CN106478677A - The chlorination copper complex of 1 (2 pyridine) 9 (2 Phenoxyethyl) β carboline and synthetic method and application - Google Patents
The chlorination copper complex of 1 (2 pyridine) 9 (2 Phenoxyethyl) β carboline and synthetic method and application Download PDFInfo
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Abstract
The invention discloses a kind of chlorination copper complex of 1 (2 pyridine) 9 (2 Phenoxyethyl) β carboline and synthetic method and application.Shown in the structural formula of the complex such as following formula (I), its synthetic method is：Compound and copper chloride as shown in following formula (II) is taken, is dissolved in polar solvent, complexation reaction is carried out, is obtained final product；Wherein, described polar solvent is one or two and one or more the combination in water, acetone, chloroform, dichloromethane and N, the N dimethylformamide in methyl alcohol and ethanol.Complex of the present invention shows the antitumor activity more higher than part and cis-platinum, with preferably potential medical value, is expected to be used for the preparation of various antineoplastics.Formula (I) and structure shown in formula (II) as follows：
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to a kind of 1- (2- pyridine) -9- (2- Phenoxyethyl)-B-carboline
Chlorination copper complex and synthetic method and application.
Background technology
B-carboline is the alkaloid that a class is distributed widely in nature, and they are primarily present in multiple terrestrial plants and ocean
In biology.Chemically classify in structure, beta-carboline alkaloid belongs to indoles alkaloid, and it is three be made up of trypoline
Member ring systems, its skeleton are planar molecules, and two nitrogen-atoms of wherein 2 and 9 are present with different hybridization states,
9 nitrogen-atoms are sp3Hydridization, is rich pi-electron system, and 2 nitrogen-atoms are sp2Hydridization, is to lack pi-electron system.Two nitrogen-atoms with
The chemical property and biologically active of such compound is closely related.Such compound has extensive biology and pharmacology is lived
Property, including：Sedative, antianxiety, hypnosis, anti-spasm, antitumor, antiviral, desinsection and antibacterial activity etc..Therefore β-click
Quinoline alkaloid is increasingly paid attention to by researcher.
On the other hand, the Pharmaceutical Inorganic Chemistry based on medical active part is studied in recent years with bioinorganic chemistry
Flourish and become 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.
But copper chloride (II) complex that has not yet to see with 1- (2- pyridine) -9- (2- Phenoxyethyl)-B-carboline as part and
Its synthetic method and the relevant report of application.
Content of the invention
The technical problem to be solved in the present invention is a kind of structure novelty of offer with 1- (2- pyridine) -9- (2- phenoxy group second
Base)-B-carboline for part copper chloride (II) complex, and its synthetic method and application.
The present invention relates to compound shown in lower formula (I) or its pharmaceutically acceptable salt：
Shown in above-mentioned formula (I), the synthetic method of compound is：Take compound and copper chloride as shown in following formula (II)
(CuCl2·2H2O), it is dissolved in polar solvent, complexation reaction is carried out, that is, obtains target product；Wherein, described polar solvent is
In methyl alcohol and ethanol one or two with water, acetone, chloroform, dichloromethane and the DMF
One or more combination；
Compound shown in the raw material formula (II) being related in above-mentioned synthetic method participates in reaction as part, and its chemical name is
1- (2- pyridine) -9- (2- Phenoxyethyl)-B-carboline, also referred to as L in this application.Compound shown in the formula (II) can be certainly
Row design synthetic route is prepared, and is preferably prepared as follows：
With tryptamines and pyridine-2-formaldehyde as raw material, react in the first organic solvent, compound is obtained through dehydrating condensation
1；Then compound 1 is placed in the second organic solvent, add oxidant cyclization dehydrogenation obtain compound 2 (1- (2- pyridine)-
B-carboline)；Again compound 2 is placed in the aprotic polar solvent of alkaline matter, adds 2- phenoxy group bromoethane to be replaced
Reaction, obtains final product；Wherein：
The first described organic solvent is the one kind or two in toluene, methyl alcohol, ethanol, dichloromethane and chloroform
Plant above combination；
The second described organic solvent is the one kind or two in benzene, toluene, paraxylene, glacial acetic acid and dichloromethane
Plant above combination；
Described oxidant is palladium carbon, manganese acetate hydrate (Mn (Ac)3·nH2O), lead tetraacetate (Pb (Ac)4) or 2,3-
Two chloro- 5,6- dicyan 1,4-benzoquinone (DDQ)；
Described alkaline matter is inorganic base；
Described aprotic polar solvent be the one kind in N,N-dimethylformamide, dimethyl sulfoxide (DMSO) and acetone or
Two or more combinations.
