CN104725431B - Cobalt (II) complex of quinolinone derivative, and synthesis method and application thereof - Google Patents

Cobalt (II) complex of quinolinone derivative, and synthesis method and application thereof Download PDF

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CN104725431B
CN104725431B CN201510120661.2A CN201510120661A CN104725431B CN 104725431 B CN104725431 B CN 104725431B CN 201510120661 A CN201510120661 A CN 201510120661A CN 104725431 B CN104725431 B CN 104725431B
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quinolinone
polar solvent
cobalt
methyl
reaction
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CN104725431A (en
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彭艳
马凤娥
杨景枚
卢幸
吴亦明
张国海
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Guangxi Normal University
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
    • C07F15/06Cobalt compounds
    • C07F15/065Cobalt compounds without a metal-carbon linkage
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/555Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol

Abstract

The invention discloses a cobalt (II) complex of quinolinone derivative, and a synthesis method and application thereof. The synthesis method of the quinolinone cobalt complex comprises the following steps: weighing cobaltous chloride and a ligand 3-(1H-benzimidazolyl-2-yl)-6-methyl-2(1H)-quinolinone according to the stoichiometric proportion, dissolving in a polar solvent, and carrying out complexing reaction. The research of the in-vitro antitumor activity indicates that the complex has certain proliferation inhibition activity for human cervical cancer cell Hela229, human stomach cancer cell MGC-803, human liver cancer cell strain Hep G2 and BEL-7404 cell strain, and has the maximum activity for human liver cancer cell strain Hep G2. The quinolinone cobalt complex is disclosed as the following formula (I).

Description

Cobalt (II) complex of qualone derivative and its synthetic method and application
Technical field
The present invention relates to pharmaceutical technology field, and in particular to a kind of cobalt of qualone derivative (II) complex and its synthesis Method and application.
Background technology
2 (1H)-quinolinone structures are the alkaloids being widely present as quinoline in natural products, contain 2 (1H)-quinoline The compound of ketone structure has multiple biological activities, and different substitution bases are introduced on its ring or on side chain, can produce and such as resist The pharmacological activity of the wide spectrum such as tumour, anti-oxidant, anti-inflammatory.It is to work as to seek the low lead compound parent nucleus of good activity, toxicity A kind of important method of preceding research and development anti-cancer agent, because 2 (1H)-quinolinones are active preferably, structure is easy to modification, toxicity Low feature, in the design and screening of its antineoplastic that is widely used.Some have the chemical combination of 2 (1H)-quinolinone skeletons Thing comes into clinic as antineoplastic, for example:Many Weis are that a kind of orally active small molecule is more for Buddhist nun (Dovitinib) Target spot tyrosine kinase inhibitor, can be done directly on tumour cell and the blood vessel and matrix of nutrition is provided for tumour cell, By antiproliferative activity and anti-angiogenic existence activity, antitumor action is shown;Tipifarnib (Tipifanib) belongs to farnesyl Inhibitors, it can prevent the activation of Ras oncogene by suppressing the protein of farnesylation, suppress cell life It is long, inducing cell apoptosis, and suppress angiogenesis.Such compound has good development prospect.
On the other hand, the Pharmaceutical Inorganic Chemistry based on medical active part is studied in recent years with bioinorganic chemistry Flourish and turn into hot research field, the first, second and third generation platinum class especially with cis-platinum, carboplatin, oxaliplatin etc. as representative Cancer therapy drug really indicates the arrival of Metal Drugs research and application New Times as the successful Application of front-line chemotherapeutic agents. Have not yet to see cobalt (II) complex with 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone as part and Its synthesis and the relevant report of application.
The content of the invention
The technical problem to be solved in the present invention is to provide cobalt (II) complex and its conjunction of a kind of new qualone derivative Into method and application.
Cobalt (II) complex of qualone derivative of the present invention be with the compound of structure shown in lower formula (I) or Its pharmaceutically acceptable salt:
The synthetic method of compound is shown in above-mentioned formula (I):Stoichiometrically weigh cobalt chloride (i.e. six chloride hydrates Cobalt) and part 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone, it is dissolved in polar solvent, be coordinated instead Should, that is, obtain target product.
