CN105669763A - 9-amino oxidized isoaporphine-platinum (II) complex, synthetic method and application thereof - Google Patents
9-amino oxidized isoaporphine-platinum (II) complex, synthetic method and application thereof Download PDFInfo
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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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a 9-amino oxidized isoaporphine-platinum (II) complex, a synthetic method and an application thereof. The 9-amino oxidized isoaporphine-platinum (II) complex is prepared with 9-amino oxidized isoaporphine and dichloro bis(dimethyl sulfoxide)platinum (II) as raw materials through a coordination reaction in a polar solvent. A research result shows that the inhibition effect of the complex on telomerase reaches 56.97% and is improved significantly than those of a 1-aza-benzanthrone platinum (II) complex and 6-hydroxy oxidized isoaporphine-platinum (II) complex. The complex has significant inhibition effect on the activity of the telomerase and has excellent selectivity and significant in-vitro antitumor activity on various human tumor cell strains and a normal liver cell strain. The structure formula of the complex is represented as the formula (I).
Description
Technical field
The present invention relates to pharmaceutical technology field, be specifically related to a kind of different aporphine-platinum (II) coordination compound of 9-amino group and synthetic method thereof and application.
Background technology
Malignant tumor constitutes about the 25% of world today's disease, is one of main disease jeopardizing human life at present. At present, chemotherapy treatment, radioactivity physiotherapy are one of traditional means for the treatment of malignant tumor, wherein, with several inorganic platinum-containing anticancer drugs that cisplatin is representative, kinds cancer type (such as carcinoma of testis, uterus carcinoma, bladder cancer, pulmonary carcinoma, carcinoma of prostate etc.) there is good curative effect. But, there is the side effect such as low, the more serious toxicity of water solublity and gastrointestinal reaction in the platinum medicine such as cisplatin, carboplatin, oxaliplatin, Lobaplatin, Eptaplatin, its clinical practice is significantly restrained (Rosenberg, B.; Etal.Nature, 1965,205:698-699.). Therefore, it will be a direction (such as targeting telomere G-tetrad or telomerase etc.) of original new drug that design synthesis has high selective platinum series antineoplastic medicament, then new study hotspot (Bowen, a M.L. is become based on the metal antitumor drug chemistry of medical active part; Etal.DaltonTrans., 2009,9928-9236.), also driven the research of inorganic pharmacochemistry.
Early 1930s, famous geneticist Muller and BarbavaMeClintock is found that the existence of telomere (telomere) structure, it can with the RNA of self for template, extend the length of telomere, maintain the telomeric sequence of end of chromosome, thus offsetting the consumption of the telomeric dna caused because of cell division. Subsequently, Kim et al. works out the TRAP-PCR method of telomerase activation detection, and the development that occurs proposing its activity and tumor has special relation (Kim, N.W.; Etal.Science, 1994,266:2011 2015.). Research points out that telomerase take part in the apoptosis to tumor cell and the stable regulation process of genome in tumor cell; And, the malignant cell of the mankind of more than 85% is able to detect that the activity of telomerase so that it is become an almost general carcinoma marker, and in most of normal somatic cells, telomerase is negative.Therefore, it is suppressed that the activity of telomerase is probably an antitumor strategy reducing growth of cancer cells well. On the other hand, the immortalization of telomerase activation and cell has close relationship, makes the crucial target spot for the treatment of senile dementia.
Aoxidizing different aporphine is a kind of excellent organic ligand, platinum (II) coordination compound of the different aporphine of a series of oxidation it has been synthetically derived, such as platinum (II) coordination compound (publication number is CN103421048A) etc. of platinum (II) coordination compound (publication number is CN103450281A) of 1-azepine benzanthrone and the different aporphine of 6-hydroxyl oxidize before the present inventor. The research of the present inventor shows, platinum (II) coordination compound of 1-azepine benzanthrone and platinum (II) coordination compound of the different aporphine of 6-hydroxyl oxidize are all alternative stablizes telomere, proto-oncogene (c-myc) G-tetra-serobila, suppression ratio respectively 40.28% and 43.96% (Chen, Z.F. to telomerase; Etal.J.Med.Chem.2015,58:2159-2179.). But, the different aporphine part that aoxidizes in above-mentioned coordination compound is all with Bidentate State mode and metal ion (such as platinum (II)) coordination by 1-N and the 11-C in female ring, although the applicant expects that this destroys the fragrant flatness aoxidizing different aporphine female ring to a certain extent, thus affecting its cloud density and possible avtive spot; And good fragrant flatness and cloud density are considered as targeting in the key structure factor of telomerase and telomere G-tetra-serobila, this is also that the inhibition of telomerase of above-mentioned two kinds of platinum complexes still compares reason on the low side.
