CN106632424B - Using 1- (2- pyridines) -9- benzyls-B-carboline as the chlorination copper complex and its synthetic method of ligand and application - Google Patents

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

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CN106632424B
CN106632424B CN201610855431.5A CN201610855431A CN106632424B CN 106632424 B CN106632424 B CN 106632424B CN 201610855431 A CN201610855431 A CN 201610855431A CN 106632424 B CN106632424 B CN 106632424B
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synthetic method
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polar solvent
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CN106632424A (en
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陈振锋
梁宏
刘延成
卢幸
李亮萍
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Guangxi Normal University
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    • 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
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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

Abstract

The invention discloses one kind using 1 (2 pyridine) 9 benzyl 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 be selected from one or both of methanol and ethyl alcohol with selected from water, acetone, chloroform, dichloromethane and N, the combination of one or more of N dimethylformamides.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 is as follows shown in formula (I) and formula (II):

Description

Using 1- (2- pyridines) -9- benzyls-B-carboline as the chlorination copper complex of ligand and its conjunction At 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- benzyls-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 2 and 9 two nitrogen-atoms 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 by researcher.
On the other hand, the Pharmaceutical Inorganic Chemistry based on medical active ligand is studied in recent years with bioinorganic chemistry It flourishes and becomes hot research field, be especially the first, second and third generation platinum class of representative with cis-platinum, carboplatin, oxaliplatin etc. Successful application of the anticancer drug as front-line chemotherapeutic agents really indicates the arrival of Metal Drugs research and application new era. But it has not yet to see using 1- (2- pyridines) -9- benzyls-B-carboline as copper chloride (II) complex and its synthetic method of ligand With the relevant report of application.
Invention content
The technical problem to be solved in the present invention is to provide a kind of structure novels with 1- (2- pyridines) -9- benzyls-B-carboline For copper chloride (II) complex of ligand 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 shown in above-mentioned formula (I) is: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 A combination of one or more;
Compound shown in raw material formula (II) involved in above-mentioned synthetic method participates in reacting as ligand, its chemical name is 1- (2- pyridines) -9- benzyls-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, oxidant cyclization is added and dehydrogenation obtains the (1- (2- pyridines)-of compound 2 B-carboline);Compound 2 is placed in the aprotic polar solvent of alkaline matter again, Xiuization Benzyl is added 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 be one kind in N,N-dimethylformamide, dimethyl sulfoxide (DMSO) and acetone or Two or more combinations.
The synthetic route of compound method shown in above-mentioned preparation formula (II) is as follows:
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), includes the following steps:
1. using tryptamines and pyridine-2-formaldehyde as raw material, reacted in the first organic solvent, discharge reaction life in reaction process At water, wait for solvent evaporated after reaction, obtain compound 1;
2. compound 1 is placed in the second organic solvent, oxidant is added, 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, compound 2 then is added and cylite is reacted, waits for anti- Should terminate, 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 that discharge reaction generates, 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 improves the yield of postorder reaction to reduce the impurity in subsequent reactions, preferably to residue obtained progress purification process after Postorder reaction is carried out again.Specific purification process can be recrystallized with small polar solvent to residue obtained, 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 preferably use 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 residue obtained upper silica gel column chromatography is purified, it is used in upper silica gel column chromatography Eluant, eluent be that petroleum ether and dichloromethane press 6:1~1:The mixed solvent of 1 volume ratio composition.
Shown in above-mentioned formula (II) the step of compound synthesis method 2. in, according to the difference of oxidant, select different Two organic solvents, it is specific as follows:
(1) when oxidant is when being selected as palladium carbon, the second organic solvent is preferably one kind in benzene, toluene and paraxylene Or two or more combinations, when the combination for being selected as above two or more 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 is added 2~4g palladium carbons and calculates.
(2) when oxidant is when being selected as manganese acetate hydrate or lead tetraacetate, the second organic solvent is preferably glacial acetic acid; The addition of the manganese acetate hydrate or lead tetraacetate is usually 2~8 times of the amount of 1 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 concentration of the aqueous solution of the alkaline matters such as sodium acetate, sodium carbonate, sodium phosphate, sodium bicarbonate or potassium carbonate, the lye is preferably 5 ~30w/w%;For extract adjust pH value after the solvent of system can be specifically ethyl acetate, dichloromethane, chloroform or ether etc..
