CN106478684B - Using 1- (2- pyridines) -9- heptyl-B-carboline as the chlorination copper complex and its synthetic method of ligand and application - Google Patents

Using 1- (2- pyridines) -9- heptyl-B-carboline as the chlorination copper complex and its synthetic method of ligand and application Download PDF

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CN106478684B
CN106478684B CN201610852936.6A CN201610852936A CN106478684B CN 106478684 B CN106478684 B CN 106478684B CN 201610852936 A CN201610852936 A CN 201610852936A CN 106478684 B CN106478684 B CN 106478684B
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synthetic method
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CN106478684A (en
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陈振锋
梁宏
刘延成
卢幸
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Guangxi Normal University
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    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F1/00Compounds containing elements of Groups 1 or 11 of the Periodic System
    • C07F1/08Copper compounds
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    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic 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
    • C07D471/02Heterocyclic 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
    • C07D471/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F1/00Compounds containing elements of Groups 1 or 11 of the Periodic System
    • C07F1/005Compounds containing elements of Groups 1 or 11 of the Periodic System without C-Metal linkages

Abstract

The invention discloses one kind using 1 (2 pyridine) 9 heptyl β carbolines as the chlorination copper complex and its synthetic method of ligand and application.Shown in the structural formula of the complex such as following formula (I), synthetic method is:Take compound and copper chloride as shown in following formula (II), be dissolved in polar solvent, carry out complexation reaction to get;Wherein, the polar solvent is selected from one or both of methanol and ethyl alcohol and the combination more than one or both of water, acetone, chloroform, dichloromethane and N, N dimethylformamide.Complex of the present invention shows antitumor activity more stronger than ligand and cis-platinum, has preferable potential medical value, is expected to be used for the preparation of various antitumor drugs.Structure shown in formula (I) and formula (II) is as follows:

Description

Using 1- (2- pyridines) -9- heptyl-B-carboline as the chlorination copper complex of ligand and its conjunction Into methods and applications
Technical field
The present invention relates to pharmaceutical technology fields, and in particular to one kind is using 1- (2- pyridines) -9- heptyl-B-carboline as ligand Chlorination copper complex and its synthetic method and application.
Background technology
B-carboline is a kind of alkaloid for being distributed widely in nature, 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, it is three be made 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, for rich pi-electron system, 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 be subject to researcher.
On the other hand, the Pharmaceutical Inorganic Chemistry based on medical active ligand is studied in recent years with bioinorganic chemistry It flourishes as hot research field, is first, second and third generation platinum class of representative especially with cis-platinum, carboplatin, oxaliplatin etc. Successful application of the anticancer drug as front-line chemotherapeutic agents really indicates Metal Drugs research and the arrival of application new era. But have not yet to see copper chloride (II) complex and its synthetic method using 1- (2- pyridines) -9- heptyl-B-carboline as ligand With the relevant report of application.
The content of the invention
The technical problem to be solved in the present invention is to provide structure novel using 1- (2- pyridines) -9- heptyl-B-carboline as with Copper chloride (II) complex of body and its synthetic method and application.