Part 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinoline involved in synthetic method of the present invention Quinoline ketone is synthesized using following synthesis thinking:
With para-totuidine as raw material, under conditions of acetic acid or hydrochloric acid are present, add acetic anhydride to be acylated, be acylated Product (i.e. compound 1);Gained acylate obtains cyclization product (i.e. compound 2) with POCl3 cyclization;Gained cyclization is produced Thing acid adding is hydrolyzed, and obtains hydrolysate (i.e. compound 3);Gained hydrolysate carries out condensation reaction with o-phenylenediamine, i.e., Obtain target product (i.e. compound 4).Specific synthetic route is as follows:
Reagent:(a) acetic anhydride, acetic acid or hydrochloric acid;(b) N,N-dimethylformamide, POCl3;(c) acid;(d) neighbour benzene Diamines, methyl alcohol and/ethanol.
Above-mentioned part 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone more specifically synthetic method, bag Include following steps:
1. with para-totuidine as raw material, under conditions of acetic acid or hydrochloric acid are present, add acetic anhydride to be reacted, reacted PH value into rear regulation system is 6~8, reactant suction filtration, and filter cake recrystallization obtains compound 1;
2. gained compound 1 is dissolved in DMF, adds POCl3 to carry out ring closure reaction, gained reaction Thing is poured into frozen water, suction filtration, obtains compound 2;
3. the gained acid adding of compound 2 is hydrolyzed, and obtains compound 3;
4. gained compound 3 carries out condensation reaction with o-phenylenediamine under conditions of methyl alcohol and/or ethanol are present, and obtains final product mesh Mark product.
The step of above-mentioned part synthetic method 1. in, the concentration of the acetic acid can be 30~90 (v/v) %, the hydrochloric acid Concentration can be 15~37w/w%, the consumption of the acetate and hydrochloride typically respectively the amount of para-totuidine material 0.9~ 1.2 times, or 1.2 times of amount more than para-totuidine material.The addition of the acetic anhydride is usually para-totuidine material 0.9~1.2 times of amount, or 1.2 times of amount more than para-totuidine material.In the step, due to exothermic heat of reaction, preferably Reaction is carried out under condition of ice bath.Whether reaction can use thin-layer chromatography (TLC) tracing detection, generally control reaction completely Time is that 1~4h is appropriate.The pH value that alkali lye regulation system is used after the completion of reaction is 6~8, and described alkali lye can be acetic acid The aqueous solution of the alkaline matters such as sodium, sodium carbonate, sodium phosphate, sodium acid carbonate or potassium carbonate, the concentration of the alkali lye is preferably 5~ 30/w/w%;Preferably it is adjusted using the aqueous solution of sodium acetate.The filter cake of collection is generally using absolute ethyl alcohol and/or anhydrous Methyl alcohol is recrystallized.
The step of above-mentioned part synthetic method 2. in, the addition of the POCl3 is usually the amount of the material of compound 1 0.9~1.2 times, or 1.2 times of amount more than para-totuidine material.The consumption of the N,N-dimethylformamide can be with Determine as needed, can specifically be calculated with the amount of 5~11ml by 10mmol compounds 1.Described ring closure reaction generally exists Carried out under heating condition, preferably carried out under the conditions of 60~90 DEG C, in 60~90 DEG C of conditions more preferably in reflux Under carry out back flow reaction.Whether reaction can use TLC tracing detections completely, generally control the reaction time relatively to be closed for 8~14h It is suitable.
The step of above-mentioned part synthetic method 3. in, acid used can be 30~90 (v/v) % ice vinegar when being hydrolyzed Acid, or 2~6mol/L hydrochloric acid, or 2~6mol/L sulfuric acid;The sour consumption for hydrolyzing is usually every 10mmol compounds 2 are hydrolyzed with 50~80ml acid solutions.The hydrolysis is generally carried out in a heated condition, preferably 60 Carried out under the conditions of~90 DEG C, more preferably flowed back under the conditions of 60~90 DEG C in reflux, in said temperature condition Lower backflow can obtain settled solution.Hydrolysis whether completely can use TLC tracing detections, generally control the reaction time be 6~ 12h is appropriate.After hydrolysis completely, gained reactant cooling has crystal to separate out, and the crystal of precipitation is compound 3.
