CN109369687A - A kind of copper complex with anti-tumor activity, Its Preparation Method And Use - Google Patents

A kind of copper complex with anti-tumor activity, Its Preparation Method And Use Download PDF

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CN109369687A
CN109369687A CN201811323020.7A CN201811323020A CN109369687A CN 109369687 A CN109369687 A CN 109369687A CN 201811323020 A CN201811323020 A CN 201811323020A CN 109369687 A CN109369687 A CN 109369687A
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copper complex
tumor activity
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copper
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顾运琼
胡飞龙
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Guangxi Teachers College
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    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
    • C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic Table without C-Metal linkages
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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Abstract

The present invention provides a kind of copper complex, preparation method and its applications with anti-tumor activity.The copper complex anti-tumor activity with higher and lower cytotoxicity, it is especially stronger to the killing ability of Human Bladder Transitional Cell Carcinoma cell (T-24), the efficient inducing apoptosis of tumour cell of energy, but it is relatively low to the toxicity of normal human liver cell strain (HL-7702), be expected to exploitation be novel efficient, wide spectrum, less toxic side effect treatment of cancer chemotherapeutics, belong to the pioneer invention of this field.The synthetic method of the copper complex with anti-tumor activity is simple and practical, low in cost, reproducible, and product purity and yield are high, has extensive industrial value, is conducive to commercialized popularization and application.

Description

A kind of copper complex with anti-tumor activity, Its Preparation Method And Use
Technical field
The present invention relates to chemically synthesized technical fields, cooperate in particular to a kind of copper with anti-tumor activity Object and preparation method thereof and the copper complex are used to prepare the purposes of anticancer drug.
Background technique
The metal ion being widely present in nature all plays an important role to environment, medicine, biology, chemical science.Its Although content is very low in vivo for some heavy metals and transition metal ions in, due to they mostly with metalloprotein and The form of metalloenzyme exists, and participates in during the intracorporal many important reactions of biology and information transmitting, energy transfer etc., to life The metabolism development of object has important influence, and important position is also taken up in medical chemistry.Copper is the micro of needed by human body Element plays an important role during the basic physiological of various organisms.Copper is the prothetic group of a variety of enzymes in human body, cupric Enzyme mostly using the derivative of oxygen molecule or oxygen as substrate.As cytochrome oxidase, dopamine beta-hydroxy enzyme, monoamine oxidase, Tyrosinase, cytosolic superoxide mutase etc..Ceruloplasmin can be catalyzed Fe2+It is oxidized to Fe3+, the latter is transferred to transferrin, has Conducive to the transport of iron.
The concentration and tumour of Copper in Serum occur, tumor load, and malignancy of tumor progress and tumor recurrence have close connection System, including meat cancer, leukemia, cervical carcinoma, liver cancer, lung cancer, the cancer of the brain and breast cancer.For example, copper rises in Tumor Angiongesis To important role.Although effect of the copper in the angiogenesis of cancerous tissue is simultaneously not known, recent x-ray fluorescence Research shows that a large amount of cell migrations of copper and extensive rearrangement in angiogenesis in cell.This discovery shows in blood vessel The conversion of copper may promote the migration of the protein of copper in generating process.The chelating agent of copper can pass through the albumen with carrying copper in this way Matter Competition hinders the angiogenesis of cancer, to inhibit the function and Tumor Angiongesis of the protein of dependence copper.
Many tumour cells can be enriched with the copper ion of high concentration.People using this characteristic of tumour cell by some and copper from The high ligand of sub- compatibility, which is added in tumour cell, forms it with proteasome inhibition activity with intracellular copper ion Compound, due to copper content very little in normal cell, the complex concentration of formation is also minimum, therefore its damage to normal cell Evil very little；On the contrary, the copper ion for the high concentration being enriched in tumour cell, so that it may form the proteasome inhibitor of higher concentration So as to cause apoptosis of tumor cells.Therefore some anti-copper reagent play certain effect in tumor therapeutic procedure, so system A kind of anticancer drug of standby cupric is very important.
Summary of the invention
In view of this, providing one kind has the technical problem to be solved in the present invention is that overcoming the deficiencies of existing technologies Copper complex of anti-tumor activity and preparation method thereof and the copper complex are used to prepare the purposes of anticancer drug.
