CN106496280A - One species specificity suppresses platinum (II) metal complex of proliferation of lung cancer cells and its synthetic method and application - Google Patents
One species specificity suppresses platinum (II) metal complex of proliferation of lung cancer cells and its synthetic method and application Download PDFInfo
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- 208000020816 lung neoplasm Diseases 0.000 title abstract description 13
- 230000035755 proliferation Effects 0.000 title abstract description 9
- -1 platinum (II) metal complex Chemical class 0.000 title abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract description 69
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- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 claims abstract description 35
- 125000003963 dichloro group Chemical group Cl* 0.000 claims abstract description 32
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Classifications
-
- 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
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
- C07F15/0086—Platinum compounds
- C07F15/0093—Platinum compounds without a metal-carbon linkage
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a species specificity suppresses platinum (II) metal complex of proliferation of lung cancer cells and its synthetic method and application.Shown in the structural formula of the coordination compound such as following formula (I), its synthetic method is：Take compound shown in following formula (II) and dichloro two (dimethyl sulfoxide) closes platinum (II), be dissolved in polar solvent, react under the conditions of being heated or not heated, that is, obtain the reactant liquor containing target product.The coordination compound energy specificity suppresses the propagation of lung carcinoma cell NCI H460, its IC50Up to 5.01 ± 0.54 μM of value, has embodied preferable potential medical value, has been expected to be used for the preparation of specificity anti-lung-cancer medicament.Formula (I) and structure shown in formula (II) are as follows.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to a species specificity suppresses platinum (II) metal of proliferation of lung cancer cells
Coordination compound and its synthetic method and application.
Background technology
Pulmonary carcinoma is the most commonly encountered diseases therefore for causing death in cancer, accounts for the 1/3 of tumor mortality rate.And it is clinically normal at present
80% pulmonary carcinoma that sees is nonsmall-cell lung cancer (NSCLC), and 70% NSCLC patient has belonged to late period when making a definite diagnosis, therefore is difficult to pass through
The means such as operation or radiotherapy carry out radical treatment (Yang, J.J.；et al.Oncology Progress,2010,8:538-
545.).This just urgently need researchers go to design and develop a kind of or a series of for lung carcinoma cell have high living
Property or the new type antineoplastic medicine of high selectivity.From the point of view of existing achievement in research, find from natural product active ingredient with
And there is derivative new anti-lung cancer chemotherapeutics good prospect, such as Herba Scutellariae Barbatae extract to have one to human lung cancer A549 of In vitro culture
Fixed inhibitory action, (Liang Xianmei, etc. the Chinese experimental pharmacology of Chinese medical formulae can to suppress DNA replication dna in tumor cell to a certain extent
Magazine, 2011,17:155-158.)；Separately there are some researches show that Rhizoma Paridis also have to the growth of Mouse lung adenocarcinomas cell strain LA795 very strong
Inhibitory action (Yan Lulu, etc. Chinese herbal medicine, 2009,40:424-428.)；Herba euphorbiae lunulatae can preferably induce Lewis lung cancer apoptosis
(Xiao Baohong, etc. Chinese Clinical rehabilitation, 2006,10:48-51.)；Additionally, the extract of Bulbus et Radix Crini Sinici leaf effectively can press down in vitro
The growing multiplication of manufacture-illegal small cell lung cancer NCI-H460 cells, and can well inducing cell apoptosis and by cell cycle arrest in
The G1/S phases (Chen Jianrong, etc. treatment and prevention of tumour is studied, and 2011,38:628-631.).These discoveries promote researchers more positive
Studied (including Metal Substrate antitumoral compounds) based on the design effectively that natural product chemistry storehouse carries out new compound on ground.
Find that cisplatin has after inhibitory action to the propagation of tumor cell from Rosenberg so that the antitumor of platinum complex
Activity becomes one of focus of scientific research personnel's research, and its discovery promotes the development of inorganic pharmacochemistry and bioinorganic chemistry
(Rosenberg,B.；et al.Nature,1965,205:698-699.).Up to the present, formed with first generation cisplatin,
Market medication (Florea, A.M. based on second filial generation carboplatin and third generation oxaliplatin；et al.Cancers,2011,3:
1351-1371.).Although in clinical practice widely, there is the secondary work of poison in the platinum medicine of classics to the platinum medicines such as cisplatin
With strong, (Yang, M. the shortcomings of nephrotoxicity, ototoxicity, big neurotoxicity；et al.J.Inorg.Biochem.,2005,99:
376-382.).Therefore, it will be innovative Metal Substrate medicine that design synthesis has high selectivity, hypotoxic platinum series antineoplastic medicament
The primary study direction of thing, wherein the antitumor metal complex with natural active compound (such as oxidation aporphine alkali) as part
Research achieves notable achievement (Chen Z.-F., et al.Dalton Trans., 2009,262-272.).