Prior art is retrieved by applicant, still find no with the different aporphine of 9-amino group be part platinum (II) coordination compound and the relevant report of synthetic method and application.
Summary of the invention
The technical problem to be solved in the present invention is to provide 9-amino group different aporphine-platinum (II) coordination compound of a kind of novel structure, and its synthetic method and application.
The present invention relates to compound or its pharmaceutically acceptable salt shown in following formula (I):
The chemical name of compound shown in above-mentioned formula (I) is that the different aporphine of dichloro-dimethyl sulfoxide 9-amino group closes platinum (II) coordination compound, and chemical formula is C18H16Cl2N2O2PtS, molecular weight is 589g/mol.
The synthetic method of above-claimed cpd is: take the different aporphine of 9-amino group and dichloro two (dimethyl sulfoxide) closes platinum (II), be dissolved in polar solvent, carry out complexation reaction, namely obtain target product. Its synthetic route is as follows:
More specifically synthetic method comprises the following steps:
1) take the different aporphine of 9-amino group and dichloro two (dimethyl sulfoxide) closes platinum (II), be dissolved in polar solvent, obtain mixed solution;
2) gained mixed solution carries out complexation reaction in the reflow temperature range of room temperature to polar solvent;
3) after reacting, solution filters, and isolates solid, namely obtains target product.
In synthetic method of the present invention, the ratio of the amount of substance that the different aporphine of 9-amino group and dichloro two (dimethyl sulfoxide) close platinum (II) is generally 1:0.8～1.2.
In synthetic method of the present invention, described polar solvent is the combination of methanol and acetonitrile, or methanol and acetonitrile and one or both the combination in acetone and dimethyl sulfoxide; The concentration of described methanol is 50～90v/v%, it is preferred to 60～70v/v%; In the composition of polar solvent, described methanol ratio shared by polar solvent is 0.5～99.5v/v%, acetonitrile ratio shared by polar solvent is 0.5～99.5v/v%, acetone ratio shared by polar solvent is 0～99v/v%, and dimethyl sulfoxide ratio shared by polar solvent is 0～99v/v%.Preferably, described methanol ratio shared by polar solvent is 1～99v/v%, acetonitrile ratio shared by polar solvent is 1～99v/v%, and acetone ratio shared by polar solvent is 0～98v/v%, and dimethyl sulfoxide ratio shared by polar solvent is 0～98v/v%; It is preferred that the ratio that methanol is shared by polar solvent is 5～95v/v%, acetonitrile ratio shared by polar solvent is 5～95v/v%, acetone ratio shared by polar solvent is 0～90v/v%, and dimethyl sulfoxide ratio shared by polar solvent is 0～90v/v%. The consumption of described polar solvent can be determined as required, it is generally the case that the different aporphine of 9-amino group of 1mmol and 0.8～1.2mmol dichloro two (dimethyl sulfoxide) close platinum (II) and dissolve with the polar solvent of 70～160mL. In concrete dissolving step, different for 9-amino group aporphine and dichloro two (dimethyl sulfoxide) can close platinum (II) dissolve (now with polar solvent respectively, the polar solvent being used for dissolving the different aporphine of 9-amino group preferably selects methanol and two kinds of mixed solvents of acetonitrile), remix and react together; After different for 9-amino group aporphine and dichloro two (dimethyl sulfoxide) also can close platinum (II) mixing, additive polarity solvent dissolves again.