The preparation method of the copper complex with anti-tumor activity, comprising the following steps:
S1: chloro- -4 picoline of 3- cyano of 2,6- bis-, hydrazine hydrate being mixed to dissolution, are condensed back, and cooling precipitation is yellowish Color solid filters, and washing obtains light yellow intermediate A after drying；
S2: weighing 1- phenyl -1,3- diacetyl, instills in the intermediate A after being dissolved in ethanol solution, cooling after reaction It to room temperature, filters, washing, drying obtains yellow ligand L；
S3: in the yellow ligand L and six Hydrated copper chlorides, being added dropwise second alcohol and water, be uniformly mixed, and heating obtains shallow Green strip crystal I, after the light green color strip crystal I water and ethanol washing, vacuum drying obtains the copper and matches Close object.
In some embodiments, 2mmol 2 is taken in the S1,4mmol water is added in chloro- -4 picoline of 3- cyano of 6- bis- Hydrazine is closed, shakes up to chloro- -4 picoline of 3- cyano of 2, the 6- bis- and dissolves.
In some embodiments, after chloro- -4 picoline of 3- cyano of 2,6- bis- described in the S1 and hydrazine hydrate dissolve, Cooling that faint yellow solid is precipitated in 120 DEG C of condensing reflux 3h, filtering with ice ethanol washing, obtains light yellow intermediate after drying A。
In some embodiments, the yield of light yellow intermediate A obtained in the S1 is 93.6%.
In some embodiments, 3mmol 1- phenyl -1,3- diacetyl is taken in the S2, the ethyl alcohol for being dissolved in 35mL is molten It instills in the intermediate A and is reacted after liquid.
In some embodiments, reaction temperature is 80 DEG C in the S2, reaction time 2h.
In some embodiments, it is cooled to room temperature after being reacted in the S2, filters, washed with ether, drying obtains institute State yellow ligand L.
In some embodiments, the yield of yellow ligand L obtained in the S2 is 82.8%.
In some embodiments, in the S3 in 0.023nmol yellow ligand L and six Hydrated copper chloride of 0.1nmol, 2ml ethyl alcohol and 0.5ml water is added dropwise, is uniformly mixed.
In some embodiments, in the S3, the temperature of heating is 90 DEG C, and heating time is 3 days.
In some embodiments, the yield of copper complex obtained in the S3 is 65%.
The present invention also protects the copper complex with anti-tumor activity prepared according to the above method.
The present invention also protects the copper complex to be used to prepare the application of anti-tumor drug.
In some embodiments, the tumour includes but is not limited to liver cancer, transitional cell carcinoma of the bladder, gastric cancer and uterine neck Cancer.
A kind of copper complex with anti-tumor activity provided by the invention anti-tumor activity with higher and lower Cytotoxicity, it is especially stronger to the killing ability of Human Bladder Transitional Cell Carcinoma cell (T-24), it can efficiently induce tumour cell Apoptosis, but it is relatively low to the toxicity of normal human liver cell strain (HL-7702), be expected to exploitation be novel efficient, wide spectrum, The chemotherapeutics of the treatment of cancer of less toxic side effect belongs to the pioneer invention of this field.The copper with anti-tumor activity is matched The synthetic method for closing object is simple and practical, low in cost, reproducible, and product purity and yield are high, has extensive industrial value, Be conducive to commercialized popularization and application.
Detailed description of the invention
It should be understood that the following drawings illustrates only certain embodiments of the present invention, therefore it is not construed as to model The restriction enclosed for those of ordinary skill in the art without creative efforts, can also be according to these Attached drawing obtains other relevant attached drawings.
Fig. 1 is the mass spectrogram of the copper complex；
Fig. 2 is the crystal structure figure of the copper complex；
Fig. 3 is that the copper complex acts on for 24 hours afterwards to the influence of its Apoptosis human bladder cancer cell T-24；
Fig. 4 is copper complex to the influence after human bladder cancer cell T-24 effect 8h to active oxygen in its cell；
Fig. 5 is that copper complex acts on the influence to calcium ion in its cell afterwards for 24 hours to human bladder cancer cell T-24.
Specific embodiment
Hereinafter, the various embodiments of the disclosure will be described more fully in conjunction with attached drawing.The disclosure can have various realities Example is applied, and can adjust and change wherein.Therefore, it will be retouched in more detail referring to the specific embodiment being shown in the accompanying drawings State the disclosure.It should be understood, however, that: there is no the meanings that the various embodiments by the disclosure are limited to specific embodiment disclosed herein Figure, but the disclosure should be interpreted as covering all adjustment in the spirit and scope for the various embodiments for falling into the disclosure, etc. Jljl and/or optinal plan.Description taken together with the accompanying drawings, the same element of same reference numerals.
