CN106478685A - Chlorination copper complex with 1 (2 pyridine) 9 propyl group β carboline as part and its synthetic method and application - Google Patents
Chlorination copper complex with 1 (2 pyridine) 9 propyl group β carboline as part and its synthetic method and application Download PDFInfo
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- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic System
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- 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
- C07D471/02—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 two hetero rings
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- C—CHEMISTRY; METALLURGY
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- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic System
- C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic System without C-Metal linkages
Abstract
The invention discloses the chlorination copper complex with 1 (2 pyridine) 9 propyl group β carboline as part for the one kind and its synthetic method and application.Shown in the structural formula of this coordination compound such as following formula (I), its synthetic method is：Take compound and copper chloride as shown in following formula (II), be dissolved in polar solvent, carry out complexation reaction, obtain final product；Wherein, described polar solvent be selected from one of methanol and ethanol or two kinds with selected from water, acetone, chloroform, dichloromethane and N, one of N dimethylformamide or two or more combinations.Coordination compound of the present invention shows the anti-tumor activity more higher than part and cisplatin, has preferably potential medical value, is expected to be used for the preparation of various antitumor drug.Formula (I) and structure shown in formula (II) are as follows：
Description
Technical field
The present invention relates to pharmaceutical technology field is and in particular to one kind is with 1- (2- pyridine) -9- propyl group-B-carboline as part
Chlorination copper complex and its 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 being made up of trypoline
Member ring systems, its skeleton is a planar molecule, and two nitrogen-atoms of wherein 2 and 9 are existed with different hybridization states,
9 nitrogen-atoms are sp3Hydridization, for rich pi-electron system, 2 nitrogen-atoms are sp2Hydridization, for lacking pi-electron system.Two nitrogen-atoms with
The chemical property of such compound and biological activity are closely related.Such compound has extensive biology and pharmacology lives
Property, including：Tranquilizer, anxiety, hypnosis, spasmolytic, antitumor, antiviral, parasite killing and antibacterial activity etc..Therefore β-click
Quinoline alkaloid is increasingly paid attention to by research worker.
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 cisplatin, carboplatin, oxaliplatin etc. as representative
Cancer therapy drug, as the successful Application of front-line chemotherapeutic agents, really indicates the arrival of Metal Drugs research and application New Times.
But have not yet to see copper (II) coordination compound with 1- (2- pyridine) -9- propyl group-B-carboline as part and its synthetic method and answer
Relevant report.
Content of the invention
The technical problem to be solved in the present invention is a kind of offer structure novelty with 1- (2- pyridine) -9- propyl group-B-carboline
Copper chloride (II) coordination compound for part, 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, carries out complexation reaction, that is, obtain target product；Wherein, described polar solvent is
Selected from one of methanol and ethanol or two kinds with water, acetone, chloroform, dichloromethane and DMF
One or more combination；
The compound shown in 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- propyl group-B-carboline, also referred to as L in this application.Compound shown in this formula (II) can designed, designed synthesis
Route is prepared, and is preferably prepared as follows：
With tryptamines and pyridine-2-formaldehyde as raw material, react in the first organic solvent, obtain compound 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 1- N-Propyl Bromide to carry out substitution reaction, that is,
?；Wherein：
The first described organic solvent is selected from one of toluene, methanol, ethanol, dichloromethane and chloroform or two
Plant above combination；
The second described organic solvent is selected from one of benzene, toluene, xylol, glacial acetic acid and dichloromethane or two
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 selected from one of N,N-dimethylformamide, dimethyl sulfoxide 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 is molten
Agent.
Compound more specifically preparation method 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 becoming, question response terminates rear solvent evaporated, obtains compound 1；
2. compound 1 is placed in the second organic solvent, adds oxidant, 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, be subsequently adding compound 2 and 1- N-Propyl Bromide is reacted, treat
Reaction terminates, and reactant is put in frozen water, gained mixture of ice and water is extracted, and collects organic faciess, solvent evaporated, obtains final product
To compound (i.e. compound 3) shown in formula (II).
