetonitrile, pyridine, chloroform etc., also can be the mixed solvent that two or more solvent mixes with any proportional quantity among them, also can be other polar solvent that can dissolve liriodendrin and metal-salt or the mixed solvent that mixes with any proportional quantity of other two or more polar solvent certainly; During concrete operations, both liriodendrin and metal-salt together can be dissolved in the polar solvent, also can earlier metal-salt and part be dissolved in respectively in the polar solvent, again hybrid reaction gradually;
2) solution of gained is at 20～100 ℃ temperature range internal reaction; Generally will be controlled in the reaction times 1～24 hour, the productive rate of the product of gained can reach the target productive rate greater than 50%; Therefore generally reaction times and temperature of reaction are controlled at above-mentioned scope and get final product, certain reaction times also can be more than 24 hours; When solution reaction, should select suitable reaction environment according to the character of reactant, for example for photosensitive material and readily oxidizable substance, need take lucifuge and inert atmosphere conditions etc. respectively;
3) will react back solution and filter, the precipitation of getting solution is purified, drying, obtains the corresponding metal title complex.The described method that the precipitation of solution is purified can adopt water, ethanol, methyl alcohol, acetone isopolarity solvent wash precipitation, wherein unreacted metal salt, part or other by product, Impurity removal; And with dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, acetonitrile, pyridine, chloroform equal solvent or the dissolution with solvents metal-salt, the part that form with two or more solvent among them, when synthesizing, the product that generates can be dissolved among these solvents, as long as at this moment the product that will be dissolved in the solvent extracts, as adopt following method to extract, 1) carries out underpressure distillation and desolvate, product is separated out, regather solid to remove; Certainly the temperature of underpressure distillation is decided on concrete solvent, and the solvent that boiling point is high more is temperature required high more; 2) remove most of solvent with underpressure distillation after, adding can be with former solvent be miscible but another kind of solvent not lysate is separated out product, refilters, washing gets final product; 3) for volatile solvent, as chloroform, directly volatilization can be separated out solid product.Certainly the product that also can adopt other method will be dissolved in the solvent extracts.
Synthetic with solvent-thermal method, step is as follows:
1), gets the molar weight ratio and be 1: 1～3 metal-salt and liriodendrin part and put into polar solvent according to the ratio of the amount of substance of ligand L A in the metal complexes and metal M expection; The polar solvent consumption can be any amount, also can need not LA and metal-salt are all dissolved, and consumption generally can be 0.5～3ml; Identical with solution method, any metal-salt of transition metal or main group metal all can synthesize; And described polar solvent can be polar solvent arbitrarily, as water, methyl alcohol, ethanol, acetone, dimethyl sulfoxide (DMSO), dimethyl formamide, N,N-DIMETHYLACETAMIDE, acetonitrile, pyridine, chloroform etc., also can be the mixed solvent that two or more solvent mixes with any proportional quantity among them, also can be other polar solvent that can dissolve liriodendrin and metal-salt or the mixed solvent that mixes with any proportional quantity of other two or more polar solvent certainly; During concrete operations, both liriodendrin and metal-salt together can be placed polar solvent, also can earlier metal-salt and part be placed polar solvent respectively, again hybrid reaction gradually;
2) mixing solutions of gained is placed under 60～150 ℃, vacuum condition and react; Generally will be controlled in the reaction times 1～24 hour, the productive rate of the product of gained can reach the target productive rate greater than 50%; Therefore generally reaction times and temperature of reaction are controlled at above-mentioned scope and get final product, certain reaction times also can be more than 24 hours;
3) the reaction back is removed and is desolvated, and solid product purification, drying with gained obtain the corresponding metal title complex; The method that described solid product is purified can adopt water, ethanol equal solvent to wash the solid product of gained, incites somebody to action wherein unreacted metal salt, part or other by product, Impurity removal.
The present invention is a part with natural radioactivity pharmaceutical component liriodendrin, synthesized the series of gold metal complex with the multiple metallic element in main group metal and the transition metal, by investigating its restraining effect to multiple knurl strain, the result shows that wherein multiple title complex has shown than liriodendrin part notable antitumor activity more, have very high pharmaceutical use, can be used for various preparing anti-tumor medicine.