Hereinafter, can the term " includes " used in the various embodiments of the disclosure or " may include " instruction disclosed in Function, operation or the presence of element, and do not limit the increase of one or more functions, operation or element.
In the various embodiments of the disclosure, states "or" or " at least one of A or/and B " includes listing file names with Any combination of text or all combinations.For example, statement " A or B " or " at least one of A or/and B " may include A, may include B may include A and B both.
The statement (" first ", " second " etc.) used in the various embodiments of the disclosure can be modified in various implementations Various constituent element in example, but respective sets can not be limited into element.For example, the above statement is not intended to limit the suitable of the element Sequence and/or importance.The above statement is only used for the purpose for differentiating an element and other elements.For example, the first user fills It sets and indicates different user device with second user device, although the two is all user apparatus.For example, not departing from each of the disclosure In the case where the range of kind embodiment, first element is referred to alternatively as second element, and similarly, second element is also referred to as first Element.
It should also be noted that if a constituent element ' attach ' to another constituent element by description, it can be by the first composition member Part is directly connected to the second constituent element, and " connection " third can form between the first constituent element and the second constituent element Element.On the contrary, when a constituent element " being directly connected to " is arrived another constituent element, it will be appreciated that in the first constituent element And second third constituent element is not present between constituent element.
The term used in the various embodiments of the disclosure is used only for the purpose of describing specific embodiments and not anticipates In the various embodiments of the limitation disclosure.As used herein, singular is intended to also include plural form, unless context is clear Chu it is indicated otherwise.Unless otherwise defined, otherwise all terms (including technical terms and scientific terms) used herein have There is meaning identical with the various normally understood meanings of embodiment one skilled in the art of the disclosure.The term (term such as limited in the dictionary generally used) is to be interpreted as having and situational meaning in the related technical field Identical meaning and it will be interpreted as having Utopian meaning or meaning too formal, unless in the various of the disclosure It is clearly defined in embodiment.
Embodiment
The present invention provides a kind of copper complexes with anti-tumor activity and preparation method thereof.
The preparation method of this kind of copper complex with anti-tumor activity the following steps are included:
1. the synthesis of intermediate A:
Chloro- -4 picoline of 3- cyano (0.374g, 2mmol) of 2,6- bis- is weighed, is put into the round-bottomed flask of 150mL, is delayed Slow that hydrazine hydrate (0.20g, 4mmol) is added, shaking up dissolves chloro- -4 picoline of 3- cyano of 2,6- bis- all, and 120 DEG C are condensed back to 3h is flowed, cools down after reaction, faint yellow solid is gradually precipitated, filters, with ice ethanol washing, light yellow centre is obtained after drying Body A 0.35g, yield 93.6%.1H NMR(400MHz,d-6DMSO):11.25(s,1H,Pyrazole-H),7.63(s,1H, Py-H),6.02(s,1H,-NH-),4.79(s,2H,-NH-NH2),4.09(s,2H,Pyrazole–NH2),2.41(s,3H,Py- CH3).
2. the synthesis of ligand L:
1- phenyl -1,3- diacetyl (0.50g, 3mmol) is weighed, after being dissolved in the ethanol solution of 35mL, is gradually dropped It states in resulting intermediate A, holding temperature is 80 DEG C of reaction 2h, is cooled to room temperature, and filters, is washed with ether, obtained after drying Yellow ligand L 0.29g, yield 82.8%.1H NMR(400MHz,d6-DMSO,Fig.S2):8.12(s,2H,Py-H),7.676 (s,2H,Ph-H),7.612(s,2H,Ph-H),7.492(s,1H,Ph-H),7.274(s,4H,Ph-H),6.533(s,1H, Pyrazole-H),3.34,3.005(s,3H,Pyrazole-CH3),2.773(s,3H,-CH3), 2.323 (s, 3H ,-CH3).13C NMR(100MHz,d6-DMSO, Fig.S2) δ=103.98,110.14,112.51,113.61,128.59,128.97,130.11, 144.77,145.03,147.70,150.13,154.82,158.60,158.64.HRMS:431.1971(M+H)+(calcd for C27H22N6,430.19).IR(KBr):1629,1577,1498,1443,1381,1161,1067,976cm-1.