The step of compound synthesis method shown in above-mentioned formula (II) 1. in, the amount of the material of tryptamines and pyridine-2-formaldehyde it
Ratio 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
Discharge the water that reaction generates, whether reaction can adopt thin layer chromatography (TLC) tracing detection completely；Preferably, reaction adopts
Heating reflux reaction, the time control now reacted is appropriate in 2～6h.In this step, obtain 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
Carry out postorder reaction again.Specific purification process can be with little polar solvent recrystallization, gained recrystallization product to residue obtained
Thing is used further to postorder reaction.The described little polar solvent for recrystallization is same as the prior art, can be specifically petroleum ether and/
Or normal hexane etc..
The step of compound synthesis method shown in above-mentioned formula (II) 2. in, reaction preferably employ heating reflux reaction, reaction
Whether thin layer chromatography tracing detection can be adopted completely.In this step, obtain 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 to residue obtained again
Reaction.Specific purification process can be to residue obtained with selected from one of methanol, ethanol and dichloromethane or two kinds with
On combination solvent carry out recrystallization, or by residue obtained upper silica gel column chromatography purification, in upper silica gel column chromatography, used
Eluant be that petroleum ether and dichloromethane press 6：1～1：The mixed solvent of 1 volume ratio composition.
The step of compound synthesis method shown in above-mentioned formula (II) 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 one of benzene, toluene and xylol
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 described 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 described manganese acetate hydrate or lead tetraacetate is usually 2～8 times of the amount of compound 1 material.Choosing when oxidant
When being selected as manganese acetate hydrate or lead tetraacetate, with pH >=7 of alkali liquor regulation system after preferably reaction terminates, then it is extracted
Take, collect organic faciess, the residue of solvent evaporated gained goes up silica gel column chromatography purification again；Wherein, described alkali liquor can be ammonia,
The aqueous solution of the alkaline matters such as sodium acetate, sodium carbonate, sodium phosphate, sodium bicarbonate or potassium carbonate, the concentration of described alkali liquor is preferably 5
～30w/w%；The solvent adjusting system after pH value for extraction can be specifically ethyl acetate, dichloromethane, chloroform or ether etc..
(3) when oxidant is when being chosen as 2,3-, bis- chloro- 5,6- dicyan 1,4-benzoquinone, 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 described 2,3- bis- is usually compound 1
1～4 times of the amount of material.
The step of compound synthesis method shown in above-mentioned formula (II) 3. in, described alkaline matter, compound 2 and 1- N-Propyl Bromide
The amount of material ratio be usually 1～4：1：1～3, alkaline matter therein can be sodium hydride, calcium hydride, hydrogen-oxygen further
Change one of calcium, sodium hydroxide, potassium hydroxide, cesium carbonate and potassium carbonate or two or more combinations, when the choosing of alkaline matter
Be selected as more than above two combination when, the proportioning between them can be any proportioning.In this step, reaction can 0～
Carry out under the conditions of 80 DEG C, whether reaction can adopt thin layer chromatography (TLC) tracing detection completely；Preferably, reaction 20～
50 DEG C, the time control now reacted is appropriate in 1～6h.The solvent that mixture of ice and water is extracted can be specifically acetic acid
The conventional extraction solvent such as ethyl ester, dichloromethane, chloroform, petroleum ether or ether.
Involved various solvents in compound synthesis method shown in above-mentioned formula (II) (such 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 prepared is the crude product of compound shown in formula (II), in order to improve further shown in formula (II)
The purity of compound, is more beneficial for the carrying out of subsequent reactions, preferably above-mentioned gained crude product is carried out using 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 purification, to obtain pure compounds shown in formula (II)；In upper silica gel column chromatography, eluant used is two
Chloromethanes and methanol 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, methanol or ethanol or
Person is that the group of methanol and ethanol is combined in shared ratio in polar solvent and 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 described 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 respectively with compound shown in formula (II), remix and react together.