(4) embodiment:
Embodiment 1: with the synthetic cis-platinum class Pt of solution method
II-LA title complex
Cis-platinum metal complexes [Pt
II. (C
17H
9NO
3) .Cl
2], have anti-tumor activity, under the condition of determining structure, will help to study the structure activity relationship of cis-platinum class medicine more, the present invention has synthesized this kind cis-platinum class title complex with following synthetic route, and synthesis step is as follows:
The K of 1mmol
2PtCl
4Be dissolved in the water of 10ml, the LA of 1mmol is dissolved in 50ml, the 70 ℃ of ethanol, and after two solution mixed, 70 ℃ of following stirring reactions 10 hours, this was reflected at lucifuge condition, inert atmosphere (N
2) under carry out; After reaction finishes, reduce to 25 ℃, obtain producing the sedimentary solution of red-purple; Filtering solution, precipitation with washing, ethanol washes, removing impurity and unreacted reactant, 40 ℃ of vacuum-drying 12 hours obtains the red-purple solid.This product process infrared spectra,
1H nucleus magnetic resonance and ultimate analysis test are defined as cis-platinum class title complex [Pt
II. (C
17H
9NO
3) .Cl
2].
Embodiment 2: with the synthetic Ru of solution method
II-LA title complex
Ru
IIMetal complexes has potential anti-tumor activity, Ru
IIBe considered to Pt
IIThe desirable surrogate of metal complexes antitumor drug, and Ru
IIThe toxic side effect of self is than Pt
IILow, it has good application prospects as antitumor drug, and the present invention has obtained this kind metal complexes with following synthesis step:
0.5 gram RuCl
3.3H
2O is back flow reaction in the DMSO of 3mL, promptly temperature 190 ℃, the reaction 10 minutes, obtain dark red solution; After reducing to 25 ℃, add the 25mL anhydrous propanone in this solution, after mixing, placed 24 hours under-4 ℃ of conditions, separate out yellow crystals, this is intermediate product RuCl
2(DMSO)
4
1mmol intermediate product RuCl
2(DMSO)
4Be dissolved in the chloroform of 25ml; The LA of 1mmol is dissolved in the chloroform of 25mL, 60 ℃ of two kinds of solution hybrid reactions 6 hours, obtains blackish green solution after the reaction; This solution evaporation falls the reaction solvent chloroform, so that product reaches supersaturation and separates out, promptly obtains the deep green solid, and this is product [RuCl
2(DMSO)
2(C
17H
9NO
3)].
Embodiment 3: with the synthetic Fe of solvent-thermal method
II-LA title complex
At one end in the heavy wall Glass tubing of opening, add 0.1mmol FeCl
2.4H
2O and 0.1mmol LA, add the mixed solvent that mixes by 1mL ethanol and 0.5mL water again, under the condition that vacuumizes, with another opening end sealing by fusing, under 110 ℃ of conditions, to react 24 hours then, the reaction back is removed and is desolvated, getting the red solid of gained washes with washing, ethanol, removing unreacted reactant and impurity, 40 ℃ of vacuum-drying 12 hours obtains red solid product FeCl
2(C
17H
9NO
3)
2
Embodiment 4: with the synthetic Mo of solution method
0-LA title complex
1mmol Mo (CO)
6Be dissolved in the 10mL ethanol; 1mmol LA is dissolved in 40mL, the 60 ℃ of ethanol, and after two solution mixed, reaction solution became green; At N
2Under the atmosphere, reaction solution must be brown muddy liquid after 60 ℃ of following lucifuges stir 5 hours; Solution filters, and obtains brown precipitate, and is with the brown precipitate thorough washing, colourless until washings with ethanol, 40 ℃ of vacuum-drying 12 hours, brown solid.This product through infrared spectra,
1H nucleus magnetic resonance and ultimate analysis test are defined as title complex Mo
0(C
17H
9NO
3) (CO)
4
Embodiment 5: with the synthetic Pd of solution method
II-LA title complex
The K of 1mmol
2PdCl
4Be dissolved in the water of 10ml, the LA of 1mmol is dissolved in 50ml, 70 ℃ the ethanol, and after two solution mixed, 70 ℃ of following stirring reactions 10 hours, this was reflected under lucifuge condition, the inert atmosphere (Ar) and carries out; After reaction finishes, reduce to 25 ℃, obtain producing the sedimentary solution of red-purple; Filtering solution, the precipitation of gained with washing, ethanol washes, removing impurity and unreacted reactant, 40 ℃ of vacuum-drying 12 hours obtains the red-purple solid.This product process infrared spectra,
1H nucleus magnetic resonance and ultimate analysis test are defined as title complex [Pd
II. (C
17H
9NO
3) .Cl
2].