Shown in above-mentioned preparation formula (II), the synthetic route of compound method is as follows：
Reagent：(a) first organic solvent；(b) oxidant, the second organic solvent；C () alkaline matter, aprotonic polar are molten
Agent.
The more specifically preparation method of compound shown in above-mentioned formula (II), comprises the following steps：
1. with tryptamines and pyridine-2-formaldehyde as raw material, react in the first organic solvent, in course of reaction, discharge reaction life
The water for becoming, question response terminate rear solvent evaporated, obtain compound 1；
2. compound 1 is placed in the second organic solvent, oxidant is added, react under heating condition, question response terminates, mistake
Filter, collects filtrate, is evaporated, obtains compound 2；
3. take alkaline matter to be dissolved in aprotic polar solvent, being subsequently adding compound 2 and 2- phenoxy group bromoethane is carried out
Reaction, question response terminate, and reactant is put in frozen water, gained mixture of ice and water is extracted, and collect organic phase, are evaporated molten
Agent, that is, obtain compound shown in formula (II) (i.e. compound 3).
Shown in above-mentioned formula (II) the step of compound synthesis method 1. in, the amount of the material of tryptamines and pyridine-2-formaldehyde it
Than being usually 0.8～1.2：1, reaction can be carried out under conditions of being heated or not heated, and can use water knockout drum in course of reaction
The water that reaction is generated is discharged, whether reaction can adopt thin-layer chromatography (TLC) tracing detection completely；Preferably, reaction is adopted
Heating reflux reaction, the time control that now reacts are appropriate in 2～6h.In the step, obtained is the thick product of compound 1
Thing, in order to reduce the impurity in subsequent reactions, improves the yield of postorder reaction, preferably carries out after purification process to residue obtained
Postorder reaction is carried out again.Specific purification process can be recrystallized with little polar solvent to residue obtained, and gained recrystallization is produced
Thing is used further to postorder reaction.Described for recrystallize little polar solvent same as the prior art, can be specifically petroleum ether and/
Or n-hexane etc..
Shown in above-mentioned formula (II) the step of compound synthesis method 2. in, reaction preferably adopt heating reflux reaction, reaction
Whether thin-layer chromatography tracing detection can be adopted completely.In the step, obtained is the crude product of compound 2, in order to reduce
Impurity in subsequent reactions, improves the yield of postorder reaction, preferably carries out carrying out postorder after purification process again to residue obtained
Reaction.Specific purification process can be to residue obtained with methyl alcohol, ethanol and dichloromethane one or two with
On combination solvent recrystallized, or residue obtained upper silica gel column chromatography is purified, in upper silica gel column chromatography, used
Eluant, eluent be that petroleum ether and dichloromethane press 6：1～1：The mixed solvent of 1 volume ratio composition.
Shown in above-mentioned formula (II) the step of compound synthesis method 2. in, according to the difference of oxidant, from different
Two organic solvents, specific as follows：
(1) when oxidant is when being chosen as palladium carbon, the second organic solvent is preferably the one kind in benzene, toluene and paraxylene
Or two or more combinations, when two organic solvents be chosen as more than above two combination when, the proportioning between them is permissible
For any proportioning.Described palladium carbon can be 5%Pd/C or 10%Pd/C, and the addition of the palladium carbon generally presses 10mmol chemical combination
Thing 1 adds 2～4g palladium carbon to calculate.