The step of above-mentioned part synthetic method 4. in, the consumption of the o-phenylenediamine is usually the amount of the material of compound 3 0.9~1.2 times, or 1.2 times of amount more than para-totuidine material.Described methyl alcohol is 70~100v/v% methyl alcohol, institute The ethanol stated is 70~100v/v% ethanol;The consumption of the methyl alcohol and/or ethanol can determine as needed, specifically can be by 10mmol compounds 3 are calculated with the amount of 50~80ml.Described condensation reaction is generally carried out in a heated condition, is preferably existed Carried out under the conditions of 60~90 DEG C, back flow reaction is more preferably carried out under the conditions of 60~90 DEG C in reflux.Condensation reaction Whether TLC tracing detections can be used completely, generally control the reaction time for 6~12h is appropriate.After the completion of reaction, gained Suction filtration after reactant cooling, collects filter cake and is target product (i.e. part).
The molecular formula of part 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone of the present invention is C17H13N3O, molecular weight is:275.1, structure is as follows:
In the molecule, the nitrogen-atoms on carbonylic oxygen atom and imidazole ring on quinolinone has stronger coordination ability, can Following coordination mode is formed in complexation reaction:
N, O bidentate chelate mode:With the N of 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone, O atom with Metal ions M is coordinated, and forms hexatomic ring chelating body.
Specifically when compound shown in formula (I) described in the invention described above is synthesized, can be carried out using solwution method or solvent-thermal method Synthesis.
When synthesizing using solwution method, following steps are specifically included:
1) cobalt chloride and part 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinoline are stoichiometrically weighed Ketone, is dissolved in polar solvent, obtains mixed solution;
2) gained mixed solution is in reaction in 20 DEG C to polar solvent of reflow temperature range;
3) gained reacting liquid filtering, sediment is scrubbed, dry, that is, obtain quinolinone cobalt complex.
The step of above-mentioned solwution method 1) in, when the selection of polar solvent is for methyl alcohol and selected from water, acetone, chloroform and N, N- bis- During a kind of combination in NMF, preferably methyl alcohol is with the volume ratio of water, acetone, chloroform or DMF 50:1~1:1.When polar solvent selection for methyl alcohol be selected from water, acetone, chloroform and N,N-dimethylformamide in it is any During two or more combination, the proportioning between them can be any proportioning.The consumption of the polar solvent can be true as needed It is fixed, it is generally the case that cobalt chloride and 1mmol 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H) of 1mmol-quinolinone is used The polar solvent of 10~80mL dissolves.In specific dissolving step, can by cobalt chloride and part 3- (1H- benzimidazolyl-2 radicals- Base) -6- methyl -2 (1H)-quinolinone respectively with polar solvent dissolve, remix and react together;Also can be by cobalt chloride and part Additive polarity solvent again after the mixing of 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone.The cobalt chloride and part 3- The ratio between amount of material of (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone is usually 1:1.
The step of above-mentioned solwution method 2) in, whether reaction can use thin-layer chromatography tracing detection completely.Reaction is preferably used Back flow reaction, reacts more preferably in 50 DEG C to polar solvent of reflow temperature range.When reaction is molten to polarity at 50 DEG C Carried out in the reflow temperature range of agent, reaction to taking around 3~18h completely.
The step of above-mentioned solwution method 3) in, it is typically to be washed with ether, acetone or dichloromethane during washing.Dried strip Part is the vacuum drying or constant pressure and dry under the conditions of 30~50 DEG C.In this method, product typically a large amount of generations in solid form, If previous step 1) in polar solvent addition larger (such as the upper limit close to proportioning) or solvent to the dissolubility of product compared with Good, then solution may be in clear state after reacting, because caused by the product precipitation for being formed is by polar solvent dissolving, now Product can be made main and separated out with powder precipitation or crystal form by the vacuum distillation of gained reaction solution to remove partial solvent, take out Next step operation is carried out after the solid of precipitation again.Concentration removes partial solvent and typically refers to concentration removing polar solvent addition 50~90%.
When using solvent structure, following steps are specifically included:
A) cobalt chloride and part 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinoline are stoichiometrically weighed Ketone, is dissolved in polar solvent, obtains mixed solution;
B) gained mixed solution is placed in container, and vacuum is evacuated to after liquid nitrogen frozen, is sealed, then in 50~140 DEG C of bars Reacted under part, that is, obtain quinolinone cobalt complex.