Based on the design concept of the antitumor metal complex of active ingredient of Chinese herbs, the applicant has been extensively study with oxygen
Change the series metal coordination compound that different aporphine alkali is part, be therefrom found that its significant anti-tumor activity.Wherein aoxidize different Ah
Plain coffee and 6- hydroxyl oxidizes different aporphine-platinum (II) coordination compound can effectively suppress cisplatin-resistant human ovarian cancer strain SK-OV-3/DDP's
Growth (Chen, Z.F.；et al.J.Med.Chem.2015,58:2159-2179.)；9- amino groups are different aporphine-platinum (II)
Coordination compound then has to human liver cancer Hep-G2 cell preferably select inhibitory action, its IC50Be worth for 9.89 ± 0.47 μM (Chen,
Z.F.；et al.Eur.J.Med.Chem.2016,417-427.)；Big epoxidation different aporphine-cobalt (III) coordination compound is to ovary
The activity of cancer cisplatin resistance strain SK-OV-3/DDP is up to 1.0 ± 0.8 μM of (Chen, Z.F.；et
al.Eur.J.Med.Chem.2016,380-392.)；And 6- amino groups different aporphine-platinum (II) coordination compound is to hepatocarcinoma Hep-
The selective inhibitory action of G2 cells, its IC50It is worth for 4.94 ± 0.46 μM that (Chen Zhenfeng, etc. Patent No.
ZL201310469432.2).However, in the antitumor activity of the metal complex of the type, not yet finding to pulmonary carcinoma
Cell (such as typical nonsmall-cell lung cancer tumor line NCI-H460) has the antitumor metal combination of proliferated specifically inhibitory action
Thing.Applicants contemplate that, at us it has been reported that the different aporphine-metal complex of oxidation in, be characterized in different by aoxidizing
1-N and 11-C Bidentate States mode in the female ring of aporphine part is coordinated with metal ion (such as platinum (II)), and this is one
Determine in degree, to destroy the flatness and independence that aoxidize different aporphine female ring, so as to have impact on its cloud density and possible
Avtive spot, and then anti-tumor activity and the advantage of coordination compound may be influenced whether.Therefore, how to design and find lung carcinoma cell
Extremely sensitive new antitumoral coordination compound becomes our new challenges.
Content of the invention
The technical problem to be solved in the present invention is to provide a species specificity and suppresses platinum (II) metal of proliferation of lung cancer cells to match somebody with somebody
Compound, and its synthetic method and application.
The present invention relates to compound shown in following formula (I)s or its pharmaceutically acceptable salt：
The chemical name of compound shown in above-mentioned formula (I) is dichloro 9- (2'- PEA base -3- propionamido-s)-oxygen
Change different aporphine and close platinum (II) coordination compound, chemical formula is C26H24Cl2N4O2Pt, molecular weight are 687.1g/mol.
Shown in above-mentioned formula (I), the synthetic method of compound is：Take two (diformazan of compound and dichloro shown in following formula (II)
Base sulfoxide) platinum (II) is closed, it is dissolved in polar solvent, reacts under the conditions of being heated or not heated, that is, obtain containing the anti-of target product
Answer liquid；
It is cis dichloro that the raw material raw material dichloro two (dimethyl sulfoxide) being related in above-mentioned synthetic method closes platinum (II)
Two (dimethyl sulfoxide) close platinum (II), refer to existing document (Al-Allaf T.A.K., et al.Trans.Met.Chem.,
1998) it is prepared；Compound shown in another kind of raw material formula (II) is that 9- (2'- PEA base -3- propionamido-s)-oxidation is different
Aporphine participates in reaction as part, in this application also referred to as L, and compound shown in the formula (II) can designed, designed synthesis road
Line is prepared, and is preferably prepared as follows：
9- (3- chlorine propionamido-s)-different aporphine of oxidation and 2- (2- aminoethyls) pyridine is taken, is dissolved in organic solvent, Yu Jia
React under heat or not heating condition, obtain final product；Wherein, described organic solvent be one kind in methanol, ethanol and acetonitrile or
Two or more combinations.
In the preparation method of compound shown in above-mentioned formula (II), raw material 9- (3- chlorine propionamido-s)-oxidation for being related to different Ah
Plain coffee refers to existing document (Tang, H.；et al.Eur.J.Med.Chem.,2009,44:2523-2532.) be prepared.
In the preparation method of compound shown in above-mentioned formula (II), the consumption of organic solvent can determine as needed, generally
In the case of, 2- (2- aminoethyls) pyridine of 9- (3- chlorine the propionamido-s)-different aporphine of oxidation and 10mmol of 1mmol can with 10～
The polar solvent of 100mL is dissolving.In specific dissolving step, different for 9- (3- chlorine propionamido-s)-oxidation aporphine can be used
After polar solvent dissolving, then reaction is mixed with 2- (2- aminoethyls) pyridine；Also can be by 9- (3- chlorine propionamido-s)-oxidation
Additive polarity solvent dissolving again after different aporphine and the mixing of 2- (2- aminoethyls) pyridine.
In the preparation method of compound shown in above-mentioned formula (II), reaction is preferably carried out in a heated condition, further excellent
Choosing is carried out under the conditions of less than or equal to 120 DEG C.Generally reaction controlling is carried out in room temperature under the conditions of 90 DEG C, is further controlled
System is carried out under the conditions of 35～90 DEG C, and it is 6～72h to react under this temperature conditions to the time for taking around completely.React
Cheng Hou, reactant are filtered, and are isolated solid, that is, are obtained compound shown in formula (II).Using change shown in the method synthesis formula (II)
The yield of compound about 65～95%.