The present invention relates to compound shown in lower formula (I) or its pharmaceutically acceptable salts:
The synthetic method of compound is shown in above-mentioned formula (I):Take compound and copper chloride as shown in following formula (II) (CuCl2·2H2O), it is dissolved in polar solvent, carries out complexation reaction to get to target product;Wherein, the polar solvent is Selected from one or both of methanol and ethyl alcohol in water, acetone, chloroform, dichloromethane and n,N-Dimethylformamide One or more kinds of combinations;
Compound shown in raw material formula (II) involved in above-mentioned synthetic method participates in reacting as ligand, and chemical name is 1- (2- pyridines) -9- heptyl-B-carboline, in this application also referred to as L.Compound shown in the formula (II) can designed, designed synthesis Prepared by route, preferably prepared as follows:
It using tryptamines and pyridine-2-formaldehyde as raw material, is reacted in the first organic solvent, compound is obtained by dehydrating condensation 1;Then compound 1 is placed in the second organic solvent, add in 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, 1- heptyl bromides is added in and carries out substitution reaction, i.e., ;Wherein:
First organic solvent is one kind or two in toluene, methanol, ethyl alcohol, dichloromethane and chloroform Kind or more combination;
Second organic solvent is one kind or two in benzene, toluene, paraxylene, glacial acetic acid and dichloromethane Kind or more combination;
The 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);
The alkaline matter is inorganic base;
The 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:
It 1. using tryptamines and pyridine-2-formaldehyde as raw material, is reacted in the first organic solvent, discharge reaction life in reaction process Into water, treat solvent evaporated after reaction, obtain compound 1;
2. compound 1 is placed in the second organic solvent, oxidant is added in, is reacted under heating condition, to the end of reaction, mistake Filter collects filtrate, is evaporated, obtains compound 2;
3. alkaline matter is taken to be dissolved in aprotic polar solvent, then add in compound 2 and 1- heptyl bromides are reacted, treat Reaction terminates, by reactant put into ice water in, gained mixture of ice and water is extracted, collect organic phase, solvent evaporated to get To 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 substance of tryptamines and pyridine-2-formaldehyde it Than being usually 0.8~1.2:1, reaction can carry out under conditions of being heated or not heated, and water knockout drum can be used in reaction process Whether the water of discharge reaction generation, reaction can be used thin-layer chromatography (TLC) tracing detection completely;Preferably, reaction uses Heating reflux reaction, the time control reacted at this time are appropriate in 2~6h.In the step, what is obtained is the thick production of compound 1 Object in order to reduce the impurity in subsequent reactions, improves 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 Object is used further to postorder reaction.It is described for recrystallization 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 is preferably using heating reflux reaction, reaction Whether thin-layer chromatography tracing detection can be 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 improves the yield of postorder reaction, 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, ethyl alcohol and dichloromethane with On combination solvent recrystallized or purified residue obtained upper silica gel column chromatography, 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, select different Two organic solvents, it is specific as follows:
(1) when the selected as palladium carbon of oxidant, the second organic solvent is preferably one kind in benzene, toluene and paraxylene Or two or more combinations, during combination more than the selected as above two of two organic solvents, proportioning between them can be with Arbitrarily to match.The palladium carbon can be 5%Pd/C or 10%Pd/C, and the addition of the palladium carbon usually presses 10mmol chemical combination Object 1 adds in 2~4g palladium carbons and calculates.
(2) when the selected as manganese acetate hydrate or lead tetraacetate of oxidant, 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 substance of compound.When the choosing of oxidant When being selected as manganese acetate hydrate or lead tetraacetate, pH >=7 of lye regulation system are preferably used after reaction, then it is extracted It takes, collects organic phase, the upper silica gel column chromatography purifying again of the residue obtained by solvent evaporated;Wherein, the lye can be ammonium hydroxide, 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 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 selected as 2 of oxidant, bis- chloro- 5,6- dicyan 1,4-benzoquinone of 3-, the second organic solvent is preferably benzene, first One or more kinds of combinations of benzene and dichloromethane, during combination more than the selected as above two of two organic solvents, Proportioning between them can be arbitrary proportioning.The addition of the bis- chloro- 5,6- dicyan 1,4-benzoquinone of 2,3- is usually compound 1 1~4 times of the amount of substance.