In the step of above-mentioned solvent-thermal method a), when polar solvent selection for methyl alcohol with selected from water, acetone, chloroform and N, N- During a kind of combination in dimethylformamide, the preferred volume ratio of methyl alcohol and water, acetone, chloroform or DMF It is 50:1~1:1.Appointing in the selection of polar solvent is for methyl alcohol and selected from water, acetone, chloroform and N,N-dimethylformamide During the two or more combinations of meaning, the proportioning between them can be any proportioning.The consumption of the polar solvent can be as needed It is determined that, it is generally the case that cobalt chloride and 1mmol 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone of 1mmol Dissolved with the polar solvent of 5~30mL.In specific dissolving step, can by cobalt chloride and part 3- (1H- benzimidazoles- 2- yls) -6- methyl -2 (1H)-quinolinone respectively with polar solvent dissolve, remix and react together;Also by cobalt chloride and can match somebody with somebody Additive polarity solvent again after the mixing of body 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone.The cobalt chloride and part The ratio between amount of material of 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone is usually 1:1.
In the step of above-mentioned solvent-thermal method b), described container is usually heavy wall borosilicate glass tube, and the time of reaction is usual Control in 12~72h, also dependent on needing for extend to more than 72h in the reaction time.More preferably mixed solution is at 80~100 DEG C Under the conditions of reacted, when being carried out under normal temperature of the reaction below 80 DEG C or heating condition, reaction needs the longer time Yield higher can be obtained.
Antineoplastic is being prepared present invention additionally comprises the compound or its pharmaceutically acceptable salt shown in above-mentioned formula (I) Application in thing.
The present invention further includes the antineoplastic prepared as active component with the compound shown in above-mentioned formula (I).
Compared with prior art, the invention provides a kind of new quinolinone cobalt complex and its synthetic method and application. Anti tumor activity in vitro research of the applicant to complex of the present invention shows that it is to human cervical carcinoma cell Hela229, people's stomach Cancer cell MGC-803, human hepatoma cell strain Hep tetra- kinds of cell lines of G2 and BEL-7404 all show certain Proliferation Ability and live Property, wherein for human hepatoma cell strain Hep G2 activity highests.
Brief description of the drawings
Fig. 1 is the hydrogen nuclear magnetic resonance spectrogram of part used in various embodiments of the present invention;
Fig. 2 is the carbon-13 nmr spectra figure of part used in various embodiments of the present invention;
Fig. 3 is the high resolution mass spectrum spectrogram of part used in various embodiments of the present invention, and its ordinate is relative abundance Value, abscissa is m/z (molecular weight);
Fig. 4 is the infrared spectrum of final product obtained in the embodiment of the present invention 1;
Fig. 5 is the high resolution mass spectrum figure of final product obtained in the embodiment of the present invention 1, and its ordinate is relative abundance value, Abscissa is m/z (molecular weight);
Fig. 6 is the x-ray crystal structure figure of final product obtained in the embodiment of the present invention 1.
Specific embodiment
With reference to specific embodiment, the present invention is described in further detail, to more fully understand present disclosure, but The present invention is not limited to following examples.
In following embodiment, described part 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone, under State the abbreviation that the BMQ occurred in each embodiment is the part) synthesized as follows:
1) by 10.7g (0.1mol) para-totuidine, 50ml water adds 250ml round-bottomed flasks, is added dropwise over 8ml concentrated hydrochloric acids, 10.2g (0.1mol) acetic anhydride, reacts 4 hours under ice bath, is then with the pH value of the sodium acetate solution regulation system of 20w/w% 7, stand, suction filtration, filter cake absolute ethyl alcohol is recrystallized to give compound 1 (white needle-like crystals, 13.3g, yield 89%).
2) by 3.5ml DMF and 17ml POCl3Mix under ice bath, be stirring evenly and then adding into 2.24g (15mmol) chemical combination Thing 1, resulting solution is placed in reflux, is heated to 90 DEG C and is flowed back 10 hours, is poured into after cooling in 500ml frozen water, and suction filtration is obtained To compound 2 (2.7g, yield 87%).
3) 2.05g (10mmol) compound 2 is dissolved in the glacial acetic acid of 80ml 70%, resulting solution is placed in reflux, plus Hot to 90 DEG C are flowed back 8 hours, and cooling obtains compound 3 (yellow needle-like crystals, 1.70g, yield 91%).