What said 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 beneficial for the carrying out of subsequent reactions, is used after preferably carrying out purification process to above-mentioned gained crude product again
In the synthetic method of target product of the present invention.Described purification process is same as the prior art, can be specifically by crude product
Upper silica gel column chromatography purification, to obtain pure compounds shown in formula (II)；In upper silica gel column chromatography, eluant used is chlorine
Imitative and methanol presses 100：1～10：The mixed solvent of 1 volume ratio composition.
In the synthetic method of compound shown in formula (I) of the present invention, described polar solvent be selected from methanol, ethanol, acetonitrile,
One or more combination in acetone and dimethyl sulfoxide, when be chosen as in above-mentioned selection any the two of polar solvent
When planting above combination, their proportioning can be any proportioning.Described polar solvent can also be water and be selected from methanol, second
One or more combination in alcohol, acetonitrile, acetone and dimethyl sulfoxide, now, the shared ratio in polar solvent of water
Example is≤90% volume, and preferably the shared ratio in polar solvent of water is≤70% volume.The consumption of the polar solvent can
Determine as needed, it is generally the case that two (diformazan of compound and 0.5～1.5mmol dichloros shown in the formula (II) of 0.5mmol
Base sulfoxide) close platinum (II) and dissolved with the polar solvent of 15～90mL.In specific dissolving step, can be by formula (II) shownization
Compound and dichloro two (dimethyl sulfoxide) close platinum (II) respectively with polar solvent dissolving (now, for dissolving shown in formula (II)
The polar solvent of compound is preferably from one or more the group in methanol, ethanol, acetonitrile, acetone and dimethyl sulfoxide
Close), remix and react together；Also compound shown in formula (II) and two (dimethyl sulfoxide)-platinum (II) of dichloro can be mixed
Additive polarity solvent dissolving again afterwards.
In the synthetic method of compound shown in formula (I) of the present invention, reaction is preferably carried out in a heated condition, further excellent
Choosing is carried out under the conditions of less than or equal to 120 DEG C.Generally reaction controlling is carried out in room temperature under the conditions of 90 DEG C, is further controlled
System is carried out under the conditions of 35～90 DEG C, can so obtain higher yield.
In the synthetic method of compound shown in institute's formula (I) of the present invention, compound shown in formula (II) and dichloro two (two
Methyl sulfoxide) ratio of amount of material that closes platinum (II) can be 1：0.5～3.
Compound shown in formula (I) of the present invention can adopt normal pressure solwution method or high pressure solvent full-boiled process at concrete synthesis
Synthesized.
When using normal pressure solwution method, its synthetic method includes：Take two (dimethyl of compound shown in formula (II) and dichloro
Sulfoxide) platinum (II) is closed, it is dissolved in polar solvent, gained mixed liquor is reacted under the conditions of being heated or not heated, reactant removing unit
Divide solvent, stand, separate out, isolate crystal, obtain final product target product.
In above-mentioned normal pressure solwution method, reaction is typically carried out in 20 DEG C to polar solvent of reflow temperature range, preferably
Using back flow reaction, further preferably reaction is carried out in 35 DEG C to polar solvent of reflow temperature range.In this method, such as
In fruit previous step, the addition of polar solvent is larger (being such as close to the upper limit of proportioning) or solvent is preferable to the dissolubility of product, then
After reaction, solution may be in clear state, this is because caused by the product precipitation for being formed is by polar solvent dissolving, now can be by
The concentration of gained reactant liquor or vacuum distillation to remove partial solvent, typically concentration remove polar solvent addition 50～
75%.Whether reaction can adopt thin layer chromatography tracing detection completely, when complexation reaction is carried out under the conditions of 35～90 DEG C, reaction
To the time for taking around 6～52h completely；Also dependent on needing for extend to more than 52h in the response time.Using normal pressure solwution method
During synthesis, the yield of target product is up to more than 75%, about 75～95%.
When high pressure solvent full-boiled process, its synthetic method includes：Take dichloro two (dimethyl sulfoxide) and close platinum (II), be dissolved in pole
In property solvent, gained mixed liquor is placed in container, is evacuated to vacuum after liquid nitrogen freezing, sealing by fusing, then under the conditions of 60～120 DEG C
Reaction, obtains target product.
In above-mentioned high pressure solvent full-boiled process, described container is usually heavy wall borosilicate glass tube, when reaction is in 60～120 DEG C of bars
When carrying out under part, the time of reaction is preferably controlled in 8～36h, extends to more than 36h also dependent on practical situation.Further excellent
Selecting mixed solution is reacted under the conditions of 60～90 DEG C.When being synthesized using high pressure solvent full-boiled process, the yield of target product can
Up to more than 63%, about 63～90%.
Present invention additionally comprises compound or its pharmaceutically acceptable salt are in antitumor drug is prepared shown in above-mentioned formula (I)
Application.