Shown in above-mentioned formula (II) the step of compound synthesis method 3. in, the alkaline matter, compound 2 and 1- heptyl bromides The ratio between the amount of substance be usually 1~4:1:1~3, alkaline matter therein can be further sodium hydride, calcium hydride, hydrogen-oxygen Change combination more than one or both of calcium, sodium hydroxide, potassium hydroxide, cesium carbonate and potassium carbonate, when the choosing of alkaline matter During the combination being selected as more than above two, the proportioning between them can be arbitrary proportioning.In the step, reaction can 0~ It is carried out under the conditions of 80 DEG C, whether reaction can be used thin-layer chromatography (TLC) tracing detection completely;Preferably, react 20~ 50 DEG C, the time control reacted at this time is appropriate in 1~6h.The solvent extracted to mixture of ice and water can be specifically acetic acid The conventional extractions solvent such as ethyl 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, so as to 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 is more advantageous to the progress of subsequent reactions, 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.The 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 ethyl alcohol or Person is that the combination of methanol and ethyl alcohol 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 n,N-Dimethylformamide, do not surpass in their total amount Go out under 50% precondition, their proportioning can be arbitrary proportioning.The dosage of the polar solvent can determine as needed, Under normal conditions, compound shown in the copper chloride of 1mmol and 1mmol formulas (II) is dissolved with the polar solvent of 5~80mL.Having In the dissolving step of body, additive polarity solvent again after generally compound shown in copper chloride and formula (II) is mixed;It also can be by copper chloride It is dissolved respectively with polar solvent with compound shown in formula (II), remixes and react together.
In the synthetic method of compound shown in formula (I) of the present invention, compound shown in the copper chloride and formula (II) The ratio between amount of substance can be 1~6:1.
Specifically in synthesis, normal pressure solwution method or high pressure solvent heat can be used in compound shown in formula (I) of the present invention Method is synthesized.
When using normal pressure solwution method, synthetic method includes:Compound shown in formula (II) and copper chloride 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 is precipitated, isolates Crystal is to get target product.
In above-mentioned normal pressure solwution method, reaction can carry out in 20 DEG C to polar solvent of reflow temperature range, preferably adopt With back flow reaction, further preferably reaction is carried out in 50 DEG C to polar solvent of reflow temperature range, more preferably 60 It is reacted under the conditions of DEG C.Whether reaction can be used thin-layer chromatography tracing detection completely.In this method, product is generally 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, this is because the product formed is precipitated dissolves institute by polar solvent It causes, can gained reaction solution be concentrated or is evaporated under reduced pressure at this time to remove partial solvent, typically concentration removes polar solvent and adds in The 50~90% of amount.Isolated solid can be washed further with ether, acetone, ethyl alcohol, methanol or dichloromethane, it It is dried again afterwards.
When the hot method of high pressure solvent, synthetic method includes:Compound shown in formula (II) and copper chloride 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, the container is usually heavy wall borosilicate glass tube, is reacted usually at 30~140 DEG C Under the conditions of carry out, under this temperature conditions, time of reaction is preferably controlled in 2~for 24 hours, can also be extended to according to actual conditions More than for 24 hours.Further preferred mixed solution is reacted under the conditions of 50~140 DEG C, more preferable mixed solution be 80~ It is reacted under the conditions of 100 DEG C.When being carried out under room 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 antitumor drug 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 ingredient Antitumor drug.
Compared with prior art, the present invention provides a kind of new using 1- (2- pyridines) -9- heptyl-B-carboline as ligand Copper chloride (II) complex and its synthetic method and application.Applicant is by investigating its suppression to various tumor cell strains It makes and uses, the results showed that the complex has stronger anti tumor activity in vitro, and apparently higher than cis-platinum, has preferable potential Medical value is expected to be used for the preparation of various antitumor drugs.
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.
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 embodiments.