The synthetic reaction formula of intermediate A and ligand L is as follows:
3. copper complex CuLCl2(H2O synthesis):
Ligand L (0.023mmol, 0.01g) is added in the horminess glass tube of a long 20cm thickness 0.1cm closed at one end, CuCl2·6H2Ethyl alcohol 2mL and water 0.5mL is added dropwise in O (0.1mmol, 0.0178g), and melting sealed open end, sets after mixing It is heated 3 days in 90 DEG C of baking oven, there is the crystal I of light green color rectangular-shape to generate in pipe, crystal I is taken out from pipe, respectively With a small amount of water, ethanol washing, it is dried in vacuo (yield: 65%).The crystal I for being suitble to X-ray single crystal diffraction is selected, it is brilliant to determine Body structure.IR(KBr):1626,1577,1498,1381,1364,1316,1254,1161,1068,995cm-1.Anal.Calc. (for C27H24CuCl2N6O)C 55.62；H 4.15；N 14.42%, Found.C55.70；H 4.11；N 14.37%, ESI- MS m/z:581.9[M-H]-(calcd for C27H24CuCl2N6O, 582.96), referring to Fig. 1 and Fig. 2.
The preparation method of present invention copper complex with anti-tumor activity is simple and practical, low in cost, reproducible, produces Product purity and yield are high, have extensive industrial value, are conducive to commercialized popularization and application.
The present invention also provides the copper complex anti-tumor activities with anti-tumor activity to test.Including following step It is rapid:
One, the anti-tumor activity test of copper complex
The copper complex CuLCl2(H2O molecular formula) are as follows: C27H24CuCl2N6O, molecular weight are as follows: 582.96, crystal knot Structure data are shown in Table 1.Ovarian cancer cell (SKOV-3) is selected to this experiment, human liver cancer cell in vitro strain (7402), human bladder migrates Cell carcinoma (T-24), stomach cancer cell (MGC80-3), cervical cancer cell (Hela), normal liver cell's strain (HL-7702) etc. The inhibiting rate of growth of tumour cell is shown in Table 2, to the IC of a variety of human tumor cell lines and Human normal hepatocyte strain50Value is shown in Table 3.
The crystal structural data of 1 copper complex of table
Inhibiting rate of the copper complex to each cell strain under 2 20 μM of concentration of table
IC50 value (μM) of 3 copper complex of table to each cell strain
Five kinds of tumor cell lines such as SKOV-3,7402, T-24, MGC80-3 and Hela have been carried out to compound using mtt assay Anti tumor activity in vitro test, while testing its toxicity to HL-7702 normal liver cell strain.With containing volume in primary dcreening operation experiment The culture solution of 10% newborn bovine serum of score is made into individual cells suspension, with 4 000~5 000, every hole cell inoculation to 96 holes Plate, every 190 μ L of pore volume cultivate 12h after cell is adherent, and every hole is separately added into the tested complex of various concentration (respectively 1.25,2.5,5,10,20 μ g/mL), each concentration sets 4 multiple holes in parallel, and wherein cosolvent DMSO final volume score is less than or equal to 1%, each group also sets 4 multiple holes, drug treating time 48h in parallel.10 μ L MTT (5g/L are added in the every hole 4h before culture terminates PBS), continue to cultivate 4h, DMSO (150 hole μ L/) is added in the blue crystallization of generation, and plate shaker vibrates 5min, sufficiently dissolves Crystal, last colorimetric are returned to zero with blank.After measuring removal background absorbance value with microplate reader with 570nm/630nm dual wavelength Absorbance value (OD), calculates cell proliferation inhibition rate.Inhibiting rate=(1- sample sets OD value/control group OD value) × 100%； Bliss method the Fitting Calculation IC50；All experiments are averaged after being repeated 3 times.As can be seen from the results, copper complex to 7402, T-24, The anti tumor activity in vitro of these four tumor cell lines of MGC80-3 and Hela is preferable, especially thin to Human Bladder Transitional Cell Carcinoma Born of the same parents T-24 is most strong to anti-tumor activity, IC50Value is 3.12 ± 0.13 μM, to the slightly weak of SKOV-3 cell, and just to HL-7702 The toxicity of the toxicity of normal liver cell line is weaker.Experiment two to four is all made of T-24 cell below.