Present invention additionally comprises prepared with compound or its pharmaceutically acceptable salt shown in above-mentioned formula (I) as active component
Antitumor drug.
Compared with prior art, the invention provides a kind of novel oxidation different aporphine platinum (II) metal complex of structure
And its synthetic method and application, applicant is by investigating the coordination compound and its part to multiple human tumor cell lines (including NCI-
H460, SK-OV-3, BEL-7402, Hep-G2 and HCT-8 tumor cell) and one plant of normal liver cell HL-7702 Proliferation Ability
Activity, as a result shows that the coordination compound energy specificity suppresses the propagation of lung carcinoma cell NCI-H460, its IC50Value up to 5.01 ± 0.54
μM, preferable potential medical value has been embodied, the preparation of specificity anti-lung-cancer medicament has been expected to be used for.
Description of the drawings
Fig. 1 is the Electrospray Mass Spectrometry spectrum of obtained 9- (3- chlorine propionamido-s)-different aporphine of oxidation in the embodiment of the present invention 1
Figure；
Infrared spectrums of the Fig. 2 for final product obtained in the embodiment of the present invention 1；
Electrospray Mass Spectrometry spectrograms of the Fig. 3 for final product obtained in the embodiment of the present invention 1；
Proton nmr spectra spectrograms of the Fig. 4 for final product obtained in the embodiment of the present invention 1；
Carbon-13 nmr spectra spectrograms of the Fig. 5 for final product obtained in the embodiment of the present invention 1；
Infrared spectrums of the Fig. 6 for final product obtained in the embodiment of the present invention 4；
Proton nmr spectra spectrograms of the Fig. 7 for final product obtained in the embodiment of the present invention 4；
Carbon-13 nmr spectra spectrograms of the Fig. 8 for final product obtained in the embodiment of the present invention 4；
Electrospray Mass Spectrometry spectrograms of the Fig. 9 for final product obtained in the embodiment of the present invention 4.
Specific embodiment
With reference to specific embodiment, the present invention is described in further detail, to more fully understand present disclosure, but
The present invention is not limited to following examples.
Embodiment 1：Ligand L is the synthesis of 9- (3- chlorine propionamido-s)-different aporphine of oxidation
Press following synthetic route synthetic ligands L：
Specifically synthetic method is：
1) prepare 9- (3- chlorine propionamido-s)-different aporphine of oxidation and refer to existing document (Tang, H.；et
al.Eur.J.Med.Chem.,2009,44:2523-2532.) carry out, its detailed step is as follows：
1.1) 15.0g (about 0.1mol) phthalic anhydrides and 12.0g (about 0.1mol) β-phenethylamine are dissolved in 100mL second
In alcohol, flow back 5 hours, filtered while hot is cooled to room temperature, separates out crystallization, and sucking filtration obtains white plates crystal compound a, yield
75%.The aluminum trichloride (anhydrous) and 15g sodium chloride of 75g (0.56mol) are mixed and heated to 140 DEG C of meltings, are slowly added to which
The compound a of 53g (0.2mol), addition are finished, and are warming up to 180 DEG C, stirring reaction 2 hours, take advantage of thermal conductivity to enter in grinding, cooling,
Smash to pieces, obtain compound b, be finally dividedly in some parts in 80 DEG C of 100mL concentrated sulphuric acids, addition is finished, be warming up to 260 DEG C, stir
Reaction 2 hours, cooling, is poured in the ice of about 600g, adjusts pH value about 2-3 with NaOH, separates out a large amount of solids, and sucking filtration is washed,
Obtain crude product.Crude product acetic acid recrystallization, 140 DEG C are vacuum dried 24 hours, obtain the 1- azepine benzanthrones of yellow, produce
Rate about 31% (Chen, Z.F.；et al.J.Med.Chem.2015,58:2159-2179)；
1.2) in ice bath, 2.3g is added in the mixed liquor of the nitric acid 1.2mL and 12mL concentrated sulphuric acid containing 63%
(0.01mol) l- azepines benzanthrone, reacts on, room temperature reaction l hours, and 55 DEG C are reacted 1 hour, cold
But import afterwards in the ice of about 100g, it is 7-8 to be neutralized to pH value with ammonia.Filter, wash with water.Crude product re crystallization from toluene,
Obtain orange-yellow acicular crystal 9- nitros -1- azepine benzanthrones, yield about 55%.By 9- nitro -1- azepine benzanthrones
2.8g (0.01mol) and nine hydrated sodium sulfide 5.5g (22.5mmol) are in 100mL second alcohol and water (ethanol：Water (volume ratio)=7：
3) flow back 6 hours, cooling, decompression evaporate ethanol, stand, sucking filtration obtains crude product.Crude product re crystallization from toluene, obtains dark
The different aporphine of the 9- amino groups of red solid；
1.3) different for 9- amino groups aporphine 1.0g (4.0mmol) is mixed backflow with β-chlorpromazine chloride 15.0mL
8.0 hours, cooling, sucking filtration, much filtrate were washed with ether, crude product DMF/ ethanol (v：V=1：2) mixed solvent recrystallization,
Obtain yellow solid 9- (3- chlorine propionamido-s)-different aporphine of oxidation, yield about 78.2%.The Electrospray Mass Spectrometry spectrum of products therefrom
Figure is as shown in Figure 1；ESI-MS m/z:371.1[M+Cl]-, molecular weight of the M for 9- (3- chlorine propionamido-s)-different aporphine of oxidation；
2) 9- (3- chlorine the propionamido-s)-different aporphine of oxidation and 2- (2- aminoethyls) pyridine of 8mmol of 4mmol are weighed,
Using acetonitrile as solvent, the consumption of acetonitrile is 50mL, obtains mixed solution after dissolving, reacts 16 hours at 65 DEG C, and gained is anti-
Thing sucking filtration is answered, is washed with ether, dried, use silica gel column chromatography (chloroform/methanol=100 afterwards:1→25：1, volume ratio) purification
Obtain yellow solid product (yield 95%).