In the synthetic method of compound shown in formula (I) of the present invention, described 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：Take compound shown in formula (II) and copper chloride, be dissolved in polarity
In solvent, gained mixed liquor reacts under the conditions of being heated or not heated, and reactant removes partial solvent, standing, separates out, isolates
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 adopts
With back flow reaction, further preferably reaction is to carry 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 (upper limit as close to proportioning) or solvent is molten to product
Preferably, then after reacting, solution may be in clear state to solution property, this is because the product precipitation 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.Separate the solid obtaining can be washed with ether, acetone, ethanol, methanol or dichloromethane further, it
It is dried afterwards again.
When high pressure solvent full-boiled process, its synthetic method includes：Take compound shown in formula (II) and copper chloride, be dissolved in polarity molten
In agent, gained mixed liquor is placed in container, is evacuated to vacuum after liquid nitrogen freezing, sealing by fusing, then anti-under the conditions of 30～140 DEG C
Should, obtain target product.
In above-mentioned high pressure solvent full-boiled process, described container is usually heavy wall borosilicate glass tube, and reaction is 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 practical situation
More than 24h.Further preferably mixed solution is to be 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 room temperature below 80 DEG C for the reaction or heating condition, when reaction needs longer
Between just can obtain higher yield.
Present invention additionally comprises compound or its pharmaceutically acceptable salt are in preparing antitumor drug shown in above-mentioned formula (I)
Application.
Present invention additionally comprises prepared with compound shown in above-mentioned formula (I) or its pharmaceutically acceptable salt for active component
Antitumor drug.
Compared with prior art, the invention provides a kind of new with 1- (2- pyridine) -9- propyl group-B-carboline as part
Copper chloride (II) coordination compound, and its synthetic method and application.Applicant passes through to investigate its suppression to various tumor cell strains
Make and use, result shows that this coordination compound has stronger anti tumor activity in vitro, and apparently higher than cisplatin, has preferably potential
Medical value, is expected to be used for the preparation of various antitumor drug.
Brief description
Fig. 1 is the x-ray crystal structure figure of the final product that the embodiment of the present invention 5 is obtained.
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- propyl group-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, condensing tube group composition water reflux, is heated to reflux 4 hours, question response terminates rear solvent evaporated, residue
It is recrystallized to give compound 1 (2.3g, yield 92%) with 100ml normal hexane；
2) 2.5g (10mmol) compound 1,2.5g palladium carbon (10%Pd/C) and 100ml xylol are added 250ml circle
Bottom flask, is heated to flowing back, and is terminated to reaction with thin layer chromatography tracing detection, and filtrate is simultaneously evaporated by standing sucking filtration, and gained is residual
Silica gel column chromatography purification (V on slagPetroleum ether：VDichloromethane=1:1), obtain compound 2 (2.1g, yield 86%)；
3) 0.24g (10mmol) sodium hydride and 15ml DMF are added to 50ml round-bottomed flask, room temperature
Stirring 10 minutes, adds 2.5g (10mmol) compound 2 and 10mmol 1- N-Propyl Bromide, and with thin layer chromatography tracing detection extremely
Reaction terminates, and then puts into reactant liquor in 500ml frozen water, is extracted three times with 100ml ethyl acetate, merges organic faciess, be evaporated
Solvent, residue obtained upper silica gel column chromatography purification (VDichloromethane：VMethanol=100:1), obtain compound 3 (2.3g, yield 80%).