(3) when oxidant is when being selected as 2,3-, bis- chloro- 5,6- dicyan 1,4-benzoquinone, the second organic solvent is preferably benzene, first The a combination of one or more of benzene and dichloromethane, when the combination for being selected as above two or more of two organic solvents, Proportioning between them can be arbitrary proportioning.The addition of bis- chloro- 5,6- dicyan 1,4-benzoquinone of the 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 cylite The ratio between amount of substance is usually 1~4:1:1~3, alkaline matter therein may further be sodium hydride, calcium hydride, hydroxide The combination of one or more of calcium, sodium hydroxide, potassium hydroxide, cesium carbonate and potassium carbonate, when the selection of alkaline matter For more than above two combination when, the proportioning between them can be arbitrary proportioning.In the step, reaction can be 0~80 It is carried out under the conditions of DEG C, whether reaction can be used thin-layer chromatography (TLC) tracing detection completely;Preferably, reaction is 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 second The conventional extractions solvent such as 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 increase 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 When 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 mixing compound shown in copper chloride and formula (II);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 and copper chloride shown in formula (II) are taken, polarity is dissolved in 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 It is a large amount of to generate, 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 be formed by product precipitation dissolves institute by polar solvent It causes, gained reaction solution can be concentrated or is evaporated under reduced pressure to remove partial solvent at this time, typically concentration removes polar solvent and is added 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 and copper chloride shown in formula (II) 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 It answers, obtains 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 condition, 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 reaction carries out under 80 DEG C of room temperature or heating condition below, when reaction needs longer Between just can get higher yield.
The invention also includes compound or its pharmaceutically acceptable salts shown in above-mentioned formula (I) in the preparation of antitumor drugs Application.
The invention also includes what is prepared as active constituent using compound or its pharmaceutically acceptable salt shown in above-mentioned formula (I) Antitumor drug.
Compared with prior art, the present invention provides a kind of new using 1- (2- pyridines) -9- benzyls-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 is 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 implementation mode
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 benzyls of compound, that is, 1- (2- pyridines) -9- shown in formula (II)-B-carboline (L)
1) 150ml round bottoms are added in 1.6g (10mmol) tryptamines, 1.1g (10mmol) pyridine-2-formaldehydes and 50ml toluene to burn Bottle, in addition water knockout drum, condenser pipe group ingredient water reflux, are heated to reflux 4 hours, wait for solvent evaporated after reaction, residue It is recrystallized to give compound 1 (2.3g, yield 92%) with 100ml n-hexanes;
2) 250ml circles are added in 2.5g (10mmol) compound 1,2.5g palladium carbons (10%Pd/C) and 100ml paraxylene Bottom flask is heated to flowing back, and thin-layer chromatography tracing detection to reaction is used in combination to terminate, and 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 1.7g (10mmol) cylite, thin-layer chromatography tracing detection is used in combination Terminate to reaction, then put into reaction solution in 500ml ice water, three times with the extraction of 100ml ethyl acetate, merges organic phase, steam Dry solvent, residue obtained upper silica gel column chromatography purify (VDichloromethane:VMethanol=100:1) compound 3 (2.9g, yield 87%), 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 8.61 (d, J=4.8Hz, 1H), 8.56 (d, J=5.1Hz, 1H), 8.22 (d, J =7.8Hz, 1H), 8.07 (d, J=5.1Hz, 1H), 7.63 (td, J=7.6,1.0Hz, 1H), 7.56 (t, J=7.7Hz, 2H), 7.43 (d, J=8.3Hz, 1H), 7.32 (t, J=7.5Hz, 1H), 7.29-7.26 (m, 1H), 7.06 (t, J=7.3Hz, 1H), 7.00 (t, J=7.5Hz, 2H), 6.50 (d, J=7.4Hz, 2H), 5.52 (s, 2H)
13C NMR(126MHz,CDCl3)δ158.40,148.16,143.18,143.10,138.62,137.45, 136.75,134.59,131.63,128.97,128.46,127.13,125.76,125.31,123.09,121.75,121.54, 120.38,114.80,110.58,48.80.
(2) high resolution mass spectrum, ESI-MS m/z:336.0[M+H]+.
Accordingly, it can be determined that above-mentioned product is 1- (2- pyridines) -9- benzyls-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, reaction carry 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, determined For target product 1- (2- pyridines) -9- benzyls-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 be 1 substance of compound amount 5 Times, reaction carries 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, determined For target product 1- (2- pyridines) -9- benzyls-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, determined For target product 1- (2- pyridines) -9- benzyls-B-carboline.
Embodiment 5:Title complex [Cu (L) Cl2] synthesis