In synthetic method of the present invention, complexation reaction preferably carries out in a heated condition, carries out and more preferably in the reflow temperature range of 60 DEG C to polar solvent. Whether complexation reaction can adopt thin layer chromatography tracing detection completely, and when complexation reaction is to carry out back flow reaction in the reflow temperature range of 60 DEG C to polar solvent, reaction extremely takes around the time of 12～48h completely; Also dependent on needs, the response time is extended to more than 48h. When reaction carries out under the heating condition of room temperature or less than 60 DEG C, reaction extremely needs the longer time completely.
In synthetic method of the present invention, when the addition relatively big (upper limit as close to proportioning) of previous step Semi-polarity solvent or solvent to the dissolubility of product better time, then after reaction, solution is likely to be clear state, this is because the product precipitation formed is by caused by polar solvent dissolves, now can by solution decompression distillation after reaction to remove partial solvent (removing the 75～90% of polar solvent addition), make product mainly precipitate out with precipitation form, after taking out the precipitation precipitated out, carry out next step operation again.
The raw material different aporphine of 9-amino group related in synthetic method of the present invention is referred to existing document (Tang, H.; Etal.Eur.J.Med.Chem., 2009,44:2523-2532.) be prepared, another kind of raw material dichloro two (dimethyl sulfoxide) is closed platinum (II) and is closed platinum (II) for cis dichloro two (dimethyl sulfoxide), it is referred to existing document (Al-AllafTAK, etal.Trans.Met.Chem., 1998) it is prepared.
Present invention additionally comprises compound shown in above-mentioned formula (I) or the application in preparing antitumor drug of its pharmaceutically acceptable salt.
The present invention farther includes the antitumor drug prepared with compound or its pharmaceutically acceptable salt shown in above-mentioned formula (I) for effective ingredient.
Further, present invention additionally comprises compound shown in above-mentioned formula (I) or the application in preparing telomerase inhibitor of its pharmaceutically acceptable salt. And with telomerase inhibitor that compound or its pharmaceutically acceptable salt shown in this above-mentioned formula (I) are prepared for effective ingredient.
Compared with prior art, the invention provides different aporphine-platinum (II) coordination compound of the 9-amino group of a kind of novel structure and synthetic method thereof and application.The present inventor on purpose selects the different aporphine alkaloid of 9-amino group to be active ligand, by the control to coordination compound synthesis condition, obtaining the different aporphine of title complex dichloro-dimethyl sulfoxide 9-amino group first and close platinum (II) coordination compound, this is also this alkaloidal metal complex of reported first at home and abroad. Compared with this type of coordination compound existing, the coordination structure of this coordination compound is significantly different, atom N on part 9-amino and platinum (II) monodentate ligand, atom or group in female ring have neither part nor lot in coordination, this coordination mode farthest remains the integrity aoxidizing different aporphine female ring, change its fragrance flatness and cloud density hardly, thus providing architecture basics for obtaining the new complexes with higher inhibition of telomerase. And experimental result also fully shows, the inhibitory action of telomerase is significantly improved by coordination compound of the present invention relative to platinum (II) coordination compound of existing 1-azepine benzanthrone and platinum (II) coordination compound of the different aporphine of 6-hydroxyl oxidize, reach 56.97%, telomerase activation inhibitory action is obvious. Additionally, the result of the test of various human tumor cell line and the proliferation inhibition activity of a strain normal liver cell HL-7702 is shown by applicant by this coordination compound, this coordination compound has good selectivity and significant anti tumor activity in vitro. Therefore, coordination compound of the present invention has good potential medical value, is expected to the preparation for various antitumor drug.
Accompanying drawing explanation
Fig. 1 is the Electrospray Mass Spectrometry spectrogram of the different aporphine of 9-amino group that the present invention prepares;
Fig. 2 is the Electrospray Mass Spectrometry spectrogram of the end product that the embodiment of the present invention 1 prepares;
Fig. 3 is the end product for preparing of the embodiment of the present invention 1 inhibitory action result figure to telomerase.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described in further detail, and to be more fully understood that present disclosure, but the present invention is not limited to following example.