Embodiment 1:The synthesis of the heptyl of compound, that is, 1- (2- pyridines) -9- shown in formula (II)-B-carboline (L)
1) 1.6g (10mmol) tryptamines, 1.1g (10mmol) pyridine-2-formaldehydes and 50ml toluene are added in 150ml round bottoms to burn Bottle, in addition water knockout drum, condenser pipe group ingredient water reflux, be heated to reflux 4 it is small when, treat solvent evaporated after reaction, 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 in into 250ml circles Bottom flask is heated to flowing back, and is terminated with thin-layer chromatography tracing detection to reaction, stands and filters 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 n,N-Dimethylformamide are added to 50ml round-bottomed flasks, room temperature Stirring 10 minutes, adds 2.5g (10mmol) compound 2 and 10mmol 1- heptyl bromides, and with thin-layer chromatography tracing detection extremely Reaction terminates, and then puts into reaction solution in 500ml ice water, with the extraction of 100ml ethyl acetate three times, merges organic phase, is evaporated Solvent, residue obtained upper silica gel column chromatography purifying (VDichloromethane:VMethanol=100:1) compound 3 (2.8g, yield 82%), is obtained.
Products therefrom is characterized:
(1) nuclear magnetic resonance spectroscopy and carbon spectrum, their spectral data are as follows:
1H NMR(500MHz,CDCl3) δ 8.75 (d, J=4.3Hz, 1H), 8.54 (d, J=5.1Hz, 1H), 8.17 (dd, J =7.9,0.7Hz, 1H), 8.07 (dd, J=5.2,1.3Hz, 1H), 7.96 (d, J=7.7Hz, 1H), 7.92 (td, J=7.6, 1.7Hz, 1H), 7.63-7.57 (m, 1H), 7.46 (d, J=8.4Hz, 1H), 7.44-7.38 (m, 1H), 7.30 (ddd, J= 7.9,7.2,0.9Hz, 1H), 4.17 (t, J=8.0Hz, 2H), 1.43-1.34 (m, 2H), 1.21-1.12 (m, 2H), 1.11- 0.96 (m, 4H), 0.87 (dd, J=15.1,7.8Hz, 2H), 0.81 (t, J=7.3Hz, 3H)
13C NMR(126MHz,CDCl3)δ158.04,148.48,142.62,142.03,137.33,136.99, 134.14,131.69,128.84,125.38,123.32,121.66,121.24,120.00,114.73,110.31,45.32, 31.65,28.93,28.82,26.71,22.52,14.06.
(2) high resolution mass spectrum, ESI-MS m/z:344.2[M+H]+.
Accordingly, it can be determined that above-mentioned product is 1- (2- pyridines) -9- heptyl-B-carboline, chemical structural formula such as following formula (II) shown in:
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 1 substance of compound, react and are carried out under the conditions of 70 DEG C, and TLC tracing detections to reaction terminate, then will with ammonium hydroxide 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.
Nuclear magnetic resonance spectroscopy, carbon-13 nmr spectra and high resolution mass spectrum analysis are carried out to the present embodiment products therefrom, is determined For target product 1- (2- pyridines) -9- heptyl-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 1 substance of compound amount 5 Times, it reacts and is carried out under the conditions of 60 DEG C.
Nuclear magnetic resonance spectroscopy, carbon-13 nmr spectra and high resolution mass spectrum analysis are carried out to the present embodiment products therefrom, is determined For target product 1- (2- pyridines) -9- heptyl-B-carboline.
Embodiment 4:The synthesis of ligand L
Embodiment 1 is repeated, unlike:
In step 2), palladium carbon is replaced with 2,3-, bis- chloro- 5,6- dicyan 1,4-benzoquinone, paraxylene is replaced with dichloromethane, 2, The addition of bis- chloro- 5,6- dicyan 1,4-benzoquinone of 3- is equal with the amount of the substance of compound 1.
Nuclear magnetic resonance spectroscopy, carbon-13 nmr spectra and high resolution mass spectrum analysis are carried out to the present embodiment products therefrom, is determined For target product 1- (2- pyridines) -9- heptyl-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 are directly added into2·2H2O and 0.1mmol ligands L, adding 0.6ml ethanol/methylenes mixed solution, (volume ratio of methanol and dichloromethane is 3:1), in the item vacuumized Under part, openend is sealed, then fully reacted under the conditions of 50 DEG C 20 it is small when, obtain green crystal type solid product.
