CN106478679B - The copper-nitrate complex of 1 (2 pyridine) 9 Cvclopropvlmethvl β carbolines and its synthetic method and application - Google Patents
The copper-nitrate complex of 1 (2 pyridine) 9 Cvclopropvlmethvl β carbolines and its synthetic method and application Download PDFInfo
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- GYRIWOFRMKNJHC-UHFFFAOYSA-N Cc1cccnc1-c1c2[n](CC3CC3)c(cccc3)c3c2ccn1 Chemical compound Cc1cccnc1-c1c2[n](CC3CC3)c(cccc3)c3c2ccn1 GYRIWOFRMKNJHC-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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
- C07F1/08—Copper compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—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
- C07D471/04—Ortho-condensed systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- 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 a kind of copper-nitrate complex of 1 (2 pyridine) 9 Cvclopropvlmethvl β carbolines and its synthetic method and application.Shown in the structural formula of the complex such as following formula (I), its synthetic method is：Compound and copper nitrate as shown in following formula (II) are taken, is dissolved in polar solvent, complexation reaction is carried out, produces；Wherein, described polar solvent is selected from one or both of methanol and ethanol and the combination more than one or both of water, acetone, chloroform, dichloromethane and N, N dimethylformamide.Complex of the present invention shows the antitumor activity more stronger than part and cis-platinum, has preferable potential medical value, is expected to be used for the preparation of various antineoplastics.Structure shown in formula (I) and formula (II) is as follows：
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to a kind of nitre of 1- (2- pyridines) -9- Cvclopropvlmethvls-B-carboline
Sour copper complex and its synthetic method and application.
Background technology
B-carboline is a kind of alkaloid for being distributed widely in nature, and they are primarily present in a variety of 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 a planar molecules, wherein two nitrogen-atoms of 2 and 9 exist with different hybridization states,
9 nitrogen-atoms are sp3Hydridization, is rich pi-electron system, and 2 nitrogen-atoms are sp2Hydridization, to lack pi-electron system.Two nitrogen-atoms with
The chemical property and bioactivity of such compound are closely related.There is such compound extensive biology and pharmacology to live
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 turn into hot research field, the first, second and third generation platinum class especially with cis-platinum, carboplatin, oxaliplatin etc. for representative
Successful application of the cancer therapy drug as front-line chemotherapeutic agents, really indicate Metal Drugs research and the arrival of application New Times.
But have not yet to see using 1- (2- pyridines) -9- Cvclopropvlmethvls-B-carboline as copper nitrate (II) complex of part and its conjunction
Into the relevant report of methods and applications.
The content of the invention
The technical problem to be solved in the present invention is to provide a kind of structure it is novel with 1- (2- pyridines) -9- Cvclopropvlmethvls -
B-carboline is copper nitrate (II) complex of part, and its synthetic method and application.
The present invention relates to compound shown in lower formula (I) or its pharmaceutically acceptable salt：
The synthetic method of compound is shown in above-mentioned formula (I)：Take compound and copper nitrate (Cu as shown in following formula (II)
(NO3)2·3H2O), it is dissolved in polar solvent, carries out complexation reaction, that is, obtain target product；Wherein, described polar solvent is
Selected from one or both of methanol and ethanol with water, acetone, chloroform, dichloromethane and DMF
One or more kinds of combinations；
Compound shown in the raw material formula (II) being related in above-mentioned synthetic method participates in reacting as part, and its chemical name is
1- (2- pyridines) -9- Cvclopropvlmethvls-B-carboline, in this application also referred to as L.Compound shown in the formula (II) can voluntarily be set
Prepared by meter synthetic route, preferably prepared as follows：
Using tryptamines and pyridine-2-formaldehyde as raw material, reacted in the first organic solvent, compound is obtained by dehydrating condensation
1；Then compound 1 is placed in the second organic solvent, add oxidant cyclization and dehydrogenation obtain compound 2 (1- (2- pyridines)-
B-carboline)；Compound 2 is placed in the aprotic polar solvent of alkaline matter again, bromomethyl cyclopropane is added and substitute instead
Should, produce；Wherein：
The first described organic solvent is one kind or two in toluene, methanol, ethanol, dichloromethane and chloroform
The combination of the kind above；
The second described organic solvent is one kind or two in benzene, toluene, paraxylene, glacial acetic acid and dichloromethane
The combination of the kind above；
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 in N,N-dimethylformamide, dimethyl sulfoxide (DMSO) and acetone one kind or
Two or more combinations.