The abbreviation that ligand L is the different aporphine of 9-amino group involved in following embodiment, the synthesis of this ligand L carries out synthesizing (Tang, H. with reference to prior art; Etal.Eur.J.Med.Chem., 2009,44:2523-2532.), specific as follows:
15.0g (about 0.1mol) phthalic anhydride and 2.0g (about 0.1mol) 4-Bretylium Tosylate are dissolved in 100mL ethanol, reflux 5 hours, filtered while hot, it is cooled to room temperature, crystallization, sucking filtration, obtain white plates crystalline compounds a, productivity 75%. The aluminum trichloride (anhydrous) of 75g (0.56mol) and 15g sodium chloride are mixed and heated to 140 DEG C melt, to its compound a being slowly added to 53g (0.2mol), add complete, be warming up to 180 DEG C, stirring reaction 2 hours, in taking advantage of thermal conductance to enter to grind, cooling, smash to pieces, obtain compound b, finally it is dividedly in some parts in the 100mL concentrated sulphuric acid of 80 DEG C, adds complete, be warming up to 260 DEG C, stirring reaction 2 hours, cooling, is poured in the ice of about 600g, regulates pH value with NaOH and is about 2-3, precipitate out a large amount of solid, sucking filtration, washing, obtain thick product. Thick product acetic acid recrystallization, 140 DEG C of vacuum dryings 24 hours, obtain the 1-azepine benzanthrone of yellow, productivity about 31%. (Chen, Z.F.; Etal.J.Med.Chem.2015,58:2159-2179).
In ice bath, to containing the nitric acid 1.2mL of 63% and the mixed liquor of 12mL concentrated sulphuric acid add 2.3g (0.01mol) l-azepine benzanthrone, react in ice bath and react l hour, room temperature reaction l hour, 55 DEG C are reacted 1 hour, importing in the ice of about 100g after cooling, being neutralized to pH value with ammonia is 7-8.Filter, wash with water. Thick product re crystallization from toluene, obtains orange-yellow acicular crystal 9-nitro-1-azepine benzanthrone, productivity about 55%. 9-nitro-1-azepine benzanthrone 2.8g (0.01mol) and nine hydrated sodium sulfide 5.5g (22.5mmol) is refluxed 6 hours at 100mL second alcohol and water (ethanol: water (volume ratio)=7:3), cooling, decompression evaporates ethanol, stand, sucking filtration, obtains thick product. Thick product re crystallization from toluene, obtaining the different aporphine of 9-amino group is dark red solid.
Gained dark red solid is identified:
(1) infrared spectrum, concrete spectroscopic characterization data are as follows:
IR(KBr):3426,3332,3206,3043,1658,1636,1597,1495,1437,1394,1348,1321,1284,1260,1167,1002,882,838,807,764,714,655,585,539,439cm-1。
(2) Electrospray Mass Spectrometry, its spectrogram is as shown in Figure 1.
ESI-MSm/z:247.2[M+H]+, wherein M is the molecular weight of L.
(3) elementary analysis result, as described in Table 1.
The elementary analysis result of coordination compound 1 in table 1 ligand L and embodiment 1
Embodiment 1:
The ligand L of precise 0.5mmol and 0.5mmol dichloro two (dimethyl sulfoxide) close platinum (II), ligand L is dissolved in 70v/v% methanol and the acetonitrile (volume ratio of methanol and acetonitrile is 1:1) of 55mL) in, dichloro two (dimethyl sulfoxide) is closed platinum (II) and is dissolved in the dimethyl sulfoxide of 2mL and the mixed solution of acetone (volume ratio of dimethyl sulfoxide and acetone is 3:1), two kinds of solution mixing, react 24 hours at 65 DEG C, after concentration and evaporation removes major part solvent (the 85% of solvent adding amount), it is cooled to room temperature to stand, precipitate out yellow solid product (productivity 95%).
Gained yellow solid product is identified:
(1) infrared spectrum, concrete spectroscopic characterization data are as follows:
IR(KBr):3527,3216,3110,2917,1653,1601,1494,1439,1396,1299,1222,1131,1026,977,920,843,768,716,655,590,503,441cm-1。
(2) proton nmr spectra spectrogram, concrete spectroscopic characterization data are as follows:
1HNMR(500MHz,DMSO-d6) δ 8.63 (d, J=5.5Hz, 1H), 8.47 (d, J=8.0Hz, 2H), 8.31 (d, J=8.1Hz, 1H), 7.97 (t, J=7.7Hz, 1H), 7.79 (d, J=5.5Hz, 1H), 7.40 (d, J=1.8Hz, 1H), 7.04 (dd, J=8.4,1.9Hz, 1H), 6.04 (s, 2H), 2.53 (s, 6H).