Embodiment 6: with the synthetic Ag of solution method
I-LA metal complexes
Under the lucifuge condition, the AgNO of 1mmol
3Be dissolved in the water of 10ml, the LA of 1mmol is dissolved in 50ml, the 70 ℃ of ethanol, after two solution mix, 70 ℃ of following stirring reactions 4 hours, reduces to 25 ℃ then, obtains producing orange-yellow sedimentary solution; Solution is filtered, and the precipitation of gained is washed with washing, ethanol, and removing impurity and unreacted reactant, 40 ℃ of vacuum-drying 12 hours obtains orange/yellow solid.This product through infrared spectra,
1H nucleus magnetic resonance and ultimate analysis test are defined as title complex Ag
I(C
17H
9NO
3) .NO
3
Embodiment 7: with the synthetic Au of solution method
III-LA metal complexes
2mmol H[AuCl
4] .4H
2O is dissolved in the 5mL water, and 2mmolKOH is dissolved in the 5mL water, dropwise reaction, reaction solution pH=7～8 of gained; 1mmol LA is dissolved in the 50mL ethanol, and it is dropped in the aforesaid reaction solution, produce orange-yellow precipitation gradually; 70 ℃ of following stirring reactions 4 hours are reduced to 25 ℃ then, obtain producing orange-yellow sedimentary solution; Solution is filtered, and the precipitation of gained is washed with washing, ethanol, and removing impurity and unreacted reactant, 40 ℃ of vacuum-drying 12 hours obtains orange/yellow solid.This product through infrared spectra,
1H nucleus magnetic resonance and ultimate analysis test are defined as title complex [Au
III(C
17H
9NO
3) Cl
2]
+.[Au
IIICl
4]
-
Embodiment 8: with the synthetic Ti of solution method
IV-LA metal complexes
1mmol K
2TiO (C
2O
4)
2.2H
2O is dissolved in the 20mL water; The LA of 1mmol is dissolved in 40mL ethanol, and it is added dropwise to K
2TiO (C
2O
4)
2.2H
2In the aqueous solution of O, produce salmon precipitation; 70 ℃ of following stirring reactions 4 hours are reduced to 25 ℃ then, obtain producing the solution of salmon precipitation; Solution is filtered, and the precipitation of gained is washed with washing, ethanol, 40 ℃ of vacuum-drying 12 hours, orange red solid.This product through infrared spectra,
1H nucleus magnetic resonance and ultimate analysis test are defined as title complex Ti
IVO (C
17H
9NO
3) C
2O
4
Embodiment 9: solvent-thermal method synthesizes Co
II-LA metal complexes
At one end in the heavy wall Glass tubing of opening, add 0.1mmol Co (ClO
4)
2.6H
2O and 0.1mmolLA, the mixed solvent that adds 1mL ethanol and 0.5mL water again, under the condition that vacuumizes,, under 110 ℃ of conditions, reacted 24 hours then another opening end sealing by fusing, the reaction back is removed and is desolvated, the red solid of getting gained is washed with washing, ethanol, removing unreacted reactant and impurity, and 40 ℃ of vacuum-drying 12 hours, obtain the red solid product, i.e. metal complexes [Co
II(C
17H
9NO
3)
2(C
2H
5OH)
2]. (ClO
4)
2
Embodiment 10: solvent-thermal method synthesizes Mn
II-LA metal complexes
At one end in the heavy wall Glass tubing of opening, add 0.1mmol MnCl
2.4H
2O and 0.1mmol LA, the mixed solvent that adds 1mL ethanol and 0.5mL water again, under the condition that vacuumizes,, under 110 ℃ of conditions, reacted 24 hours then another opening end sealing by fusing, the reaction back is removed and is desolvated, the red solid of getting gained is washed with washing, ethanol, removing unreacted reactant and impurity, and 40 ℃ of vacuum-drying 12 hours, obtain the garnet solid, i.e. metal complexes Mn
II(C
17H
9NO
3)
2Cl
2
Embodiment 11: solvent-thermal method synthesizes Zn
II-LA metal complexes
At one end in the heavy wall Glass tubing of opening, add 0.15mmol ZnCl