The synthetic route of compound method is as follows shown in above-mentioned preparation formula (II)：
Reagent：(a) the 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. using tryptamines and pyridine-2-formaldehyde as raw material, reacted in the first organic solvent, discharge reaction life in course of reaction
Into water, question response terminates rear solvent evaporated, obtains compound 1；
2. compound 1 is placed in the second organic solvent, oxidant is added, is reacted under heating condition, question response terminates, mistake
Filter, filtrate is collected, is evaporated, obtains compound 2；
3. taking alkaline matter to be dissolved in aprotic polar solvent, then add compound 2 and bromomethyl cyclopropane is carried out instead
Should, question response terminates, and reactant is put into frozen water, gained mixture of ice and water is extracted, and collects organic phase, is evaporated molten
Agent, that is, obtain compound (i.e. compound 3) shown in formula (II).
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 water knockout drum can be used in course of reaction
Whether the water of discharge reaction generation, reaction can use thin-layer chromatography (TLC) tracing detection completely；Preferably, reaction uses
Heating reflux reaction, the time control now reacted are appropriate in 2~6h.In the step, what is obtained is the thick production of compound 1
Thing, in order to reduce the impurity in subsequent reactions, improve the yield of postorder reaction, preferably to residue obtained progress purification process after
Postorder reaction is carried out again.Specific purification process can be recrystallized to residue obtained with small polar solvent, gained recrystallization production
Thing is used further to postorder reaction.It is described be used for recrystallize small polar solvent it is 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 use heating reflux reaction, reaction
Whether thin-layer chromatography tracing detection be able to can be used completely.In the step, what is obtained is the crude product of compound 2, in order to reduce
Impurity in subsequent reactions, the yield of postorder reaction is improved, preferably to carrying out postorder again after residue obtained progress purification process
Reaction.Specific purification process can be to it is residue obtained with selected from one or both of methanol, ethanol and dichloromethane with
On combination solvent recrystallized, or residue obtained upper silica gel column chromatography is purified, it is used in upper silica gel column chromatography
Eluant, eluent press 6 for petroleum ether and dichloromethane：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, it is specific as follows：
(1) when the selection of oxidant is palladium carbon, the second organic solvent is preferably one kind in benzene, toluene and paraxylene
Or two or more combinations, when two organic solvents selection for more than above two combination when, proportioning between them can be with
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 carbons and calculated.
(2) when the selection of oxidant is 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 the material of compound 1.When the choosing of oxidant
When being selected as manganese acetate hydrate or lead tetraacetate, preferably reaction uses pH >=7 of alkali lye regulation system after terminating, then it is extracted
Take, collect organic phase, the upper silica gel column chromatography purifying again of the residue obtained by solvent evaporated；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 is preferably 5
~30w/w%；Solvent for system after extraction tune pH value can be specifically ethyl acetate, dichloromethane, chloroform or ether etc..
(3) when the selection of oxidant 5,6- dicyan 1,4-benzoquinone chloro- for 2,3- bis-, the second organic solvent is preferably benzene, first
One or more kinds of combinations of benzene and dichloromethane, when the selection of two organic solvents is the combination of more than above two,
Proportioning between them can be any proportioning.The addition of the chloro- 5,6- dicyan 1,4-benzoquinone of 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 bromomethyl ring
The ratio between amount of material of propane is usually 1~4：1：1~3, alkaline matter therein can be further sodium hydride, calcium hydride,
Combination more than one or both of calcium hydroxide, sodium hydroxide, potassium hydroxide, cesium carbonate and potassium carbonate, works as alkaline matter
Selection for more than above two combination when, the proportioning between them can be any proportioning.In the step, reaction can be
Carried out under the conditions of 0~80 DEG C, whether reaction can use thin-layer chromatography (TLC) tracing detection completely；Preferably, react 20
~50 DEG C, the time control now reacted is appropriate in 1~6h.The solvent extracted to mixture of ice and water can be specifically second
The conventional extraction solvent such as acetoacetic ester, dichloromethane, chloroform, petroleum ether or ether.
(such as the first organic solvent, second have involved various solvents in compound synthesis method shown in above-mentioned formula (II)
Solvent and aprotic polar solvent etc.) dosage, with can dissolve participated in each step reaction raw material be advisable.