(2) when oxidant is when being chosen as manganese acetate hydrate or lead tetraacetate, the second organic solvent is preferably glacial acetic acid；
The addition of the manganese acetate hydrate or lead tetraacetate is usually 2～8 times of the amount of 1 material of compound.Choosing when oxidant
When manganese acetate hydrate or lead tetraacetate is selected as, pH >=7 with alkali lye regulation system after terminating preferably is reacted, then which is extracted
Take, organic phase is collected, the residue of solvent evaporated gained goes up silica gel column chromatography purifying again；Wherein, described alkali lye can be ammoniacal liquor,
The aqueous solution of the alkaline matters such as sodium acetate, sodium carbonate, sodium phosphate, sodium acid carbonate or potassium carbonate, the concentration of the alkali lye are preferably 5
～30w/w%；Can be specifically ethyl acetate, dichloromethane, chloroform or ether etc. for extracting the solvent for adjusting system after pH value.
(3) when oxidant is when being chosen as bis- chloro- 5,6- dicyan 1,4-benzoquinone of 2,3-, the second organic solvent is preferably benzene, first
One or more combination of benzene and dichloromethane, when two organic solvents be chosen as more than above two combination when,
Proportioning between them can be any proportioning.The addition of the chloro- 5,6- dicyan 1,4-benzoquinone of the 2,3- bis- is usually compound 1
1～4 times of the amount of material.
Shown in above-mentioned formula (II) the step of compound synthesis method 3. in, the alkaline matter, compound 2 and 2- phenoxy group
The ratio of the amount of the material of bromoethane is usually 1～4：1：1～3, alkaline matter therein can be sodium hydride, hydrogenation further
One or more combination in calcium, calcium hydroxide, NaOH, potassium hydroxide, cesium carbonate and potassium carbonate, works as basic species
Matter be chosen as more than above two combination when, the proportioning between them can be any proportioning.In the step, react permissible
Carry out under the conditions of 0～80 DEG C, whether reaction can adopt thin-layer chromatography (TLC) tracing detection completely；Preferably, reaction exists
20～50 DEG C, the time control that now reacts is appropriate in 1～6h.The solvent extracted by mixture of ice and water can be specifically
The conventional extraction solvent such as ethyl acetate, dichloromethane, chloroform, petroleum ether or ether.
In compound synthesis method shown in above-mentioned formula (II), involved various solvents are (as the first organic solvent, second have
Machine solvent and aprotic polar solvent etc.) consumption, with can dissolve participate in each step react raw material be advisable.
What said method was prepared is the crude product of compound shown in formula (II), in order to be improved shown in formula (II) further
The purity of compound, is more beneficial for the carrying out of subsequent reactions, preferably above-mentioned gained crude product is carried out being used after purification process again
In the synthetic method of target product of the present invention.Described purification process is same as the prior art, can be specifically by crude product
Upper silica gel column chromatography purifying, to obtain pure compounds shown in formula (II)；In upper silica gel column chromatography, eluant, eluent used is two
Chloromethanes and methyl alcohol press 1000：1～50：The mixed solvent of 1 volume ratio composition.
In the synthetic method of compound shown in formula (I) of the present invention, in the composition of polar solvent, methyl alcohol or ethanol or
Person is that the ratio shared in polar solvent of combination of methyl alcohol and ethanol is preferably 50～98v/v%；When containing in polar solvent
During two or more selection in water, acetone, chloroform, dichloromethane and DMF, do not surpass in their total amount
Go out under 50% precondition, their proportioning can be any proportioning.The consumption of the polar solvent can determine as needed,
Under normal circumstances, the copper chloride of 1mmol and compound shown in 1mmol formula (II) are dissolved with the polar solvent of 5～80mL.In tool
In the dissolving step of body, typically by additive polarity solvent again after copper chloride and the mixing of compound shown in formula (II)；Also can be by copper chloride
Dissolved with polar solvent with compound shown in formula (II) respectively, remix and react together.
In the synthetic method of compound shown in formula (I) of the present invention, the copper chloride and compound shown in formula (II)
The ratio of the amount of material can be 1～6：1.
Compound shown in formula (I) of the present invention, can be using normal pressure solwution method or high pressure solvent warm specifically in synthesis
Method is synthesized.
When using normal pressure solwution method, its synthetic method includes：Compound shown in formula (II) and copper chloride is taken, is dissolved in polarity
In solvent, gained mixed liquor is reacted under the conditions of being heated or not heated, and reactant removes partial solvent, is stood, and is separated out, is isolated
Crystal, obtains final product target product.