This enforcement gained final product (yellow solid product) is identified：
(1) infrared spectrum, its spectrogram are as shown in Figure 2；
IR(KBr):3855,3747,3676,3415,3276,2932,2843,2773,2668,2599,2450,2347,
2296,2134,1881,1663,1596,1565,1523,1479,1435,1395,1325,1288,1218,1154,1112,
1053,1005,969,906,850,774,710,655,617,589,512,442,409cm-1.
(3) Electrospray Mass Spectrometry, its spectrogram are as shown in Figure 3；
ESI-MS m/z:457.1[M+Cl]-, molecular weight of the wherein M for L.
(4) proton nmr spectra, its spectrogram are as shown in Figure 4；
1H NMR(500MHz,DMSO-d6) δ 10.88 (s, 1H), 9.18 (s, 1H), 8.76 (dd, J=12.2,7.1Hz,
2H), 8.61 (d, J=2.2Hz, 1H), 8.54 (dt, J=5.6,2.8Hz, 2H), 8.44 8.39 (m, 1H), 8.11 8.02 (m,
2H), 7.98 (d, J=5.6Hz, 1H), 7.77 (td, J=7.7,1.8Hz, 1H), 7.36 (d, J=7.8Hz, 1H), 7.29 (dd,
J=7.1,5.4Hz, 1H), 3.38 (t, J=7.5Hz, 3H), 3.31 (s, 2H), 3.20 (t, J=7.5Hz, 2H), 2.97 (t, J
=6.9Hz, 2H).
(5) carbon-13 nmr spectra, its spectrogram are as shown in Figure 5；
13C NMR(126MHz,DMSO-d6)δ182.71(s),169.49(s),163.56(s),157.77(s),149.47
(s),147.96(s),144.49(s),141.53(s),137.44(s),135.25(s),134.75(s),132.95(s),
131.77(s),131.48(s),130.30(s),126.55(s),125.09(s),123.87(s),122.55(s),122.02
(s),121.32(s),116.89(s),46.55(s),43.23(s),33.41(s),32.92(s).
(6) the elementary analysiss result of 4 gained final product of the present embodiment final product and embodiment, as shown in table 1.
The elementary analysiss result of 4 gained final product of 1 ligand L of table and embodiment
Hence, it can be determined that gained yellow solid is ligand L, shown in its structural formula such as following formula (II)：
Embodiment 2：The synthesis of ligand L
1) with embodiment 1；
2) 9- (3- chlorine the propionamido-s)-different aporphine of oxidation and 2- (2- aminoethyls) pyrrole of 0.8mmol of 1mmol are weighed
Pyridine, using ethanol as solvent, the consumption of ethanol is 10mL, obtains mixed solution after dissolving, reacts 72 hours, gained at 37 DEG C
Reactant sucking filtration, is washed with ether, is dried, and uses silica gel column chromatography (chloroform/methanol=100 afterwards:1→10：1, volume ratio) pure
Change and obtain yellow solid product (yield 65%).
The analysis such as infrared spectrum, high resolution mass spectrum, proton nmr spectra, carbon-13 nmr spectra is carried out to products therefrom, really
It is set to target product ligand L.
Embodiment 3：The synthesis of ligand L
1) with embodiment 1；
1) 9- (3- chlorine the propionamido-s)-different aporphine of oxidation and 2- (2- aminoethyls) pyridine of 10mmol of 1mmol are weighed,
With methanol as solvent, the consumption of methanol is about 100mL, obtains mixed solution after dissolving, reacts 6 hours at 90 DEG C, and gained is anti-
Thing sucking filtration is answered, is washed with ether, dried, use silica gel column chromatography (chloroform/methanol=50 afterwards：1→15：1, volume ratio) purification obtains
Arrive yellow solid product (yield 80%).
The analysis such as infrared spectrum, high resolution mass spectrum, proton nmr spectra, carbon-13 nmr spectra is carried out to products therefrom, really
It is set to target product ligand L.
Embodiment 4：The synthesis of coordination compound of the present invention
The amount of precise material closes platinum for the ligand L of 0.8mmol with 0.8mmol dichloros two (dimethyl sulfoxide)
(II) L is dissolved in 75% (volume) methanol and acetonitrile of 65mL, and (volume ratio is 1:1), in, by dichloro two, (dimethyl is sub-
Sulfone) close platinum (II) and be dissolved in the dimethyl sulfoxide and acetone of 5mL (volume ratio is 4:1) in mixed solution, two kinds of solution mixing,
React 24 hours at 65 DEG C, after concentration and evaporation removes most of solvent (the 65% of solvent adding amount), be cooled to and be stored at room temperature,
Separate out red brown solid product (yield 95%).