What the above method was prepared is the crude product of compound shown in formula (II), in order to further improve shown in formula (II)
The purity of compound, the progress of subsequent reactions is more beneficial for, is used again after preferably carrying out purification process to above-mentioned gained crude product
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 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 combination of methanol and ethanol ratio shared in polar solvent is preferably 50~98v/v%；When containing in polar solvent
During two or more selections 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 dosage of the polar solvent can determine as needed,
Under normal circumstances, compound shown in 1mmol copper nitrate and 1mmol formulas (II) is dissolved with 5~80mL polar solvent.Having
In the dissolving step of body, additive polarity solvent again after typically compound shown in copper nitrate and formula (II) is mixed；Also can be by copper nitrate
Dissolved respectively with polar solvent with compound shown in formula (II), remix and react together.
In the synthetic method of compound shown in formula (I) of the present invention, compound shown in the copper nitrate and formula (II)
The ratio between amount of material can be 1~6：1.
Compound shown in formula (I) of the present invention specifically in synthesis, can use normal pressure solwution method or high pressure solvent heat
Method is synthesized.
When using normal pressure solwution method, its synthetic method includes：Compound shown in formula (II) and copper nitrate are taken, is dissolved in polarity
In solvent, gained mixed liquor reacts under the conditions of being heated or not heated, and reactant removes partial solvent, stands, and separates out, isolates
Crystal, produce 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 be 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
Reacted under the conditions of DEG C.Whether reaction can use thin-layer chromatography tracing detection completely.In this method, product is typically in the form of crystal
A large amount of generations, if the addition of polar solvent is larger in previous step (such as the upper limit close to proportioning) or solvent is to the molten of product
Solution property is preferable, then solution may be in clear state after reacting, because the product formed precipitates dissolves institute by polar solvent
Cause, gained reaction solution can now be concentrated or is evaporated under reduced pressure to remove partial solvent, typically concentration removes polar solvent and added
The 50~90% of amount.Isolated solid can be washed further with ether, acetone, ethanol, methanol or dichloromethane, 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 nitrate are taken, it is molten to be dissolved in polarity
In agent, gained mixed liquor is placed in container, and vacuum is evacuated to after liquid nitrogen frozen, sealing, then anti-under the conditions of 30~140 DEG C
Should, obtain target product.
In the above-mentioned hot method of high pressure solvent, described container is usually heavy wall borosilicate glass tube, is reacted 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, can also be extended to according to actual conditions
More than 24h.Further preferred 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 being carried out under normal temperature or heating condition of the reaction below 80 DEG C, when reaction needs longer
Between can just obtain higher yield.
Present invention additionally comprises compound or its pharmaceutically acceptable salt shown in above-mentioned formula (I) in antineoplastic is prepared
Application.
Present invention additionally comprises what is prepared using compound or its pharmaceutically acceptable salt shown in above-mentioned formula (I) as active component
Antineoplastic.
Compared with prior art, the invention provides it is a kind of it is new using 1- (2- pyridines) -9- Cvclopropvlmethvls-B-carboline as
Copper nitrate (II) complex of part, and its synthetic method and application.Applicant is by investigating it to kinds of tumor cells
The inhibitory action of strain, the results showed that the complex has stronger anti tumor activity in vitro, and apparently higher than cis-platinum, has preferable
Potential medical value, be expected to be used for the preparation of various antineoplastics.
Brief description of the drawings
Fig. 1 is the x-ray crystal structure figure of final product made from the embodiment of the present invention 5.
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- pyridines) -9- Cvclopropvlmethvls-B-carboline (L)
1) 1.6g (10mmol) tryptamines, 1.1g (10mmol) pyridine-2-formaldehydes and 50ml toluene are added into 150ml round bottoms to burn
Bottle, plus water knockout drum, condenser pipe group composition water reflux, is heated to reflux 4 hours, question response terminates rear solvent evaporated, residue
Compound 1 (2.3g, yield 92%) is recrystallized to give with 100ml n-hexanes；
2) 2.5g (10mmol) compound 1,2.5g palladium carbons (10%Pd/C) and 100ml paraxylene are added into 250ml circles
Bottom flask, it is heated to flowing back, and is terminated with thin-layer chromatography tracing detection to reaction, stands and filter and be evaporated filtrate, gained is residual
Silica gel column chromatography purifies (V on slagPetroleum ether：VDichloromethane=1:1) compound 2 (2.1g, yield 86%), is obtained；
3) 0.24g (10mmol) sodium hydrides and 15ml DMFs are added to 50ml round-bottomed flasks, room temperature
Stirring 10 minutes, adds 2.5g (10mmol) compound 2 and 10mmol bromomethyl cyclopropanes, and with thin-layer chromatography tracing detection
Terminate to reaction, then put into reaction solution in 500ml frozen water, with the extraction of 100ml ethyl acetate three times, merge organic phase, steam
Dry solvent, residue obtained upper silica gel column chromatography purifying (VDichloromethane：VMethanol=100:1) compound 3 (2.4g, yield 80%), is obtained.