Products therefrom is characterized：
(1) proton nmr spectra and carbon spectrum, their spectral data is as follows：
1H NMR(500MHz,CDCl3) δ 8.73 (d, J=4.9Hz, 1H), 8.52 (d, J=5.1Hz, 1H), 8.14 (d, J
=7.8Hz, 1H), 8.01 (d, J=5.1Hz, 1H), 7.91 7.85 (m, 2H), 7.57 7.53 (m, 1H), 7.43 (d, J=
8.3Hz, 1H), 7.36 (ddd, J=6.9,4.9,2.1Hz, 1H), 7.26 (t, J=7.5Hz, 1H), 4.13 4.06 (m, 2H),
1.46 1.37 (m, 2H), 0.48 (t, J=7.4Hz, 3H).
13C NMR(126MHz,CDCl3)δ158.88,148.48,142.67,142.50,138.12,137.06,
134.35,131.24,128.61,125.25,123.19,121.64,121.36,119.89,114.74,110.38,46.77,
22.35,11.23.
(2) high resolution mass spectrum, ESI-MS m/z:288.1[M+H]+.
Accordingly, it can be determined that above-mentioned product is 1- (2- pyridine) -9- propyl group-B-carboline, its chemical structural formula such as following formula
(II) shown in：
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 xylol with glacial acetic acid, control Mn (Ac)3Addition be
2 times of the amount of compound 1 material, reaction is carried out under the conditions of 70 DEG C, and TLC tracing detection terminates to reaction, then will with ammonia
The pH of system is adjusted to 7, then is extracted with ethyl acetate three times, merges organic faciess, solvent evaporated, residue obtained upper silicagel column (chromatography
Purification (VPetroleum ether：VDichloromethane=1:1), obtain compound 2.
The present embodiment products therefrom is carried out with proton nmr spectra, carbon-13 nmr spectra and high resolution mass spectrum analysis, determines
For target product 1- (2- pyridine) -9- propyl group-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 be compound 1 material amount 5
Times, reaction is carried out under the conditions of 60 DEG C.
The present embodiment products therefrom is carried out with proton nmr spectra, carbon-13 nmr spectra and high resolution mass spectrum analysis, determines
For target product 1- (2- pyridine) -9- propyl group-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 xylol 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 present embodiment products therefrom is carried out with proton nmr spectra, carbon-13 nmr spectra and high resolution mass spectrum analysis, determines
For target product 1- (2- pyridine) -9- propyl group-B-carboline.
Embodiment 5：Title complex [Cu (L) Cl2] synthesis
At one end in the heavy wall borosilicate glass tube of opening, it is directly added into 0.1mmol CuCl2·2H2O and 0.1mmol part
L, (volume ratio of methanol and dichloromethane is 3 to add 0.6ml ethanol/methylene mixed solution:1), in the bar of evacuation
Under part, then opening 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:463[Cu(L)(DMSO)Cl]+. (DMSO is derived from and uses during mass spectrometric measurement
Solvent)
(2) X-ray single crystal diffraction analysis, as shown in Figure 1.
Therefore can determine that above-mentioned product is copper (II) coordination compound with 1- (2- pyridine) -9- propyl group-B-carboline as part
I.e. title complex [Cu (L) Cl2], shown in its structural formula such as following formula (I)：
Embodiment 6：Title complex [Cu (L) Cl2] synthesis
At one end in the heavy wall borosilicate glass tube of opening, it is directly added into 0.2mmol CuCl2·2H2O 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 evacuation, 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 and the analysis of X-ray single crystal diffraction, is defined as target cooperation
Thing [Cu (L) Cl2].
Embodiment 7：Title complex [Cu (L) Cl2] synthesis
At one end in the heavy wall borosilicate glass tube of opening, it is directly added into 0.3mmol CuCl2·2H2O and 0.1mmol part
Abbreviation L, adds 0.6ml methanol/ethanol/N,N-dimethylformamide mixed solution (methanol, ethanol and N, N- dimethyl formyl
The volume ratio of amine is 5：1：1), under conditions of evacuation, by opening sealing by fusing, then under the conditions of 100 DEG C, fully reaction 4 is little
When, obtain green crystal type solid product.