(3) carbon-13 nmr spectra spectrogram, concrete spectroscopic characterization data are as follows:
13CNMR(125MHz,DMSO-d6)δ183.57,151.86,149.32,144.48,135.26,134.60,133.62,131.29,129.88,129.12,127.28,124.89,121.27,120.42,119.60,110.46,40.82×2.
(4) Electrospray Mass Spectrometry, its spectrogram is as shown in Figure 2.
ESI-MSm/z:589.11[M-DMSO+Cl+CH3CN]-, wherein M is the molecular weight of coordination compound 1.
(5) elementary analysis result, as shown in Table 1 above.
Hence, it can be determined that the yellow solid product of gained is the different aporphine of target product dichloro-dimethyl sulfoxide 9-amino group closes platinum (II) coordination compound (hereinafter referred to as coordination compound 1), its structural formula is as follows:
Embodiment 2
The ligand L that precise amount of substance is 0.5mmol closes platinum (II) with 0.4mmol dichloro two (dimethyl sulfoxide), ligand L is dissolved in 85v/v% methanol and acetonitrile (volume ratio of methanol and acetonitrile the is 20:80) mixed solution of 35mL, dichloro two (dimethyl sulfoxide) is closed platinum (II) and is dissolved in the acetone of 5mL, two kinds of solution mixing, react 48 hours at 80 DEG C, after concentration and evaporation removes major part solvent (the 90% of solvent adding amount), it is cooled to room temperature to stand, precipitates out yellow solid target product (productivity 80%).
Embodiment 3
The ligand L that precise amount of substance is 0.5mmol closes platinum (II) with 0.55mmol dichloro two (dimethyl sulfoxide), ligand L is dissolved in 60v/v% methanol and acetonitrile (volume ratio of methanol and acetonitrile the is 0.6:99.4) mixed solution of 43mL, dichloro two (dimethyl sulfoxide) is closed platinum (II) and is dissolved in the dimethyl sulfoxide of 1mL, two kinds of solution mixing, react 12 hours at 60 DEG C, after concentration and evaporation removes major part solvent (the 75% of solvent adding amount), it is cooled to room temperature to stand, precipitate out yellow solid target product (productivity 85%).
Embodiment 4
The ligand L that precise amount of substance is 0.5mmol closes platinum (II) with 0.5mmol dichloro two (dimethyl sulfoxide), ligand L is dissolved in 81v/v% methanol and acetonitrile (volume ratio of methanol and acetonitrile the is 50:1) mixed solution of 69mL, dichloro two (dimethyl sulfoxide) is closed in the mixed solution that platinum (II) is dissolved in 5mL dimethyl sulfoxide and acetone (volume ratio is 1:1), two kinds of solution mixing, react 36 hours at 78 DEG C, after concentration and evaporation removes major part solvent (the 77% of solvent adding amount), it is cooled to room temperature to stand, precipitate out yellow solid target product (productivity 92%).
Embodiment 5
The ligand L that precise amount of substance is 0.5mmol closes platinum (II) with 0.48mmol dichloro two (dimethyl sulfoxide), ligand L is dissolved in 64v/v% methanol and acetonitrile (volume ratio the is 5:1) mixed solution of 41mL, dichloro two (dimethyl sulfoxide) is closed platinum (II) and is dissolved in 0.5mL dimethyl sulfoxide and acetone (dimethyl sulfoxide and acetone volume ratio are 5:1), two kinds of solution mixing, react 32 hours at 70 DEG C, after concentration and evaporation removes major part solvent (the 79% of solvent adding amount), it is cooled to room temperature to stand, precipitate out yellow solid target product (productivity 82%).
Embodiment 6
The ligand L that precise amount of substance is 0.5mmol closes platinum (II) with 0.6mmol dichloro two (dimethyl sulfoxide), ligand L is dissolved in 64v/v% methanol and acetonitrile (volume ratio of methanol and acetonitrile the is 99.5:0.5) mixed solution of 80mL, then it is added thereto to dichloro two (dimethyl sulfoxide) and closes platinum (II), react 28 hours at 77 DEG C after dissolving, after concentration and evaporation removes major part solvent (the 75% of solvent adding amount), it is cooled to room temperature to stand, precipitates out yellow solid target product (productivity 95%).