Products therefrom is characterized：
(1) proton nmr spectra and carbon spectrum, their spectral data are as follows：
1H NMR(500MHz,CDCl3) δ 8.76 (d, J=4.7Hz, 1H), 8.57 (d, J=5.2Hz, 1H), 8.19 (dd, J
=7.9,0.7Hz, 1H), 8.11 (d, J=5.2Hz, 1H), 8.03 (d, J=7.8Hz, 1H), 7.94 (td, J=7.7,1.8Hz,
1H), 7.63-7.58 (m, 1H), 7.50 (d, J=8.4Hz, 1H), 7.42 (ddd, J=7.6,4.9,1.1Hz, 1H), 7.32
(td, J=7.5,0.8Hz, 1H), 4.24 (d, J=6.7Hz, 2H), 0.79-0.69 (m, 1H), 0.19-0.12 (m, 2H) ,-
0.12–-0.17(m,2H).
13C NMR(126MHz,CDCl3)δ157.07,148.55,143.16,141.46,137.23,136.78,
134.29,132.34,129.15,125.76,123.60,121.72,121.28,120.28,114.84,110.78,49.05,
10.51,3.58.
(2) high resolution mass spectrum, ESI-MS m/z:300.1[M+H]+.
Accordingly, it can be determined that above-mentioned product is 1- (2- pyridines) -9- Cvclopropvlmethvls-B-carboline, its chemical structural formula is such as
Shown in following formula (II)s：
Embodiment 2：The synthesis of ligand L
Embodiment 1 is repeated, unlike：
In step 2), with Mn (Ac)3Instead of palladium carbon, paraxylene, control Mn (Ac) are replaced with glacial acetic acid3Addition be
2 times of the amount of the material of compound 1, react and are carried out under the conditions of 70 DEG C, and TLC tracing detections to reaction terminate, 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
Purify (VPetroleum ether：VDichloromethane=1:1) compound 2, is obtained.
Proton nmr spectra, carbon-13 nmr spectra and high resolution mass spectrum analysis are carried out to the present embodiment products therefrom, it is determined that
For target product 1- (2- pyridines) -9- Cvclopropvlmethvls-B-carboline.
Embodiment 3：The synthesis of ligand L
Embodiment 2 is repeated, unlike：
In step 2), with Pb (Ac)4Instead of Mn (Ac)3, control Pb (Ac)4Addition for the material of compound 1 amount 5
Times, react and carried out under the conditions of 60 DEG C.
Proton nmr spectra, carbon-13 nmr spectra and high resolution mass spectrum analysis are carried out to the present embodiment products therefrom, it is determined that
For target product 1- (2- pyridines) -9- Cvclopropvlmethvls-B-carboline.
Embodiment 4：The synthesis of ligand L
Embodiment 1 is repeated, unlike：
In step 2), palladium carbon is replaced with chloro- 5, the 6- dicyan 1,4-benzoquinone of 2,3- bis-, paraxylene is replaced 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.
Proton nmr spectra, carbon-13 nmr spectra and high resolution mass spectrum analysis are carried out to the present embodiment products therefrom, it is determined that
For target product 1- (2- pyridines) -9- Cvclopropvlmethvls-B-carboline.
Embodiment 5：Title complex [Cu (L) (NO3)2] synthesis
In the heavy wall borosilicate glass tube being open at one end, 0.1mmol Cu (NO are directly added into3)2·3H2O and 0.1mmol match somebody with somebody
Body L, adding 0.6ml ethanol/methylenes mixed solution, (volume ratio of methanol and dichloromethane is 3:1), vacuumizing
Under the conditions of, openend is sealed, is then fully reacted 20 hours under the conditions of 50 DEG C, obtains green crystal type solid product.
Products therefrom is characterized：
(1) high resolution mass spectrum, ESI-MS m/z:502.1[Cu(L)(DMSO)(NO3)]+(when DMSO comes from mass spectrometric measurement
The solvent used)
(2) X ray single crystal diffraction is analyzed, as shown in Figure 1.