4) 1.87g (10mmol) compound 3 and 1.08g (10mmol) o-phenylenediamine are added in 80ml absolute methanols, Resulting solution is placed in reflux, is flowed back 8 hours in 90 DEG C, and cooling, suction filtration obtains yellow solid (2.48g, 90%).
Gained yellow solid product is identified:
(1) proton nmr spectra and carbon are composed, and their spectrogram difference is as illustrated in fig. 1 and 2.
1H NMR (500MHz, DMSO-d6) δ 12.65 (s, 1H), 12.40 (s, 1H), 9.00 (d, J=1.7Hz, 1H), 7.74-7.70 (m, 1H), 7.69 (s, 1H), 7.68-7.63 (m, 1H), 7.42 (d, J=8.4Hz, 1H), 7.33 (d, J= 8.4Hz,1H),7.22–7.17(m,2H),2.36(s,3H).13C NMR(126MHz,DMSO-d6)δ160.79,147.96, 142.83,138.90,136.85,134.49,133.15,131.89,128.38,122.41,122.05,119.93,119.19, 118.38,115.29,112.88,20.56.
(2) electrospray ionization mass spectrum, as shown in figure 3, ESI-MS m/z:276.1[M+H]+.
Accordingly, it can be determined that above-mentioned yellow solid product is 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinoline Ketone, its chemical structural formula is as follows:
Embodiment 1
In the heavy wall borosilicate glass tube being open at one end, 0.1mmol CoCl are directly added into2·6H2O and 0.1mmol BMQ, (volume ratio of methyl alcohol and chloroform is 3 to add 0.6ml methyl alcohol/chloroform mixed solution:1).Under conditions of vacuumizing, by opening End sealing, then fully reacts 72h, you can obtain blue crystalline solids product under the conditions of 80 DEG C.Product is by infrared light Spectrum (as shown in Figure 4), elementary analysis, electrospray ionization mass spectrum (as shown in Figure 5) carry out structure (such as with reference to the analysis of X-ray single crystal diffraction Shown in Fig. 6) determine, it is defined as title complex [Co (BMQ) Cl2], shown in its structural formula such as following formula (I).
Embodiment 2
Embodiment 1 is repeated, unlike:
1) polar solvent is changed to methyl alcohol;
2) reaction temperature is changed to 50 DEG C, and the reaction time is changed to 50h.
Products therefrom carries out structure by infrared spectrum, elementary analysis, the analysis of electrospray ionization mass spectrum combination X-ray single crystal diffraction Determine, be defined as title complex [Co (BMQ) Cl2]。
Embodiment 3
1) 0.1mmol CoCl are weighed respectively2·6H2O and 0.1mmol BMQ, are dissolved in the mixing of 80mL methanol/acetones after mixing (volume ratio of methyl alcohol and acetone is 1 to solution:1) in, mixed solution is obtained;
2) gained mixed solution is in 100 DEG C of back flow reaction 8h;
3) gained reaction solution is evaporated off partial solvent, stands, and has blue crystalline solid product to separate out, and isolates solid, uses second Ether is washed, and is dried.
Products therefrom carries out structure by infrared spectrum, elementary analysis, the analysis of electrospray ionization mass spectrum combination X-ray single crystal diffraction Determine, be defined as title complex [Co (BMQ) Cl2]。
Embodiment 4
Embodiment 3 is repeated, unlike:
1) polar solvent be changed to methanol/water (volume ratio of first alcohol and water be 5:1);
2) reaction temperature is changed to 70 DEG C, and the reaction time is changed to 12h.
In order to absolutely prove purposes of the complex of the present invention in pharmacy, applicant has carried out extracorporeal anti-tumor to it Activity experiment.
First, quinolinone cobalt complex is to 5 kinds of proliferation inhibition activity experiments of cell line:
1st, cell line and cell culture
This experiment is from gastric carcinoma cells MGC-803, human hepatoma cell strain Hep G2, BEL-7404, human cervical carcinoma cell Hela229 and human normal cell line HL-7702 totally 5 kinds of cell lines.
All tumor cell lines are cultivated containing 10wt% small ox bloods, 100U/mL penicillin, 100U/mL streptomysins In RPMI-1640 nutrient solutions, 37 DEG C of 5%CO containing volumetric concentration are put2Cultivated in incubator;Human normal cell line strain is then cultivated and contained In the small ox bloods of 10wt%, 100U/mL penicillin, the DMEM nutrient solutions of 100U/mL streptomysins.