2With 0.2mmol LA, the mixed solvent that adds 1mL ethanol and 0.5mL water again, under the condition that vacuumizes,, under 110 ℃ of conditions, reacted 24 hours then another opening end sealing by fusing, the reaction back is removed and is desolvated, the red solid of getting gained is washed with washing, ethanol, removing unreacted reactant and impurity, and 40 ℃ of vacuum-drying 12 hours, obtain red solid, this product through infrared spectra,
1H nucleus magnetic resonance and ultimate analysis test are defined as title complex Zn
II(C
17H
9NO
3)
2Cl
2
Embodiment 12: solution method is synthesized Sn
IV-LA metal complexes
1mmol SnCl
4.5H
2O is dissolved in the 10mL water; Be added dropwise in the 40mL ethanolic soln of 1mmol LA, reaction solution becomes redness by yellow; 80 ℃ of following stirring reactions 4 hours, reaction solution is reduced to 25 ℃, has obtained the sedimentary solution of bright red; Solution filters, and the precipitation of gained is with washing with alcohol, 40 ℃ of vacuum-drying 12 hours, the red solid product.This product through infrared spectra,
1H nucleus magnetic resonance and ultimate analysis test are defined as title complex Sn
IV(C
17H
9NO
3) Cl
4
Embodiment 13: solution method is synthesized Pt
IV-LA metal complexes
1mmol K
2PtCl
6Be dissolved in 15mL, the 70 ℃ of water 2mmol AgNO
3Be dissolved in the 5mL water, after two solution drip to mix, promptly produce yellow mercury oxide,, reduce to 25 ℃ 70 ℃ of following lucifuge stirring reactions 2 hours, filter light-yellow precipitate; The precipitation of gained removes by filter undissolved white AgCl precipitation with 5mL DMSO dissolving, drips the 40mL ethanol liquid of 1mmol LA in the yellow filtrate of gained, and reaction solution promptly becomes orange, after 8 hours, is the turbid liquid of pale brown color contamination at 80 ℃ of following stirring reactions; 90% solvent is removed in decompression, adds 50mL water then, places 12 hours after reducing to 25 ℃, produces yellow mercury oxide, gets precipitation and washes with washing, ethanol, and 40 ℃ of vacuum-drying 12 hours obtains pale brown look solid.This product process infrared spectra,
1H nucleus magnetic resonance and ultimate analysis test are defined as title complex [Pt
IV. (C
17H
9NO
3) .Cl
4].
Embodiment 14: with the synthetic Cu of solvent-thermal method
II-LA metal complexes
At one end in the heavy wall Glass tubing of opening, add 0.1mmol Cu (ClO
4)
2.5H
2O and 0.2mmolLA, the mixed solvent that adds 1ml ethanol and 1ml water again, under the condition that vacuumizes, with another opening end sealing by fusing, under 110 ℃ of conditions, to react 24 hours then, the reaction back is removed and is desolvated, getting the red solid of gained washes with washing, ethanol, removing unreacted reactant and impurity, 40 ℃ of vacuum-drying 12 hours obtains purple solid product [Cu
II(C
17H
9NO
3)
2(C
2H
5OH)
2]. (ClO
4)
2
Experimental example 1:
Table 1 and table 2 have been listed the preliminary antitumor activity screening result to multiple metal complexes:
Table 1:
Annotate:
1, all drug levels are every milliliter of 10 microgram, and DMSO concentration is 1% in the end-body system;
2, data are under above-mentioned concentration inhibiting rate percentage ratio to various tumour cells in the table;
3, inhibiting rate is greater than 0.50, and promptly 50% is effectively (the effective standard of monomer is: concentration must be less than every milliliter of 10 microgram during 50% inhibiting rate);
4, subscript a, b represent that respectively synthetic method is solvent-thermal method and solution method;
5, the KB in the table refers to that nasopharyngeal carcinoma cell, KBV200 refer to that anti-vincristine(VCR) bacterial strain, the MDA-MB-231 of nasopharyngeal carcinoma cell refer to breast cancer cell.