Therefore can determine that above-mentioned product is the copper (II) using 1- (2- pyridines) -9- Cvclopropvlmethvls-B-carboline as part
Complex is title complex [Cu (L) (NO3)2], shown in its structural formula such as following formula (I)：
Embodiment 6：Title complex [Cu (L) (NO3)2] synthesis
In the heavy wall borosilicate glass tube being open at one end, 0.2mmol Cu (NO are directly added into3)2·3H2O and 0.1mmol match somebody with somebody
Body L, adding 0.6ml ethanol/chloroform mixed solution, (volume ratio of ethanol and chloroform is 3:1), will, under conditions of vacuumizing
Openend seals, and is then fully reacted 12 hours under the conditions of 80 DEG C, obtains green crystal type solid product.
Products therefrom carries out structure determination by high resolution mass spectrum and the analysis of X ray single crystal diffraction, is defined as target cooperation
Thing [Cu (L) (NO3)2]。
Embodiment 7：Title complex [Cu (L) (NO3)2] synthesis
In the heavy wall borosilicate glass tube being open at one end, 0.3mmol Cu (NO are directly added into3)2·3H2O and 0.1mmol match somebody with somebody
Body abbreviation L, add 0.6ml methanol/ethanols/N,N-dimethylformamide mixed solution (methanol, ethanol and N, N- dimethyl methyl
The volume ratio of acid amides is 5：1：1), under conditions of vacuumizing, openend is sealed, the then fully reaction 4 under the conditions of 100 DEG C
Hour, obtain green crystal type solid product.
Products therefrom carries out structure determination by high resolution mass spectrum and the analysis of X ray single crystal diffraction, is defined as target cooperation
Thing [Cu (L) (NO3)2]。
Embodiment 8：Title complex [Cu (L) (NO3)2] synthesis
In the heavy wall borosilicate glass tube being open at one end, 0.4mmol Cu (NO are directly added into3)2·3H2O and 0.1mmol match somebody with somebody
Body L, adding 0.6ml ethanol/acetones mixed solution, (volume ratio of ethanol and acetone is 10:1), under conditions of vacuumizing,
Openend is sealed, is then fully reacted 4 hours under the conditions of 80 DEG C, obtains green crystal type solid product.
Products therefrom carries out structure determination by high resolution mass spectrum and the analysis of X ray single crystal diffraction, is defined as target cooperation
Thing [Cu (L) (NO3)2]。
Embodiment 9：Title complex [Cu (L) (NO3)2] synthesis
Take 6mmol Cu (NO3)2·3H2O and 1mmol ligand Ls are placed in round-bottomed flask, add 80ml ethanol/waters thereto
(volume ratio of second alcohol and water is 1 to mixed solution:1), after stirring and dissolving, 60 DEG C is heated to and is reacted 12 hours, reactant decompression is dense
Contracting removes partial solvent, stands, has green crystal precipitation, isolate solid, washed with ethanol, dries, obtains green crystal.
Products therefrom carries out structure determination by high resolution mass spectrum and the analysis of X ray single crystal diffraction, is defined as target cooperation
Thing [Cu (L) (NO3)2]。
Embodiment 10：Title complex [Cu (L) (NO3)2] synthesis
Take 2mmol Cu (NO3)2·3H2O and 1mmol ligand Ls are placed in round-bottomed flask, add 50ml methanol/the third thereto
(volume ratio of methanol, acetone and water is 30 to ketone/water mixed solution：1：10), after stirring and dissolving, it is small that 50 DEG C of reactions 12 are heated to
When, reactant, which is concentrated under reduced pressure, removes partial solvent, stands, has green crystal precipitation, isolate solid, washed with ethanol, dries,
Obtain green crystal.
Products therefrom carries out structure determination by high resolution mass spectrum and the analysis of X ray single crystal diffraction, is defined as target cooperation
Thing [Cu (L) (NO3)2]。
Embodiment 11：Title complex [Cu (L) (NO3)2] synthesis
Take 3mmol Cu (NO3)2·3H2O and 1mmol ligand Ls are placed in round-bottomed flask, add 30ml methanol/chlorine thereto
(volume ratio of methanol and chloroform is 1 to imitative mixed solution：1), after stirring and dissolving, reacted 18 hours in 20 DEG C, reactant decompression is dense
Contracting removes partial solvent, stands, has green crystal precipitation, isolate solid, washed with ethanol, dries, obtains green crystal.
Products therefrom carries out structure determination by high resolution mass spectrum and the analysis of X ray single crystal diffraction, is defined as target cooperation
Thing [Cu (L) (NO3)2]。
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.