In above-mentioned normal pressure solwution method, reaction can be carried out in 20 DEG C to polar solvent of reflow temperature range, preferably adopted
With back flow reaction, further preferably reaction is carried out in 50 DEG C to polar solvent of reflow temperature range, more preferably 60
React under the conditions of DEG C.Whether reaction can adopt thin-layer chromatography tracing detection completely.In this method, product is typically in the form of crystal
A large amount of generations, if in previous step, the addition of polar solvent is larger (being such as close to the upper limit of proportioning) or solvent is to the molten of product
Preferably, then after reacting, solution may be in clear state to solution property, this is because the product precipitation for being formed is dissolved institute by polar solvent
Cause, now gained reactant liquor can be concentrated or vacuum distillation is to remove partial solvent, typically concentrate and remove polar solvent addition
The 50～90% of amount.Isolated solid can be washed with ether, acetone, ethanol, methyl alcohol or dichloromethane further, it
It is dried again afterwards.
When the hot method of high pressure solvent, its synthetic method includes：Compound shown in formula (II) and copper chloride is taken, is dissolved in polarity molten
In agent, gained mixed liquor is placed in container, is evacuated to vacuum after liquid nitrogen frozen, sealing by fusing, then anti-under the conditions of 30～140 DEG C
Should, obtain target product.
In the hot method of above-mentioned high pressure solvent, described container is usually heavy wall borosilicate glass tube, reacts generally at 30～140 DEG C
Under the conditions of carry out, under this temperature conditions, the time of reaction is preferably controlled in 2～24h, extends to also dependent on actual conditions
More than 24h.Further preferably mixed solution is reacted under the conditions of 50～140 DEG C, more preferably mixed solution be 80～
Reacted under the conditions of 100 DEG C.When carrying out under normal temperature of the reaction below 80 DEG C or heating condition, when reaction needs longer
Between can just obtain higher yield.
Present invention additionally comprises compound or its pharmaceutically acceptable salt are in antineoplastic is prepared shown in above-mentioned formula (I)
Application.
Present invention additionally comprises prepared with compound or its pharmaceutically acceptable salt shown in above-mentioned formula (I) as active component
Antineoplastic.
Compared with prior art, the invention provides a kind of new with 1- (2- pyridine) -9- (2- Phenoxyethyl)-β-click
Quinoline is copper chloride (II) complex of part, and its synthetic method and application.Applicant is by investigating which to kinds of tumors
The inhibitory action of cell line, as a result shows that the complex has stronger anti tumor activity in vitro, and apparently higher than cis-platinum, has
Preferably potential medical value, is expected to be used for the preparation of various antineoplastics.
Description of the drawings
Fig. 1 is the mass spectrogram of final product obtained in the embodiment of the present invention 5.
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.
Embodiment 1：Compound shown in formula (II) is the synthesis of 1- (2- pyridine) -9- (2- Phenoxyethyl)-B-carboline (L)
1) 1.6g (10mmol) tryptamines, 1.1g (10mmol) pyridine-2-formaldehyde and 50ml toluene are added 150ml round bottom to burn
Bottle, adds water knockout drum, condenser pipe group composition water reflux, is heated to reflux 4 hours, and question response terminates rear solvent evaporated, residue
Compound 1 (2.3g, yield 92%) is recrystallized to give with 100ml n-hexane；
2) 2.5g (10mmol) compound 1,2.5g palladium carbon (10%Pd/C) and 100ml paraxylene are added 250ml circle
Bottom flask, is heated to backflow, and is terminated to reaction with thin-layer chromatography tracing detection, and filtrate is simultaneously evaporated by standing suction filtration, and gained is residual
Silica gel column chromatography purifying (V on slagPetroleum ether：VDichloromethane=1:1) compound 2 (2.1g, yield 86%), is obtained；
3) 50ml round-bottomed flask, room temperature are added to 0.24g (10mmol) sodium hydride and 15ml DMF
Stirring 10 minutes, adds 2.5g (10mmol) compound 2 and 10mmol 2- phenoxy group bromoethane, and is tracked with thin-layer chromatography
Detect and terminate to reaction, then reactant liquor is put in 500ml frozen water, extracted three times with 100ml ethyl acetate, merge organic
Phase, solvent evaporated, residue obtained upper silica gel column chromatography purify (VDichloromethane：VMethyl alcohol=100:1), compound 3 (2.3g, yield are obtained
63%).