Gained red brown solid product is identified：
(1) infrared spectrum, its spectrogram are as shown in Figure 6；
IR(KBr):3855,3747,3450,3267,3204,3117,2939,2376,2344,2277,1692,1655,
1597,1564,1534,1487,1439,1392,1343,1238,1154,1064,1029,971,912,843,771,716,
655,591,539,496,443cm-1.
(2) proton nmr spectra, its spectrogram are as shown in Figure 7；
1H NMR(600MHz,DMSO-d6) δ 10.54 (s, 1H), 8.98 (d, J=5.3Hz, 1H), 8.73 (dd, J=
36.4,6.3Hz, 2H), 8.54 (d, J=6.7Hz, 1H), 8.46 (s, 1H), 8.41 (d, J=7.7Hz, 1H), 8.02 (dt, J=
20.6,10.1Hz, 4H), 7.54 (d, J=7.5Hz, 1H), 7.42 (t, J=6.4Hz, 1H), 6.91 (s, 1H), 3.30 3.23
(m, 2H), 3.01 (d, J=9.7Hz, 2H), 2.90 2.76 (m, 2H), 2.54 (s, 2H).
(3) carbon-13 nmr spectra, its spectrogram are as shown in Figure 8；
13C NMR(151MHz,DMSO-d6)δ182.24(s),169.18(s),159.13(s),153.34(s),147.55
(s),144.08(s),141.16(s),139.53(s),134.81(s),134.28(s),132.40(s),131.02(s),
129.83(s),128.25(s),126.02(s),124.85(s),124.57(s),123.76(s),121.52(s),120.81
(s),116.56(s),116.37(s),50.81(s),45.61(s),40.41(s),34.95(s).
(4) Electrospray Mass Spectrometry, its spectrogram are as shown in Figure 9；
ESI-MS m/z:723.1[M+Cl]-, molecular weight of the wherein M for coordination compound 1.
(5) elementary analysiss result, as shown in table 1.
Hence, it can be determined that it is dichloro 9- (2'- PEAs that gained red brown solid product is title complex
Base -3- propionamido-s) different aporphine conjunction platinum (II) coordination compound of-oxidation, shown in its structural formula such as following formula (I)：
Embodiment 5：The synthesis of coordination compound of the present invention
The amount of precise material closes platinum (II) for the L and 0.5mmol dichloro two (dimethyl sulfoxide) of 1mmol, and L is molten
In 45% (volume) methanol and acetonitrile of 15mL, (volume ratio is 1 to solution:2) in mixed solution, by dichloro two (dimethyl sulfoxide)
Close platinum (II) to be dissolved in the acetone of 3mL, two kinds of solution mixing are reacted 28 hours at 70 DEG C, and concentration and evaporation removes most of
After solvent (the 55% of solvent adding amount), it is cooled to and is stored at room temperature, separates out red brown solid product (yield 75%).
The analysis such as infrared spectrum, high resolution mass spectrum, proton nmr spectra, carbon-13 nmr spectra is carried out to products therefrom, really
It is set to the different aporphine of title complex i.e. dichloro 9- (2'- PEA base -3- propionamido-s)-oxidation and closes platinum (II) cooperation
Thing.
Embodiment 6：The synthesis of coordination compound of the present invention
The amount of precise material closes platinum (II) for the L and 1.5mmol dichloro two (dimethyl sulfoxide) of 1mmol, and L is molten
In 60% (volume) methanol and acetonitrile of 50mL, (volume ratio is 5 to solution:1) in mixed solution, by dichloro two (dimethyl sulfoxide)
Close platinum (II) to be dissolved in 1.0mL dimethyl sulfoxide and acetone (volume ratio is 10:1), in, two kinds of solution mixing are reacted at 37 DEG C
52 hours, after concentration and evaporation removes most of solvent (the 75% of solvent adding amount), it is cooled to and is stored at room temperature, separate out rufous solid
Body product (yield 80%).
The analysis such as infrared spectrum, high resolution mass spectrum, proton nmr spectra, carbon-13 nmr spectra is carried out to products therefrom, really
It is set to the different aporphine of title complex i.e. dichloro 9- (2'- PEA base -3- propionamido-s)-oxidation and closes platinum (II) cooperation
Thing.
Embodiment 7：The synthesis of coordination compound of the present invention
The amount of precise material closes platinum (II) for the L and 4mmol dichloro two (dimethyl sulfoxide) of 2mmol, and L is dissolved
In 80% (volume) methanol and acetonitrile of 60mL, (volume ratio is 1:100) in mixed solution, by dichloro two (dimethyl sulfoxide)
Close platinum (II) to be dissolved in the water (heating for dissolving) of 5mL, two kinds of solution mixing are reacted 24 hours at 80 DEG C, and concentration and evaporation is removed
After removing most of solvent (the 60% of solvent adding amount), it is cooled to and is stored at room temperature, separates out red brown solid product (yield 85%).