Experimental example 1：Using copper nitrate (II) complex that 1- (2- pyridines) -9- Cvclopropvlmethvls-B-carboline is part (by originally
The methods described of inventive embodiments 5 is made) and ligand L (being made by the methods described of the embodiment of the present invention 1) to a variety of human tumor strains
Carry 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 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 then cultivate containing
The small ox bloods of 10wt%, 100U/mL penicillin, 100U/mL streptomysins DMEM nutrient solutions in.
2nd, the preparation of testing compound
The DMSO liquid storages (concentration 0.002mol/L) of each testing compound are diluted successively by RMPI1640 culture mediums
Into five concentration gradients, respectively 20,10,5,2.5,1.25 μm of ol/L, wherein cosolvent DMSO final concentration≤1%.Survey first
20 μm of ol/L each testing compound is tried for the inhibiting rate of tumor cell proliferation, is considered as primary dcreening operation result；Test is different respectively again
Each testing compound is to the Proliferation Ability degree of various tumour cells under gradient concentration, 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, 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 every μ L of hole 190 in 96 well culture plates, makes cell density to be measured extremely
1000~10000/hole (edge hole is filled with sterile PBS)；
(2) 5%CO2, 37 DEG C of incubation 24h, bottom hole is paved with to cell monolayer, the medicine 10 of finite concentration gradient is added per hole
μ L, each concentration gradient set 4 multiple holes；
(3) 5%CO2, 37 DEG C are incubated 48 hours, are observed under inverted microscope；
(4) 10 μ L MTT solution (5mg/mL PBS, i.e. 0.5%MTT) is added per hole, continues to cultivate 4h；
(5) culture is terminated, carefully sucks nutrient solution in hole, 150 μ L DMSO are added per hole and fully dissolve first a ceremonial jade-ladle, used in libation precipitation, are shaken
Swing after device mixes, with wavelength be 570nm in ELIASA, reference wavelength is the OD value that 450nm determines each hole；
(6) while zeroing hole (culture medium, MTT, DMSO) is set, (the medicine dissolving of cell, same concentrations is situated between control wells
Matter, nutrient solution, MTT, DMSO).
(7) according to the OD value (OD values) measured, to judge living cells quantity, OD values are 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 further fitted, obtain compound to different tumours by strain by SPSS softwares
Half-inhibition concentration (the IC of strain50Value, unit μm ol/L), IC of the compound for different cell lines50Value is as shown in table 1.
Table 1：IC of the compound of the present invention to 5 kinds of cell lines50It is worth (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 exploitation into antineoplastic.
Claims (10)
1. compound shown in lower formula (I)：
2. the synthetic method of compound described in claim 1, it is characterised in that：Take compound and nitric acid as shown in following formula (II)
Copper, it is dissolved in polar solvent, carries out complexation reaction, that is, obtain target product；Wherein, described polar solvent be selected from methanol and
One or both of ethanol with selected from one or both of water, acetone, chloroform, dichloromethane and DMF
Combination above；
3. synthetic method according to claim 2, it is characterised in that：Compound shown in formula (II) and copper nitrate are taken, is dissolved in
In polar solvent, gained mixed liquor reacts under the conditions of being heated or not heated, and reactant removes partial solvent, stands, and separates out, point
Crystal is separated out, produces 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
Enclose interior progress.
5. synthetic method according to claim 2, it is characterised in that：Compound shown in formula (II) and copper nitrate are taken, is dissolved in
In polar solvent, gained mixed liquor is placed in container, and vacuum is evacuated to after liquid nitrogen frozen, sealing, 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 the formula (II)
Prepared as follows：
Using tryptamines and pyridine-2-formaldehyde as raw material, reacted in the first organic solvent, compound 1 is obtained by dehydrating condensation；So
Compound 1 is placed in the second organic solvent afterwards, oxidant cyclization is added and dehydrogenation obtains compound 2；Compound 2 is placed in again
In the aprotic polar solvent of alkaline matter, add bromomethyl cyclopropane and carry out substitution reaction, produce；Wherein：
The first described organic solvent be selected from one or both of toluene, methanol, ethanol, dichloromethane and chloroform with
On combination；
The second described organic solvent be selected from one or both of benzene, toluene, paraxylene, glacial acetic acid and dichloromethane 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 or both of N,N-dimethylformamide, dimethyl sulfoxide (DMSO) and acetone
Combination above；
The structure difference of the compound 1 and compound 2 is as follows：
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. application of the compound described in claim 1 in antineoplastic is prepared.
A kind of 10. antineoplastic pharmaceutical compositions, it is characterised in that：Contain compound described in the claim 1 as active component.
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