In the heavy wall borosilicate glass tube being open at one end, it is directly added into 0.1mmol CuCl2·2H2O 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, open end is sealed, is then fully reacted under the conditions of 50 DEG C 20 hours, green crystal type solid product is obtained.
Products therefrom is characterized:
(1) high resolution mass spectrum, ESI-MS m/z:443.04[Cu(L)Cl]+.
(2) X-ray single crystal diffraction is analyzed, as shown in Figure 1.
Therefore it can determine that above-mentioned product is using 1- (2- pyridines) -9- benzyls-B-carboline as copper (II) complex of 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, it is directly added into 0.2mmol CuCl2·2H2O and 0.1mmol ligands L, adding 0.6ml ethyl alcohol/chloroform mixed solution, (volume ratio of ethyl alcohol and chloroform is 3:1) it, under conditions of vacuumizing, will open Mouth end sealing, then fully reacts 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 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, it is directly added into 0.3mmol CuCl2·2H2O and 0.1mmol ligands Abbreviation L adds 0.6ml methanol/ethanols/N,N-dimethylformamide mixed solution (methanol, ethyl alcohol and N, N- dimethyl formyls The volume ratio of amine is 5:1:1), under conditions of vacuumizing, open end is sealed, it is small then fully to react 4 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, it is directly added into 0.4mmol CuCl2·2H2O 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 Open end seals, and is then fully reacted under the conditions of 80 DEG C 4 hours, 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 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, and it is mixed that 80ml ethanol/waters are added thereto Closing solution, (volume ratio of second alcohol and water is 1:1), after stirring and dissolving, 60 DEG C is heated to and is reacted 12 hours, 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, be added 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 react 12 hours, instead It answers object to be concentrated under reduced pressure and removes partial solvent, stand, have 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, and 30ml methanol/chloroform is added thereto (volume ratio of methanol and chloroform is 1 to mixed solution:1) it, after stirring and dissolving, is reacted 18 hours in 20 DEG C, 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 that purposes of the complex of the present invention in pharmacy, applicant have carried out extracorporeal anti-tumor to it Activity experiment.
Experimental example 1:(embodiment of the present invention is pressed by copper (II) complex of ligand of 1- (2- pyridines) -9- benzyls-B-carboline 5 the methods are made) and ligand L (obtained by 1 the method for the embodiment of the present invention) a variety of human tumor strains are pressed down in vitro Activity experiment processed
1, 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 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 set2It 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.
2, the preparation of untested compound
The DMSO liquid storages (a concentration of 0.002mol/L) of each untested compound are diluted successively by RMPI1640 culture mediums At five concentration gradients, respectively 20,10,5,2.5,1.25 μm of ol/L, wherein cosolvent DMSO final concentration≤1%.It surveys first Each untested 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 untested compound is to the Proliferation Ability degree of various tumour cells under gradient concentration, to the Fitting Calculation half-inhibition concentration, That is IC50Value.
3, cell growth inhibition test (mtt assay)
(1) tumour cell of logarithmic growth phase is matched after trypsin digestion with the culture solution containing 10% calf serum The cell suspension of a concentration of 5000/mL is made, is inoculated in 96 well culture plates with 190 μ L of every hole, makes cell density to be measured extremely 1000~10000/hole (edge hole is filled with 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 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) the MTT solution (5mg/mL PBS, i.e. 0.5%MTT) of 10 μ L is added per hole, continues to cultivate 4h;
(5) culture is terminated, culture solution in hole is carefully sucked, 150 μ L DMSO are added per hole and fully dissolve first a ceremonial jade-ladle, used in libation precipitation, shake With wavelength it is 570nm in microplate reader, reference wavelength is the OD value that 450nm measures each hole 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 cell activity is stronger.
Calculate the inhibiting rate of compound on tumor cell growth.For under primary dcreening operation concentration inhibiting rate be more than 50% cell Strain, is further fitted by the inhibiting rate data of five concentration gradients of SPSS softwares pair, finds out compound to different tumours Half-inhibition concentration (the IC of strain50Value, unit μm ol/L), IC of the compound for different cell strains50Value is as shown in table 1.
Table 1:
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 and copper chloride shown in formula (II) 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 and copper chloride shown in formula (II) 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 and dehydrogenation obtains compound 2;Compound 2 is placed in again In the aprotic polar solvent of alkaline matter, be added Xiuization Benzyl 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. compound application in preparation of anti-tumor drugs described in claim 1.
10. a kind of antineoplastic pharmaceutical compositions, it is characterised in that:Contain compound described in the claim 1 as active constituent Or its pharmaceutically acceptable salt is antitumor drug prepared by active constituent.
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