Products therefrom is characterized：
(1) proton nmr spectra and carbon spectrum, their spectral data are as follows：
1H NMR(500MHz,CDCl3) δ 8.71 (d, J=4.6Hz, 1H), 8.59 (d, J=5.2Hz, 1H), 8.20 (dd, J
=7.9,0.8Hz, 1H), 8.13 (dd, J=5.2,0.8Hz, 1H), 8.08 (d, J=7.7Hz, 1H), 7.98 7.91 (m, 1H),
7.69 7.62 (m, 2H), 7.44 7.39 (m, 1H), 7.39 7.33 (m, 1H), 7.19 7.13 (m, 2H), 6.87 (td, J=
7.4,1.0Hz, 1H), 6.64 6.56 (m, 2H), 4.68 (t, J=5.9Hz, 2H), 4.07 (t, J=5.9Hz, 2H).
13C NMR(126MHz,CDCl3)δ158.27,156.69,148.56,143.31,141.37,137.44,
136.77,134.53,132.68,129.51,125.88,123.88,121.80,121.28,121.19,120.80,115.00,
114.40,111.13,110.91,66.16,44.92.
(2) high resolution mass spectrum, ESI-MS m/z:366[M+H]+
Accordingly, it can be determined that above-mentioned product is 1- (2- pyridine) -9- (2- Phenoxyethyl)-B-carboline, its chemical constitution
Shown in formula such as following formula (II)：
Embodiment 2：The synthesis of ligand L
Repeat embodiment 1, except for the difference that：
Step 2) in, with Mn (Ac)3Replace palladium carbon, replace paraxylene, control Mn (Ac) with glacial acetic acid3Addition be
2 times of the amount of 1 material of compound, reaction are carried out under the conditions of 70 DEG C, and TLC tracing detection terminates to reaction, then will with ammoniacal liquor
The pH of system is adjusted to 7, then is extracted with ethyl acetate three times, merges organic phase, solvent evaporated, residue obtained upper silicagel column (chromatography
Purifying (VPetroleum ether：VDichloromethane=1:1), compound 2 is obtained.
The analysis of proton nmr spectra, carbon-13 nmr spectra and high resolution mass spectrum is carried out to the present embodiment products therefrom, is determined
For target product 1- (2- pyridine) -9- (2- Phenoxyethyl)-B-carboline.
Embodiment 3：The synthesis of ligand L
Repeat embodiment 2, except for the difference that：
Step 2) in, with Pb (Ac)4Replace Mn (Ac)3, control Pb (Ac)4Addition for 1 material of compound amount 5
Times, reaction is carried out under the conditions of 60 DEG C.
The analysis of proton nmr spectra, carbon-13 nmr spectra and high resolution mass spectrum is carried out to the present embodiment products therefrom, is determined
For target product 1- (2- pyridine) -9- (2- Phenoxyethyl)-B-carboline.
Embodiment 4：The synthesis of ligand L
Repeat embodiment 1, except for the difference that：
Step 2) in, use chloro- 5, the 6- dicyan 1,4-benzoquinone of 2,3- bis- to replace palladium carbon, replace paraxylene with dichloromethane, 2,
The addition of the chloro- 5,6- dicyan 1,4-benzoquinone of 3- bis- is equal with the amount of the material of compound 1.
The analysis of proton nmr spectra, carbon-13 nmr spectra and high resolution mass spectrum is carried out to the present embodiment products therefrom, is determined
For target product 1- (2- pyridine) -9- (2- Phenoxyethyl)-B-carboline.
Embodiment 5：Title complex [Cu (L) Cl2] synthesis
In the heavy wall borosilicate glass tube being open at one end, 0.1mmol CuCl is directly added into2·2H2O and 0.1mmol part
L, (volume ratio of methyl alcohol and dichloromethane is 3 to add 0.6ml ethanol/methylene mixed solution:1), in the bar for vacuumizing
Under part, then openend sealing by fusing fully reacts 20 hours under the conditions of 50 DEG C, obtain green crystal type solid product.