2nd, the preparation of testing compound
Quinolinone cobalt complex used is the products therefrom of the embodiment of the present invention 1, purity >=95%, by its DMSO liquid storage (concentration is 0.001mol/L) is diluted to five concentration gradients successively by RMPI1640 culture mediums, respectively 40,20,10,5, 2.5 μm of ol/L, wherein cosolvent DMSO final concentration≤1%.20 μm of target products of ol/L are tested first to increase for tumour cell The inhibiting rate grown, is considered as primary dcreening operation result;Test propagation of the target product to various tumour cells under different gradient concentrations respectively again Inhibition level, to the Fitting Calculation half-inhibition concentration, i.e. IC50Value.
3rd, cell growth inhibition test (mtt assay)
(1) take the logarithm the tumour cell in growth period, through Trypsin Induced after, matched somebody with somebody with the nutrient solution containing 10% calf serum The cell suspension that concentration is 5000/mL is made, is inoculated in 96 well culture plates with the μ L of every hole 190, make cell density to be measured extremely 1000~10000/hole (edge hole is filled with aseptic PBS);
(2) 5%CO2, 37 DEG C are incubated 24h, and bottom hole is paved with to cell monolayer, and the medicine 10 of finite concentration gradient is added per hole μ L, each concentration gradient sets 4 multiple holes;
(3) 5%CO2, 37 DEG C are incubated 48 hours, are observed under inverted microscope;
(4) the MTT solution (5mg/mL PBS, i.e. 0.5%MTT) of 10 μ L is added per hole, continues to cultivate 4h;
(5) terminate culture, carefully suck nutrient solution in hole, add 150 μ L DMSO fully to dissolve first a ceremonial jade-ladle, used in libation precipitation per hole, shake It is 570nm in ELIASA wavelength after swinging device mixing, reference wavelength is the OD value that 450nm determines each hole;
(6) while setting zeroing hole (culture medium, MTT, DMSO), (cell, the medicine dissolving of same concentrations are situated between control wells Matter, nutrient solution, MTT, DMSO).
(7) living cells quantity is judged according to the OD value (OD values) for measuring, OD values are bigger, and cytoactive is stronger.
Using formula:
Calculate the inhibiting rate of compound on tumor cell growth.For cell of the inhibiting rate more than 50% under primary dcreening operation concentration The inhibiting rate data of five concentration gradients are further fitted by strain by SPSS softwares, obtain compound to different tumours Half-inhibition concentration (the IC of strain50Value, unit μm ol/L), IC of the compound for different lung cancer cell lines50Value is as shown in table 1.
Table 1:

Claims (6)

1. compound shown in formula (I) or its pharmaceutically acceptable salt are descended:
2. the synthetic method of the compound described in claim 1, it is characterised in that:Stoichiometrically weigh cobalt chloride and part 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone, is dissolved in polar solvent, carries out complexation reaction, that is, obtain mesh Mark product;
Described polar solvent is methyl alcohol, or methyl alcohol with selected from water, acetone, chloroform and DMF Plant or two or more combinations.
3. synthetic method according to claim 2, it is characterised in that:Comprise the following steps:
1) cobalt chloride and part 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone are stoichiometrically weighed, it is molten In polar solvent, mixed solution is obtained;
2) gained mixed solution is in reaction in 20 DEG C to polar solvent of reflow temperature range;
3) gained reacting liquid filtering, sediment is scrubbed, dry, that is, obtain quinolinone cobalt complex.
4. synthetic method according to claim 2, it is characterised in that:Comprise the following steps:
A) cobalt chloride and part 3- (1H- benzimidazolyl-2 radicals-yl) -6- methyl -2 (1H)-quinolinone are stoichiometrically weighed, it is molten In polar solvent, mixed solution is obtained;
B) gained mixed solution is placed in container, and vacuum is evacuated to after liquid nitrogen frozen, is sealed, then under the conditions of 50~140 DEG C Reaction, that is, obtain quinolinone cobalt complex.
5. the application of compound described in claim 1 or its pharmaceutically acceptable salt in antineoplastic is prepared.
6. the antineoplastic for being prepared as active component with compound described in claim 1.
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