Products therefrom is characterized:
(1) high resolution mass spectrum, ESI-MS m/z:519[Cu(L)(DMSO)Cl]+(DMSO is used when coming from mass spectrometric measurement Solvent)
(2) X-ray single crystal diffraction is analyzed, as shown in Figure 1.
Therefore can determine above-mentioned product is copper (II) complex using 1- (2- pyridines) -9- heptyl-B-carboline as ligand That is title complex [Cu (L) Cl2], shown in 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 are directly added into2·2H2O and 0.1mmol ligands L, adding 0.6ml ethyl alcohol/chloroform mixed solution, (volume ratio of ethyl alcohol and chloroform is 3:1), under conditions of vacuumizing, will open Mouthful end sealing, then fully reacted under the conditions of 80 DEG C 12 it is small when, 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 determined as target cooperation Object [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 are directly added into2·2H2O and 0.1mmol ligands Abbreviation L adds 0.6ml methanol/ethanols/N,N-dimethylformamide mixed solution (methanol, ethyl alcohol and N, N- dimethyl formyl The volume ratio of amine is 5:1:1), under conditions of vacuumizing, openend is sealed, it is small that 4 are then fully reacted under the conditions of 100 DEG C When, 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 determined as target cooperation Object [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 are directly added into2·2H2O and 0.1mmol ligands L, adding 0.6ml ethanol/acetones mixed solution, (volume ratio of ethyl alcohol and acetone is 10:It 1), will, under conditions of vacuumizing Openend seal, then fully reacted under the conditions of 80 DEG C 4 it is small when, 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 determined as target cooperation Object [Cu (L) Cl2]。
Embodiment 9:Title complex [Cu (L) Cl2] synthesis
Take 6mmol CuCl2·2H2O and 1mmol ligand Ls are placed in round-bottomed flask, are added in 80ml ethanol/waters thereto and are mixed Closing solution, (volume ratio of second alcohol and water is 1:1), after stirring and dissolving, be heated to 60 DEG C reaction 12 it is small when, reactant is concentrated under reduced pressure Partial solvent is removed, is stood, is had green crystal precipitation, isolate solid, washed with ethyl alcohol, it is dry, obtain green crystal.
Products therefrom carries out structure determination by high resolution mass spectrum and the analysis of X-ray single crystal diffraction, is determined as target cooperation Object [Cu (L) Cl2]。
Embodiment 10:Title complex [Cu (L) Cl2] synthesis
Take 2mmol CuCl2·2H2O and 1mmol ligand Ls are placed in round-bottomed flask, add in thereto 50ml methanol/acetones/ (volume ratio of methanol, acetone and water is 30 to water mixed solution:1:10), after stirring and dissolving, be heated to 50 DEG C reaction 12 it is small when, instead Object is answered to be concentrated under reduced pressure and removes partial solvent, is stood, is had green crystal precipitation, isolate solid, washed with ethyl alcohol, it is dry, it obtains Green crystal.
Products therefrom carries out structure determination by high resolution mass spectrum and the analysis of X-ray single crystal diffraction, is determined as target cooperation Object [Cu (L) Cl2]。
Embodiment 11:Title complex [Cu (L) Cl2] synthesis
Take 3mmol CuCl2·2H2O and 1mmol ligand Ls are placed in round-bottomed flask, add in 30ml methanol/chloroform thereto (volume ratio of methanol and chloroform is 1 to mixed solution:1), after stirring and dissolving, when 20 DEG C of reactions 18 are small, reactant is concentrated under reduced pressure Partial solvent is removed, is stood, is had green crystal precipitation, isolate solid, washed with ethyl alcohol, it is dry, obtain green crystal.
Products therefrom carries out structure determination by high resolution mass spectrum and the analysis of X-ray single crystal diffraction, is determined as target cooperation Object [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 it Activity experiment.