Products therefrom is characterized：
(1) high resolution mass spectrum, ESI-MS m/z:541[Cu(L)(DMSO)Cl]+. (DMSO from mass spectrometric measurement when use
Solvent), as shown in Figure 1.
Therefore can determine that above-mentioned product is with 1- (2- pyridine) -9- (2- Phenoxyethyl) copper of-B-carboline as part
(II) complex is title complex [Cu (L) Cl2], shown in its structural formula such as following formula (I)：
Embodiment 6：Title complex [Cu (L) Cl2] synthesis
In the heavy wall borosilicate glass tube being open at one end, 0.2mmol CuCl is directly added into2·2H2O and 0.1mmol part
L, (volume ratio of ethanol and chloroform is 3 to add 0.6ml ethanol/chloroform mixed solution:1), under conditions of vacuumizing, will open
Mouth end sealing by fusing, then fully reacts 12 hours under the conditions of 80 DEG C, obtains green crystal type solid product.
Products therefrom carries out structure determination through high resolution mass spectrum analysis, is defined as title complex [Cu (L) Cl2].
Embodiment 7：Title complex [Cu (L) Cl2] synthesis
In the heavy wall borosilicate glass tube being open at one end, 0.3mmol CuCl is directly added into2·2H2O and 0.1mmol part
Abbreviation L, adds 0.6ml methanol/ethanol/N,N-dimethylformamide mixed solution (methyl alcohol, ethanol and N, N- dimethyl formyl
The volume ratio of amine is 5：1：1), under conditions of vacuumizing, then openend sealing by fusing fully reacts 4 little under the conditions of 100 DEG C
When, obtain green crystal type solid product.
Products therefrom carries out structure determination through high resolution mass spectrum analysis, is defined as title complex [Cu (L) Cl2].
Embodiment 8：Title complex [Cu (L) Cl2] synthesis
In the heavy wall borosilicate glass tube being open at one end, 0.4mmol CuCl is directly added into2·2H2O and 0.1mmol part
L, (volume ratio of ethanol and acetone is 10 to add 0.6ml ethanol/acetone mixed solution:1), under conditions of vacuumizing, will
Openend sealing by fusing, then fully reacts 4 hours under the conditions of 80 DEG C, obtains green crystal type solid product.
Products therefrom carries out structure determination through high resolution mass spectrum analysis, is defined as title complex [Cu (L) Cl2].
Embodiment 9：Title complex [Cu (L) Cl2] synthesis
Take 6mmol CuCl2·2H2O and 1mmol ligand L is placed in round-bottomed flask, is added thereto to 80ml ethanol/water and is mixed
(volume ratio of second alcohol and water is 1 to close solution:1), after stirring and dissolving, 60 DEG C are heated to and are reacted 12 hours, reactant reduced pressure concentration
Partial solvent is removed, is stood, have green crystal to separate out, solid is isolated, is washed with ethanol, dry, obtain green crystal.
Products therefrom carries out structure determination through high resolution mass spectrum analysis, is defined as title complex [Cu (L) Cl2].
Embodiment 10：Title complex [Cu (L) Cl2] synthesis
Take 2mmol CuCl2·2H2O and 1mmol ligand L is placed in round-bottomed flask, be added thereto to 50ml methanol/acetone/
(volume ratio of methyl alcohol, acetone and water is 30 to water mixed solution：1：10), after stirring and dissolving, 50 DEG C of reactions 12 hours are heated to, instead
Answer thing reduced pressure concentration that partial solvent is removed, stand, have green crystal to separate out, solid is isolated, is washed with ethanol, dry, obtain
Green crystal.
Products therefrom carries out structure determination through high resolution mass spectrum analysis, is defined as title complex [Cu (L) Cl2].