Products therefrom carries out structure determination through high resolution mass spectrum and the analysis of X-ray single crystal diffraction, is defined as target cooperation
Thing [Cu (L) Cl2].
Embodiment 8：Title complex [Cu (L) Cl2] synthesis
At one end in the heavy wall borosilicate glass tube of opening, it is directly added into 0.4mmol CuCl2·2H2O 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 evacuation, will
Opening 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 and the analysis of X-ray single crystal diffraction, is defined as target cooperation
Thing [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 mixes
(volume ratio of second alcohol and water is 1 to close solution:1), after stirring and dissolving, it is heated to 60 DEG C and reacts 12 hours, reactant concentrating under reduced pressure
Remove partial solvent, standing, have green crystal to separate out, isolate solid, with washing with alcohol, be dried, obtain green crystal.
Products therefrom carries out structure determination through high resolution mass spectrum and the analysis of X-ray single crystal diffraction, is defined as target cooperation
Thing [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 methanol, acetone and water is 30 to water mixed solution：1：10), after stirring and dissolving, it is heated to 50 DEG C of reactions 12 hours, instead
Answer thing concentrating under reduced pressure to remove partial solvent, standing, have green crystal to separate out, isolate solid, with washing with alcohol, be dried, obtain
Green crystal.
Products therefrom carries out structure determination through high resolution mass spectrum and the analysis of X-ray single crystal diffraction, is defined as target cooperation
Thing [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 methanol/chloroform
(volume ratio of methanol and chloroform is 1 to mixed solution：1), after stirring and dissolving, react 18 hours in 20 DEG C, reactant concentrating under reduced pressure
Remove partial solvent, standing, have green crystal to separate out, isolate solid, with washing with alcohol, be dried, obtain green crystal.
Products therefrom carries out structure determination through high resolution mass spectrum and the analysis of X-ray single crystal diffraction, is defined as target cooperation
Thing [Cu (L) Cl2].
In order to absolutely prove purposes in pharmacy for the coordination compound of the present invention, applicant has carried out extracorporeal anti-tumor to it
Activity experiment.
Experimental example 1：Copper chloride (II) coordination compound with 1- (2- pyridine) -9- propyl group-B-carboline as part is (real by the present invention
Apply example 5 methods described be obtained) and ligand L (by the embodiment of the present invention 1 methods described be obtained) body is carried out to multiple human tumor strains
Outer inhibitory activity experiment
1st, cell strain and cell culture
This experiment selects gastric carcinoma cells MGC-803, human hepatoma cell strain Hep G2, human bladder cancer cell T-24, people non-
Small cell lung cancer cell NCI-H460 and human normal cell line HL-7702 totally 5 kinds of cell strains.
All tumor cell lines are all cultivated in calf blood containing 10wt%, 100U/mL penicillin, 100U/mL streptomycin
In RPMI-1640 culture fluid, put 37 DEG C of 5%CO containing volumetric concentration2Cultivate in incubator；Human normal cell line strain is then cultivated and is being contained
In 10wt% calf blood, 100U/mL penicillin, the DMEM culture fluid of 100U/mL streptomycin.
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 Concentraton gradient, 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, for the suppression ratio of tumor cell proliferation, is considered as primary dcreening operation result；Test different more respectively
The Proliferation Ability degree to various tumor cells for each testing compound under gradient concentration, in order to the Fitting Calculation half-inhibition concentration,
I.e. IC50Value.