Table 2:
(SGC-7901 is human stomach cancer cell line, and the hela cell is human cervical cancer cell strain, and cne-1 and cne-2 are human human nasopharyngeal epithelioma 1, and skov3 is the strain of ovarian cancer taxol resistance)
Annotate: screening method and condition are as follows:
1. cell strain and cell cultures
Mammary cancer MDA-MB-231 and laryngeal cancer cell KB and persister KBv200 cell thereof, human stomach cancer cell line SGC-7901, human hela cell strain hela cell, human human nasopharyngeal epithelioma 1 cne-1 and cne-2, ovarian cancer taxol resistance strain skov3 etc. are selected in this experiment for use.The KBv200 cell than the KB cell to about 100 times of VCR (vincristine sulphate) resistance, well-grown when VCR concentration is 200nmol/L.The all cells strain is all cultivated in the RPMI-1640 nutrient solution that contains the little ox blood of 10wt%, 100 ∪/ml penicillin, 100 ∪/ml Streptomycin sulphate, puts 37 ℃ and contains volumetric concentration 5%CO
2Cultivate in the incubator.Add VCR during the KBv200 cell cultures and keep its multidrug resistance, 1 week of drug withdrawal before the experiment.
2.1 primary dcreening operation
According to one of judgement criteria of antitumor drug curative effect, promptly external inhibition test: the half-inhibition concentration IC of synthetic compound or the pure product of plant milk extract
50The IC of＜10 μ g/ml or plant crude extract
50＜20 μ g/ml, and cytotoxic dose-dependence, and the highest inhibition efficient should reach more than 80%, judges that then sample has lethal effect at external pair cell.This research compound used therefor, purity higher (〉=95%), so anticaustic this antitumor drug therapeutic evaluation standard is mixed with 10 μ g/ml with all compounds, solubility promoter DMSO final concentration≤1wt%, test under this concentration compound to the inhibition of cancer cells, all inhibiting rates are greater than 50% and meet the metamorphosis that cell under the light microscopic is subjected to press down (as cell shrinkage, fragmentation, floating etc.), it is effective then to be judged to be primary dcreening operation, enters next step and asks IC
50The two is in full accord on anti-tumor activity is judged as a result, and wherein each compound 10 μ g/ml inhibiting rate primary dcreening operation result is as described in table 1 and the table 2.
2.2 cell growth inhibition test (mtt assay)
Annotate: mtt assay is a tetramethyl-azo azoles salt trace enzyme reaction colorimetry.MTT is a kind of thiazole salt, chemical name 3-(4,5-dimethyl-2-thiazole)-2, and 5-phenylbenzene bromination tetrazolium, the aqueous solution is yellowish-orange.English MTT by name, and promptly ([4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazoliumbromide);
According to table 1,2, the primary dcreening operation antitumous effect is tried title complex preferably, behind the DMSO hydrotropy, use perfect medium half-and-half to be diluted to five gradients successively, 20 times to the working fluid of final concentration, and except that the drug level difference, solubility promoter DMSO equal size is all consistent between each gradient.Be 4 ℃ of preservations of filtering with microporous membrane degerming of 0.22um again with diameter.With MDA-MB-231, the KB of logarithmic phase and KBv200 cell etc., be inoculated in 96 orifice plates respectively with every hole 0.19ml, cell concn is about 0.5 * 10 successively
4/ hole, 0.4 * 10
4/ hole, 0.5 * 10
4/ hole, after cultivation 12h treats cell attachment, the test-compound that adds different concns respectively, every hole 10 μ L, make its final concentration be respectively 12 μ g/ml, 6 μ g/ml, 3 μ g/ml, 1.5 μ g/ml, 0.75 μ g/ml, each gradient is established 4 multiple holes, DMSO final concentration≤0.5wt% wherein, establish corresponding negative control group simultaneously and (have only cell and equivalent DMSO in the nutrient solution, no medicine) and the blank group (medicine that has only equivalent in the nutrient solution, acellular), each group is also established 4 multiple holes, drug effect 48h.4h adds 10 μ L MTT (5mg/ml PBS) before cultivating end, after continuing to cultivate 4h, nutrient solution inclines, add DMSO 0.15ml, dull and stereotyped oscillator vibration 5min fully dissolves crystallisate, the zeroing of blank group, measure to remove absorbancy (A) value after the bias light absorption value with microplate reader with the 550nm/655nm dual wavelength, calculate the IC of each compound respectively various cancer cells with the Bliss method
50Value, all experiments repeat 3 times.IC
50The result is as follows for value:
Below be cell inhibition concentration (IC after measured with anti-tumor activity metal complexes
50Value) tabulation: IC
50(μ g/mL) is inhibition rate of tumor cell and reaches 50% o'clock required complex solution concentration, the μ g/mL of unit.