Experimental example 1:It is (real by the present invention as copper chloride (II) complex of ligand using 1- (2- pyridines) -9- heptyl-B-carboline 5 the method for example is applied to be made) and ligand L (being made by 1 the method for the embodiment of the present invention) to a variety of human tumor strains carry out body Outer inhibitory activity experiment
1st, cell line 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 lines.
All tumor cell lines are cultivated containing 10wt% small ox bloods, 100U/mL penicillin, 100U/mL streptomysins In RPMI-1640 culture solutions, 37 DEG C of 5%CO containing volumetric concentration are put2It is cultivated in incubator;Human normal cell line strain then cultivate containing The small ox bloods of 10wt%, 100U/mL penicillin, 100U/mL streptomysins DMEM culture 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 It is respectively 20,10,5,2.5,1.25 μm of ol/L, wherein cosolvent DMSO final concentration≤1% into five concentration gradients.It surveys first Each testing compound of 20 μm of ol/L 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 culture solution containing 10% calf serum The cell suspension that concentration is 5000/mL is made, is inoculated in every 190 μ L of hole 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 are incubated for 24 hours, until cell monolayer is paved with bottom hole, the drug 10 of a certain concentration gradient is added in per hole μ L, each concentration gradient set 4 multiple holes;
(3) 5%CO2, when 37 DEG C of incubations 48 are small, observed under inverted microscope;
(4) the MTT solution (5mg/mL PBS, i.e. 0.5%MTT) of 10 μ L is added in per hole, continues to cultivate 4h;
(5) culture is terminated, carefully sucks culture solution in hole, 150 μ L DMSO are added in per hole and fully dissolve first a ceremonial jade-ladle, used in libation precipitation, are shaken With wavelength it is 570nm in microplate reader, reference wavelength measures the OD value in each hole for 450nm after swinging device mixing;
(6) while zeroing hole (culture medium, MTT, DMSO) is set, (the drug dissolving of cell, same concentrations is situated between control wells Matter, culture 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 Strain, is further fitted the inhibiting rate data of five concentration gradients by SPSS softwares, compound is obtained to different tumours 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:Compound of the present invention is to the IC of 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, Activity is substantially better than cis-platinum, is expected to exploitation into antitumor drug.

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 chlorination as shown in following formula (II) Copper is dissolved in polar solvent, carries out complexation reaction to get to target product;Wherein, the polar solvent be selected from methanol and One or both of ethyl alcohol with selected from one or both of water, acetone, chloroform, dichloromethane and n,N-Dimethylformamide Above combination;
3. synthetic method according to claim 2, it is characterised in that:Compound shown in formula (II) and copper chloride 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 is precipitated, point Crystal is separated out to get 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 chloride 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 carries 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) It is prepared as follows:
It using tryptamines and pyridine-2-formaldehyde as raw material, is 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 in and dehydrogenation obtains compound 2;Compound 2 is placed in again In the aprotic polar solvent of alkaline matter, add in 1- heptyl bromides carry out substitution reaction to get;Wherein:
First organic solvent be selected from one or both of toluene, methanol, ethyl alcohol, dichloromethane and chloroform with On combination;
Second organic solvent be selected from one or both of benzene, toluene, paraxylene, glacial acetic acid and dichloromethane with On combination;
The oxidant is palladium carbon, bis- chloro- 5,6- dicyan 1,4-benzoquinone of manganese acetate hydrate, lead tetraacetate or 2,3-;
The alkaline matter is inorganic base;
The aprotic polar solvent is selected from one or both of N,N-dimethylformamide, dimethyl sulfoxide (DMSO) and acetone Above combination;
The structure of the compound 1 and compound 2 difference 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 antitumor drug is prepared.
10. a kind of antineoplastic pharmaceutical compositions, it is characterised in that:Contain compound described in claim 1 as active component.
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