Embodiment 11：Title complex [Cu (L) Cl2] synthesis
Take 3mmol CuCl2·2H2O and 1mmol ligand L is placed in round-bottomed flask, is added thereto to 30ml methyl alcohol/chloroform
(volume ratio of methyl alcohol and chloroform is 1 to mixed solution：1), after stirring and dissolving, react 18 hours in 20 DEG C, reactant reduced pressure concentration
Partial solvent is removed, is stood, have green crystal to separate out, solid is isolated, is washed with ethanol, dry, obtain green crystal.
Products therefrom carries out structure determination through high resolution mass spectrum analysis, is defined as title complex [Cu (L) Cl2].
In order to absolutely prove purposes of the complex of the present invention in pharmacy, applicant has carried out extracorporeal anti-tumor to which
Activity experiment.
Experimental example 1：Copper chloride (II) complex with 1- (2- pyridine) -9- (2- Phenoxyethyl)-B-carboline as part
(being obtained by 5 methods described of the embodiment of the present invention) and ligand L (being obtained by 1 methods described of the embodiment of the present invention) are swollen to multiple mankind
Knurl strain carries out external inhibitory activity experiment.
1st, cell line and cell culture
This experiment is non-from gastric carcinoma cells MGC-803, human hepatoma cell strain Hep G2, human bladder cancer cell T-24, people
Small cell lung cancer cell NCI-H460 and human normal cell line HL-7702 totally 5 kinds of cell lines.
All tumor cell lines are all cultivated containing 10wt% little ox blood, 100U/mL penicillin, 100U/mL streptomysin
In RPMI-1640 nutrient solution, 37 DEG C of 5%CO containing volumetric concentration are put2Cultivate in incubator；Human normal cell line strain is then cultivated and is being contained
In the little ox blood of 10wt%, 100U/mL penicillin, the DMEM nutrient solution of 100U/mL streptomysin.
2nd, the preparation of testing compound
The DMSO liquid storage (concentration is 0.002mol/L) of each testing compound is diluted successively by RMPI1640 culture medium
Become five concentration gradients, respectively 20,10,5,2.5,1.25 μm of ol/L, wherein cosolvent DMSO final concentration≤1%.Survey first
Each testing compound of 20 μm of ol/L of examination is considered as primary dcreening operation result for the inhibiting rate of tumor cell proliferation；Test respectively again different
Proliferation Ability degree of each testing compound to various tumour cells under gradient concentration, in order to the Fitting Calculation half-inhibition concentration,
That is IC50Value.
3rd, cell growth inhibition test (mtt assay)
(1) take the logarithm the tumour cell in growth period, after Trypsin Induced, joined with the nutrient solution containing 10% calf serum
Cell suspension of the concentration for 5000/mL is made, is inoculated in 96 well culture plates with 190 μ L of every hole, makes cell density to be measured extremely
1000～10000/hole (edge hole is filled with aseptic PBS)；
(2) 5%CO2, 37 DEG C of incubation 24h, bottom hole is paved with to cell monolayer, add the medicine 10 of finite concentration gradient per hole
μ L, each concentration gradient set 4 multiple holes；
(3) 5%CO2, 37 DEG C are incubated 48 hours, observe under inverted microscope；
(4) the MTT solution (5mg/mL PBS, i.e. 0.5%MTT) of 10 μ L is added per hole, continues culture 4h；
(5) terminate culture, in the hole nutrient solution is carefully sucked, add per hole 150 μ L DMSO that first a ceremonial jade-ladle, used in libation precipitation is fully dissolved, shake
After swinging device mixing, it is 570nm in ELIASA wavelength, reference wavelength is the OD value that 450nm determines each hole；
(6) while arranging zeroing hole (culture medium, MTT, DMSO), (cell, the medicine dissolving of same concentrations are situated between control wells
Matter, nutrient solution, MTT, DMSO).
(7) according to the OD value (OD value) for measuring, judge living cells quantity, OD value is bigger, and cytoactive is stronger.
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 fitted by SPSS software, obtain compound to different tumours by strain further
Half-inhibition concentration (the IC of strain50Value, unit μm ol/L), compound is for the IC of different cell lines50Value is as shown in table 1.
Table 1：IC of the compound of the present invention to 5 kinds of cell lines50Value (μm ol/L)
From the point of view of anti tumor activity in vitro test result, complex of the present invention has stronger antitumor activity, its
Activity is substantially better than cis-platinum, is expected to develop into antineoplastic.