The analysis such as infrared spectrum, high resolution mass spectrum, proton nmr spectra, carbon-13 nmr spectra is carried out to products therefrom, really
It is set to the different aporphine of title complex i.e. dichloro 9- (2'- PEA base -3- propionamido-s)-oxidation and closes platinum (II) cooperation
Thing.
Embodiment 8：The synthesis of coordination compound of the present invention
The amount of precise material closes platinum (II) for the L and 3mmol dichloro two (dimethyl sulfoxide) of 1mmol, and L is dissolved
In the acetonitrile mixed solution of 90mL, dichloro two (dimethyl sulfoxide) is closed platinum (II) and is dissolved in 6mL ethanol, two kinds of solution
Mixing, reacts 6 hours at 90 DEG C, after concentration and evaporation removes most of solvent (the 68% of solvent adding amount), is cooled to room temperature
Stand, separate out red brown solid product (yield 78%).
The analysis such as infrared spectrum, high resolution mass spectrum, proton nmr spectra, carbon-13 nmr spectra is carried out to products therefrom, really
It is set to the different aporphine of title complex i.e. dichloro 9- (2'- PEA base -3- propionamido-s)-oxidation and closes platinum (II) cooperation
Thing.
Embodiment 9：The synthesis of coordination compound of the present invention
The amount of precise material closes platinum (II) for the ligand L of 1mmol with 3mmol dichloros two (dimethyl sulfoxide), puts
In the heavy wall borosilicate glass tube of one end open, 10mL methanol is added, under conditions of evacuation, by opening sealing by fusing, then
Fully react 36 hours under the conditions of 80 DEG C, obtain red brown solid product (yield 86%).
The analysis such as infrared spectrum, high resolution mass spectrum, proton nmr spectra, carbon-13 nmr spectra is carried out to products therefrom, really
It is set to the different aporphine of title complex i.e. dichloro 9- (2'- PEA base -3- propionamido-s)-oxidation and closes platinum (II) cooperation
Thing.
Embodiment 10：The synthesis of coordination compound of the present invention
The amount of precise material closes platinum (II) for the ligand L of 1mmol with 1mmol dichloros two (dimethyl sulfoxide), puts
In the heavy wall borosilicate glass tube of one end open, 15mL acetone is added, under conditions of evacuation, by opening sealing by fusing, then
Fully react 48 hours under the conditions of 60 DEG C, obtain red brown solid product (yield 63%).
The analysis such as infrared spectrum, high resolution mass spectrum, proton nmr spectra, carbon-13 nmr spectra is carried out to products therefrom, really
It is set to the different aporphine of title complex i.e. dichloro 9- (2'- PEA base -3- propionamido-s)-oxidation and closes platinum (II) cooperation
Thing.
Embodiment 11：The synthesis of coordination compound of the present invention
The amount of precise material closes platinum (II) for the ligand L of 1mmol with 3mmol dichloros two (dimethyl sulfoxide), puts
In the heavy wall borosilicate glass tube of one end open, 15mL is added to press 1 by acetonitrile and water：The mixed solvent of 2 volume ratio composition,
Under conditions of evacuation, by opening sealing by fusing, then fully react 24 hours under the conditions of 80 DEG C, obtain red brown solid product
(yield 90%).
The analysis such as infrared spectrum, high resolution mass spectrum, proton nmr spectra, carbon-13 nmr spectra is carried out to products therefrom, really
It is set to the different aporphine of title complex i.e. dichloro 9- (2'- PEA base -3- propionamido-s)-oxidation and closes platinum (II) cooperation
Thing.
In order to absolutely prove ligand L of the present invention and coordination compound of the present invention (hereinafter referred to as coordination compound 1) in system
Purposes in medicine, applicant have carried out anti-tumor activity experiment to ligand L and coordination compound 1.
First, ligand L and coordination compound 1 are tested to the proliferation inhibition activity of multiple human tumor cell lines：
1st, cell strain and cell culture
Human lung carcinoma cell NCI-H460, human liver cancer cell Hep-G2, ovarian cancer cell SK-OV-3 and BEL- are selected in this experiment
7402nd, 6 kinds of human cell's strains such as people's Colon and rectum gland cancer cell HCT-8 and Human normal hepatocyte HL-7702.
All cell strains cultivate calf blood containing 10wt%, 100U/mL penicillins, 100U/mL streptomycins RPMI-
In RPMI-1640,37 DEG C of 5%CO containing volumetric concentration are put2Cultivate in incubator.
2nd, the preparation of testing compound
Ligand L used and purity >=95% of coordination compound 1, will be configured to after its DMSO liquid storages physiological buffer dilution
The whole solution of 20 μm of ol/L, wherein final concentration≤1% of cosolvent DMSO, test under the concentration compound to various tumor cells
The inhibition level of propagation.