Two .AO/EB dyeing detection apoptosis experiment:
It takes after being washed with PBS buffer solution in logarithmic phase cell, with trypsin digestion, 1000r/min is centrifuged 10min, Cell is collected, takes about 2mL cell suspending liquid (about 1 × 10 with blood counting chamber counting6A cell), after being inoculated in the burnt capsule of copolymerization Cell incubator is put into continue to cultivate；When the adherent length of cell monolayer is to 85% or so, the training of 10% newborn bovine serum renewed Nutrient solution, while it being separately added into copper complex stock solution by a certain concentration gradient, it is reentered into cell incubator after shaking up and is acting on For 24 hours, culture solution is discarded, PBS washs orange (AO) and Ethidium Bromide (EB) dyeing liquor of bifurcation heavy stone used as an anchor that 100 μ g/mL are added dropwise three times, 37 DEG C of dyes Color 30min discards dyeing liquor, and PBS is washed three times, and fluorescence microscopy microscopic observation photographs to record.As a result as shown in figure 3, with matching The increase of object concentration is closed, T-24 Apoptosis number increases, and cell volume becomes smaller, and Chinese red is deepened, this is the spy of Apoptosis Sign.Illustrate that this complex can expeditiously induce the apoptosis of T-24 cell.
The detection of three, active oxygen ROS:
It takes after being washed with PBS buffer solution in logarithmic phase cell, with trypsin digestion, 1000r/min is centrifuged 10min, Cell is collected, takes about 2mL cell suspending liquid (about 1 × 10 with blood counting chamber counting6A cell), it is put after being inoculated in six orifice plates Enter cell incubator to continue to cultivate；When cell monolayer it is adherent 85% or so when, the culture solution of 10% newborn bovine serum renewed, together When by a certain concentration gradient prepare copper complex stock solution respectively, cell incubator is reentered into after shaking up and is remake with 8h, is discarded Culture medium is added the DCFH-DA that 1:1000 has diluted, is placed in 37 DEG C of incubation 30min in cell incubator, runs every 3~5min It shakes up once, is then washed three times with the culture medium without serum, examined using Cytation5 cell imaging micropore board detector The case where surveying ROS variation in cell.Active oxygen radical ROS is in normal cell in a kind of balance, stable state；If Cell will be broken by extraneous stimulation, intracellular ROS level, and ROS increases, and cause to damage to cell, so as to cause thin Born of the same parents' apoptosis.DCFH-DA itself can pass through cell membrane and enter cell without fluorescence, into cell after by intracellular esterase hydrolyzed At DCFH, and DCFH cannot pass through cell membrane, and DCFH is further oxidized to the DCF of fluoresced green by intracellular active oxygen, So can reflect intracellular reactive oxygen species by the fluorescence intensity of DCF.The experimental results showed that complex can increase T- 24 intracellular reactive oxygen species.As a result as shown in figure 4, the copper complex of various concentration to T-24 cytosis 8h after, warp 5 cell imaging microwell plate detector test of Cytation, compared with blank control group T-24 cell, the cell of dosing group is aobvious Reveal apparent green fluorescence, and complex concentration is bigger, green-emitting fluorescent is more obvious, the experimental results showed that the copper complex lures It leads active oxygen in T-24 cell to increase, and then causes Apoptosis.
Four .Ca2+The detection of plasma diffusing W,Mo:
It takes after being washed with PBS buffer solution in logarithmic phase cell, with trypsin digestion, 1000r/min is centrifuged 10min, Cell is collected, takes about 2mL cell suspending liquid (about 1 × 10 with blood counting chamber counting6A cell), it is put after being inoculated in six orifice plates Enter cell incubator to continue to cultivate；When cell monolayer it is adherent 85% or so when, the culture solution of 10% newborn bovine serum renewed, together When by a certain concentration gradient distinguish copper complex stock solution, be reentered into after shaking up cell incubator effect for 24 hours, discard culture Base is added the Fluo-3AM that 1:2000 has diluted, is placed in 37 DEG C of incubation 30min in cell incubator, overturns and shakes every 3~5min It is even primary, it is then washed three times with the culture medium without serum, using 5 cell imaging microwell plate detector test of Cytation Ca in cell2+The case where ion changes.Fluo-3AM is a kind of for detecting the fluorescence probe of intracellular calcium, its own is glimmering Luminous intensity is very weak, but it can shear shape by intracellular esterase after Fluo-3AM enters cell with penetrating cell film At Fluo-3, Fluo-3 can with intracellular calcium in conjunction with and generate stronger fluorescence, and fluorescence intensity with calcium ion it is dense The raising of degree and constantly enhance.As a result as shown in figure 5, the copper complex of various concentration to T-24 cytosis for 24 hours after, with blank Group compares, the Ca in dosing group in Fluo-3AM and cell2+Ions binding fluorescence intensity is remarkably reinforced, and complex concentration is got over Greatly, fluorescence is more obvious, and tentatively illustrates that copper complex can make Ca in T-24 cell2+Ion largely discharges, so as to cause Apoptosis.