Claims (10)
1. compound shown in formula (I) or its pharmaceutically acceptable salt are descended：
2. the synthetic method of compound described in claim 1, it is characterised in that：Take compound and chlorination as shown in following formula (II)
Copper, is dissolved in polar solvent, carries out complexation reaction, that is, obtain target product；Wherein, described polar solvent be selected from methyl alcohol and
One or two and one or two in water, acetone, chloroform, dichloromethane and the DMF in ethanol
Above combination；
3. synthetic method according to claim 2, it is characterised in that：Compound shown in formula (II) and copper chloride is taken, is dissolved in
In polar solvent, gained mixed liquor is reacted under the conditions of being heated or not heated, and reactant removes partial solvent, is stood, and is separated out, point
Crystal is separated out, obtains final product target product.
4. synthetic method according to claim 3, it is characterised in that：React the reflux temperature model at 50 DEG C to polar solvent
Carry out in enclosing.
5. synthetic method according to claim 2, it is characterised in that：Compound shown in formula (II) and copper chloride is taken, is dissolved in
In polar solvent, gained mixed liquor is placed in container, is evacuated to vacuum after liquid nitrogen frozen, and sealing by fusing, then in 30～140 DEG C of conditions
Lower reaction, obtains target product.
6. synthetic method according to claim 5, it is characterised in that：Reaction is carried out under the conditions of 50～140 DEG C.
7. the synthetic method according to any one of claim 2～6, it is characterised in that：Compound shown in formula (II)
It is prepared as follows：
With tryptamines and pyridine-2-formaldehyde as raw material, react in the first organic solvent, compound 1 is obtained through dehydrating condensation；So
Afterwards compound 1 is placed in the second organic solvent, adds oxidant cyclization and dehydrogenation obtains compound 2；Again compound 2 is placed in
In the aprotic polar solvent of alkaline matter, add 2- phenoxy group bromoethane that substitution reaction is carried out, obtain final product；Wherein：
The first described organic solvent be in toluene, methyl alcohol, ethanol, dichloromethane and chloroform one or two with
On combination；
The second described organic solvent be in benzene, toluene, paraxylene, glacial acetic acid and dichloromethane one or two with
On combination；
Described oxidant is palladium carbon, manganese acetate hydrate, lead tetraacetate or the chloro- 5,6- dicyan 1,4-benzoquinone of 2,3- bis-；
Described alkaline matter is inorganic base；
Described aprotic polar solvent is one or two in N,N-dimethylformamide, dimethyl sulfoxide (DMSO) and acetone
Above combination.
8. synthetic method according to claim 7, it is characterised in that：Purifying behaviour is carried out to compound shown in gained formula (II)
Make.
9. the application of compound described in claim 1 or its pharmaceutically acceptable salt in antineoplastic is prepared.
10. the antineoplastic for being prepared with compound described in claim 1 or its pharmaceutically acceptable salt as active component.
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|---|---|---|---|---|
| CN1500789A (en) * | 2002-11-19 | 2004-06-02 | 北京大学 | Complex ML(DCA) of copper(II), gallium(III) and rare earth ion(Ln**) containing non-methyl canthridic acid radical |
| EP2508570A2 (en) * | 2009-12-02 | 2012-10-10 | SFC Co., Ltd. | Organic metal dye, and photoelectric element and dye-sensitized solar cell using the organic metal dye |
| CN103254239A (en) * | 2013-03-20 | 2013-08-21 | 中山大学 | aryl ruthenium-beta-carboline complex and its preparation method and application |
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|---|---|---|---|---|
| CN1500789A (en) * | 2002-11-19 | 2004-06-02 | 北京大学 | Complex ML(DCA) of copper(II), gallium(III) and rare earth ion(Ln**) containing non-methyl canthridic acid radical |
| EP2508570A2 (en) * | 2009-12-02 | 2012-10-10 | SFC Co., Ltd. | Organic metal dye, and photoelectric element and dye-sensitized solar cell using the organic metal dye |
| CN103254239A (en) * | 2013-03-20 | 2013-08-21 | 中山大学 | aryl ruthenium-beta-carboline complex and its preparation method and application |
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