3rd, cell growth inhibition test (mtt assay)
(1) take the logarithm the tumor cell of trophophase, after trypsinization, joined with the culture fluid containing 10% calf serum
Make the cell suspension that concentration is 5000/mL, be inoculated in 96 well culture plates with every hole 190 μ L, make 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, it is paved with bottom hole to cell monolayer, every hole adds the medicine 10 of finite concentration gradient
μ L, each Concentraton gradient sets 4 multiple holes；
(3) 5%CO2, 37 DEG C are incubated 48 hours, observe under inverted microscope；
(4) every hole adds the MTT solution (5mg/mL PBS, i.e. 0.5%MTT) of 10 μ L, continues culture 4h；
(5) terminate culture, carefully suck in the hole culture fluid, every hole adds 150 μ L DMSO fully to dissolve first a ceremonial jade-ladle, used in libation precipitation, shakes
After swinging device mixing, it is 570nm in microplate reader wavelength, reference wavelength is the optical density value that 450nm measures each hole；
(6) setting zeroing hole (culture medium, MTT, DMSO) simultaneously, (cell, the medicine dissolution of same concentrations are situated between control wells
Matter, culture fluid, MTT, DMSO).
(7) according to the optical density value (OD value) recording, to judge living cells quantity, OD value is bigger, and cytoactive is stronger.
Calculate the suppression ratio to growth of tumour cell for the compound.For the cell more than 50% for the suppression ratio under primary dcreening operation concentration
Strain, is fitted to the suppression ratio data of five Concentraton gradient by SPSS software further, obtains compound to different tumors
Half-inhibition concentration (the IC of strain50Value, unit μm ol/L), compound is for the IC of different cell strains50Value is as shown in table 1.
Table 1：The IC to 5 kinds of cell strains for the compound of the present invention50Value (μm ol/L)
From the point of view of anti tumor activity in vitro test result, coordination compound of the present invention has stronger anti-tumor activity, its
Activity is substantially better than cisplatin, is expected to develop into antitumor drug.
Claims (10)
1. descend compound shown in formula (I) or its pharmaceutically acceptable salt：
2. compound described in claim 1 synthetic method 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 methanol and
One of ethanol or two kinds with selected from one of water, acetone, chloroform, dichloromethane and DMF or two kinds
Above combination；
3. synthetic method according to claim 2 it is characterised in that：Take compound shown in formula (II) and copper chloride, be dissolved in
In polar solvent, gained mixed liquor reacts under the conditions of being heated or not heated, and reactant removes partial solvent, standing, separates out, point
Separate out crystal, obtain 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：Take compound shown in formula (II) and copper chloride, be dissolved in
In polar solvent, gained mixed liquor is placed in container, is evacuated to vacuum, sealing by fusing, then in 30～140 DEG C of conditions after liquid nitrogen freezing
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 described formula (II)
It is prepared as follows：
With tryptamines and pyridine-2-formaldehyde as raw material, react in the first organic solvent, obtain compound 1 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 1- N-Propyl Bromide to carry out substitution reaction, obtain final product；Wherein：
The first described organic solvent be selected from one of toluene, methanol, ethanol, dichloromethane and chloroform or two kinds with
On combination；
The second described organic solvent be selected from one of benzene, toluene, xylol, glacial acetic acid and dichloromethane or two kinds 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 selected from one of N,N-dimethylformamide, dimethyl sulfoxide and acetone or two kinds
Above combination.
8. synthetic method according to claim 7 it is characterised in that：Purification behaviour is carried out to compound shown in gained formula (II)
Make.
9. compound described in claim 1 or its pharmaceutically acceptable salt application in preparing antitumor drug.
10. the antitumor drug prepared with compound described in claim 1 or its pharmaceutically acceptable salt for active component.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2016
- 2016-09-26 CN CN201610852974.1A patent/CN106478685B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Non-Patent Citations (2)
| Title |
|---|
| KE-BIN HUANG ET AL: "Copper(II/I) complexes of 5-pyridin-2-yl-[1,3]dioxolo[4,5-g] isoquinoline: Synthesis, crystal structure, antitumor activity and DNA interaction", 《EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY》 * |
| 张前亮: "3_甲基_咔啉衍生物的合成及其抑菌活性研究", 《西北农林科技大学硕士学位论文》 * |
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