In conclusion copper complex anti-tumor activity with higher provided by the invention and lower cytotoxicity etc. are all More advantages and value, and there are no similar method in similar product and publish or use and really belong to innovation, it produces Handy and practical effect, more existing technology have effects that the multinomial of enhancement, thus more suitable for practical, and have extensive Industrial value.
It should be appreciated that although this specification is described in terms of embodiments, but not each embodiment only includes one A independent technical solution, this description of the specification is merely for the sake of clarity, and those skilled in the art should will say As a whole, the technical solution in each embodiment may also be suitably combined to form those skilled in the art can for bright book With the other embodiments of understanding.
Inventor's statement, the present invention can only for of the invention by the series of detailed descriptions listed above Row embodiment illustrates, but the present invention is not limited to the above detailed process equipment and process flow.And i.e. not Mean that the present invention should rely on above-mentioned detailed process equipment and process flow and could implement.Person of ordinary skill in the field answers This is illustrated, any improvement in the present invention, the addition of equivalence replacement and auxiliary element to each raw material of product of the present invention, specific side The selection etc. of formula, all of which fall within the scope of protection and disclosure of the present invention.

Claims (10)

1. a kind of preparation method of copper complex with anti-tumor activity, it is characterised in that: the following steps are included:
S1: chloro- -4 picoline of 3- cyano of 2,6- bis-, hydrazine hydrate being mixed to dissolution, are condensed back, cooling that pale yellow colored solid is precipitated Body filters, and washing obtains light yellow intermediate A after drying；
S2: weighing 1- phenyl -1,3- diacetyl, instills in the intermediate A after being dissolved in ethanol solution, room is cooled to after reaction Temperature filters, and washing, drying obtains yellow ligand L；
S3: in yellow ligand L and six Hydrated copper chlorides, being added dropwise second alcohol and water, be uniformly mixed, and heating obtains light green color strip Shape crystal I, after crystal I water and ethanol washing, vacuum drying obtains the copper complex.
2. the preparation method of copper complex with anti-tumor activity as described in claim 1, it is characterised in that: in the S1 2mmol 2 is taken, chloro- -4 picoline of 3- cyano of 6- bis- is added 4mmol hydrazine hydrate, shakes up to the chloro- 3- cyano -4 of 2, the 6- bis- Picoline dissolution.
3. the preparation method of copper complex with anti-tumor activity as described in claim 1, it is characterised in that: in the S1 After chloro- -4 picoline of 3- cyano of 2, the 6- bis- and hydrazine hydrate dissolution, in 120 DEG C of condensing reflux 3h, cooling precipitation is faint yellow Solid, filtering, with ice ethanol washing, obtains light yellow intermediate A after drying.
4. the preparation method of copper complex with anti-tumor activity as described in claim 1, it is characterised in that: in the S2 3mmol 1- phenyl -1,3- diacetyl is taken, is dissolved in after the ethanol solution of 35mL to instill in the intermediate A and be reacted.
5. the preparation method of copper complex with anti-tumor activity as described in claim 1, it is characterised in that: in the S2 Reaction temperature is 80 DEG C, reaction time 2h.
6. the preparation method of copper complex with anti-tumor activity as described in claim 1, it is characterised in that: in the S2 It is cooled to room temperature after reaction, filters, washed with ether, drying obtains the yellow ligand L.
7. the preparation method of copper complex with anti-tumor activity as described in claim 1, it is characterised in that: in the S3 In 0.023nmol yellow ligand L and six Hydrated copper chloride of 0.1nmol, 2ml ethyl alcohol and 0.5ml water is added dropwise, is uniformly mixed.
8. the preparation method of copper complex with anti-tumor activity as described in claim 1, it is characterised in that: the S3 In, the temperature of heating is 90 DEG C, and heating time is 3 days.
9. a kind of copper complex with anti-tumor activity, it is characterised in that: the preparation method system as described in claim 1~8 ?.
10. the copper complex in the claim 9 is used to prepare the application of anti-tumor drug, the tumour include liver cancer, At least one of transitional cell carcinoma of the bladder, gastric cancer and cervical carcinoma.
CN201811323020.7A 2018-11-08 2018-11-08 A kind of copper complex with anti-tumor activity, Its Preparation Method And Use Pending CN109369687A (en)

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Citations (3)

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