3rd, cell growth inhibition test (mtt assay)
(1) take the logarithm the tumor cell of trophophase, through trypsinization after, matched somebody with somebody with the culture fluid containing 10% calf serum
The cell suspension that concentration is 5000/mL is made, is inoculated in 96 well culture plates with 190 μ L of every hole, is made cell density to be measured extremely
1000～10000 holes (edge hole is filled with aseptic PBS)；
(2) 5%CO2, 37 DEG C are incubated 24h, are paved with bottom hole to cell monolayer, add the medicine 10 of finite concentration gradient per hole
μ L, each Concentraton gradient set 4 multiple holes；
(3) 5%CO2, 37 DEG C are incubated 48 hours, observe under inverted microscope；
(4) the MTT solution (5mg/mL PBS, i.e. 0.5%MTT) of 10 μ L is added per hole, continues culture 4h；
(5) terminate culture, carefully suck culture fluid in hole, add per hole the DMSO of 150 μ L fully to dissolve first a ceremonial jade-ladle, used in libation precipitation, shake
After swinging device mixing, it is 570nm in microplate reader wavelength, reference wavelength is the optical density value that 450nm determines each hole；
(6) while arranging zeroing hole (culture medium, MTT, DMSO), (cell, the medicine dissolution of same concentrations are situated between control wells
Matter, culture fluid, MTT, DMSO).
(7) according to the optical density value (OD values) for measuring, judge living cells quantity, OD values are bigger, and cytoactive is stronger.Profit
Use formula：
Suppression ratio of the compound to growth of tumour cell is calculated, then each test-compound is calculated respectively to several with Bliss methods
Plant the IC of tumor cell line50Value.Its result is as shown in the following Table 2.
Table 2：The IC of ligand L and 1 pair of different tumor cell line of coordination compound50Value (μM)
From IC50From the point of view of the anti-tumor activity test result of value, ligand L is (thin including 5 kinds of human tumours to various typical cells strains
Born of the same parents' strain and Human normal hepatocyte strain) inactive, IC50Value is>100 μM, illustrate that the oxidation aporphine of this new design derives
Thing does not show obvious cytotoxicity, and not there is medical value.But its platinum (II) coordination compound is that coordination compound 1 then can be special
Property ground suppress pulmonary carcinoma NCI-H460 cell propagation, its IC50It is worth for 5.01 ± 0.54 μM, and to other several classifiable tumor cells
Strain is then without proliferation inhibition activity.Therefore, compared with ligand L, coordination compound 1 shows significant external anti-lung cancer cytoactive；And
Its activity is also significantly greater than clinical anti-cancer medicine-cisplatin, about the 3.6 of cisplatin times.On the other hand, coordination compound 1 is to people's normal hepatocytes
Dirty cell HL-7702 does not show significant cytotoxicity yet, and toxicity selectivity is projected, and shows that coordination compound 1 has to lung carcinoma cell
There is very excellent proliferated specifically inhibitory activity.
In sum, coordination compound of the present invention 1, shows the energy that specificity suppresses pulmonary carcinoma NCI-H460 cell propagation
Power, anti-tumor activity are significantly better than ligand L.As can be seen here, of the present invention suppress proliferation of lung cancer cells with specificity
Coordination compound 1 has good potential medical value, is a kind of preferable anti-lung cancer metal complex, is expected to be used for various antitumor
The preparation of medicine.
Claims (10)
1. compound shown in formula (I) or its pharmaceutically acceptable salt are descended：
2. the synthetic method of compound described in claim 1, it is characterised in that：Take compound and dichloro shown in following formula (II)
Two (dimethyl sulfoxide) close platinum (II), are dissolved in polar solvent, react under the conditions of being heated or not heated, that is, obtain producing containing target
The reactant liquor of thing；
3. synthetic method according to claim 2, it is characterised in that：Described polar solvent is selected from methanol, ethanol, second
One or more combination in nitrile, acetone and dimethyl sulfoxide；Or water be selected from methanol, ethanol, acetonitrile, acetone
With one or more the combination in dimethyl sulfoxide, now, the shared ratio in polar solvent of water is≤90% body
Product.
4. the synthetic method according to Claims 2 or 3, it is characterised in that：Reaction is entered under the conditions of less than or equal to 120 DEG C
OK.
5. the synthetic method according to Claims 2 or 3, it is characterised in that：Reaction is carried out under the conditions of 90 DEG C in room temperature.
6. the synthetic method according to Claims 2 or 3, it is characterised in that：Compound shown in formula (II) presses following sides
Method is prepared：
Take 9- (3- chlorine propionamido-s)-different aporphine of oxidation and 2- (2- aminoethyls) pyridine, be dissolved in organic solvent, in heating or
Do not react under heating condition, obtain final product；Wherein, described organic solvent is one or two in methanol, ethanol and acetonitrile
Above combination.
7. synthetic method according to claim 6, it is characterised in that：Reaction is carried out under the conditions of less than or equal to 120 DEG C.
8. synthetic method according to claim 6, it is characterised in that：Purification behaviour is carried out to compound shown in gained formula (II)
Make.
9. the application of compound described in claim 1 or its pharmaceutically acceptable salt in antitumor drug is prepared.
10. the antitumor drug for being prepared with compound described in claim 1 or its pharmaceutically acceptable salt as effective ingredient.
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