(1) tumour cell is subjected to examination system one
(KB, KBV200, MDA-MB-231 are respectively oral squamous carcinoma cell strain, the anti-vincristine(VCR) strain of oral epithelium cancer and breast carcinoma cell strain)
(2) tumour cell is subjected to examination system two
(3) tumour cell is subjected to examination system three
(SGC-7901 is human stomach cancer cell line, and the hela cell is human cervical cancer cell strain, and cne-1 and cne-2 are human human nasopharyngeal epithelioma 1, and skov3 is the strain of ovarian cancer taxol resistance)
Claims (4)
1, with the liriodendrin be the metal complexes of part,
It is characterized in that: described metal complexes is Ag
I(C
17H
9NO
3) .NO
3, [Au
III(C
17H
9NO
3) Cl
2]
+.[Au
IIICl
4]
-, [Pt
II. (C
17H
9NO
3) .Cl
2], Sn
IV(C
17H
9NO
3) Cl
4, Ti
IVO (C
17H
9NO
3) C
2O
4, Mo
0(C
17H
9NO
3) (CO)
4Or [Pt
IV. (C
17H
9NO
3) .Cl
4], their structural formula respectively is:
2, claim 1 is described is the preparation method of the metal complexes of part with the liriodendrin, and its step is as follows:
1) be that 1: 1～3 metal-salt and liriodendrin part are dissolved in the polar solvent with the molar weight ratio;
2) solution of gained reacts under 20～100 ℃;
3) will react back solution and filter, the precipitation of getting solution is purified, drying, obtains the corresponding metal title complex.
3, claim 1 is described is the preparation method of the metal complexes of part with the liriodendrin, and its step is as follows:
1) getting the molar weight ratio is that 1: 1～3 metal-salt and liriodendrin part place polar solvent;
2) mixing solutions of gained is placed under 60～150 ℃, vacuum condition and react;
3) the reaction back is removed and is desolvated, and solid product purification, drying with gained obtain the corresponding metal title complex.
4, claim 1 is described is the application of metal complexes in the preparation antitumor drug of part with the liriodendrin.
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| CN102260293B (en) * | 2011-05-04 | 2013-08-28 | 广西师范大学 | Transition metal coordination compounds with oxoglaucine as ligand, synthesizing method thereof, and application thereof |
| CN103421048B (en) * | 2013-08-23 | 2015-08-19 | 广西师范大学 | The different aporphine of one Chlorodimethyl sulfoxide 6-hydroxyl oxidize closes platinum (II) and synthetic method thereof and application |
| CN104387423A (en) * | 2014-11-07 | 2015-03-04 | 广西师范大学 | Platinum (II) complex by taking chiral compound as ligand as well as synthetic method and application of platinum (II) complex |
| CN104478908A (en) * | 2014-12-12 | 2015-04-01 | 广西师范大学 | Zinc and cobalt metal complex taking nantenine oxide as ligand as well as synthetic method and application thereof |
| CN104558054A (en) * | 2014-12-12 | 2015-04-29 | 广西师范大学 | Metal complex taking oxidized nantenine as ligand and synthetic method and applications thereof |
| CN104774221B (en) * | 2015-03-19 | 2017-02-08 | 广西师范大学 | Metal complexes of quinolinone derivatives, synthesis method and applications thereof |
| CN104725431B (en) * | 2015-03-19 | 2017-05-17 | 广西师范大学 | Cobalt (II) complex of quinolinone derivative, and synthesis method and application thereof |
| CN104744520A (en) * | 2015-04-17 | 2015-07-01 | 广西师范大学 | Ruthenium and rhodium metal complexes taking lysicamine as ligands as well as synthetic method and application of ruthenium and rhodium metal complex |
| KR102542467B1 (en) | 2017-11-08 | 2023-06-12 | 삼성전자주식회사 | Organometallic compound, organic light emitting device including the same and a composition for diagnosing including the same |
| CN109320534B (en) * | 2018-11-30 | 2021-04-06 | 广西师范大学 | Oxidized bicuculline rare earth complex and synthesis method and application thereof |
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