Embodiment 7
The ligand L of precise 0.5mmol and 0.6mmol dichloro two (dimethyl sulfoxide) close platinum (II), ligand L and dichloro two (dimethyl sulfoxide) are closed platinum (II) and is dissolved in the polar solvent (being made up of by the volume ratio of 0.5:0.5:99 90v/v% methanol, acetonitrile and acetone) of 80mL, react 48 hours at 60 DEG C, after concentration and evaporation removes major part solvent (the 80% of solvent adding amount), it is cooled to room temperature to stand, precipitates out yellow solid target product (productivity 82%).
In order to absolutely prove the coordination compound 1 of the present invention purposes in pharmacy, coordination compound 1 has been carried out anti-tumor activity experiment by applicant, secondly inquires into the inhibitory action to telomerase in Hep-G2 cell.
One, the proliferation inhibition activity of various human tumor cell line is tested by coordination compound 1:
1, cell strain and cell are cultivated
6 kinds of human cell's strains such as human liver cancer cell BEL-7402 and Hep-G2, ovarian cancer cell SK-OV-3, human lung carcinoma cell NCI-H460, people Colon and rectum adenocarcinoma cell HCT-8 and Human normal hepatocyte HL-7702 are selected in this experiment.
All cells strain all cultivate containing 10wt% calf blood, 100U/mL penicillin, 100U/mL streptomycin RPMI-1640 culture fluid in, put 37 DEG C containing volumetric concentration 5%CO2Incubator is cultivated.
2, the preparation of testing compound
Ligand L used and purity >=95% of coordination compound 1 (preparing by method described in embodiment 1), the whole solution of 20 μm of ol/L it is configured to after being diluted by its DMSO liquid storage physiological buffer, wherein final concentration≤1% of cosolvent DMSO, tests the compound suppression degree to various growth of tumour cell under this concentration.
3, cell growth inhibition test (mtt assay)
(1) take the logarithm the tumor cell of trophophase, after trypsinization, it is configured to the cell suspension that concentration is 5000/mL with the culture fluid containing 10% calf serum, it is inoculated in 96 well culture plates with every hole 190 μ L, makes cell density to be measured to 1000～10000 holes (edge hole is filled with aseptic PBS);
(2) 5%CO2, to hatch 24h for 37 DEG C, be paved with at the bottom of hole to cell monolayer, every hole adds the medicine 10 μ L of finite concentration gradient, and each Concentraton gradient sets 4 multiple holes;
(3) 5%CO2, hatch 48 hours for 37 DEG C, observe under inverted microscope;
(4) every hole adds the MTT solution (5mg/mLPBS, i.e. 0.5%MTT) of 10 μ L, continues to cultivate 4h;
(5) terminating cultivating, carefully suck culture fluid in hole, every hole adds the DMSO of 150 μ L and fully dissolves first a ceremonial jade-ladle, used in libation precipitation, after agitator mixing, is 570nm at microplate reader wavelength, and reference wavelength is the 450nm optical density value measuring each hole;
(6) zeroing hole (culture medium, MTT, DMSO), control wells (cell, the medicine dissolution medium of same concentrations, culture fluid, MTT, DMSO) are set simultaneously.
(7) according to the optical density value (OD value) recorded, judging living cells quantity, OD value is more big, and cytoactive is more strong. Utilize formula:
The computerized compound suppression ratio to growth of tumour cell, then calculate each test-compound IC to several tumor cell lines respectively with Bliss method50Value. Its result is as shown in the following Table 2.
Table 2: ligand L and the coordination compound 1 IC to different tumor cell lines50Value (μM)
From based on IC50The anti-tumor activity test result of value, various human tumor cell line is all demonstrated very strong proliferation inhibition activity by coordination compound 1, is significantly higher than ligand L. Wherein, coordination compound 1 is the strongest to the inhibitory action of human liver cancer cell Hep-G2 and human lung carcinoma cell NCI-H460, its IC50Value respectively 9.89 ± 0.47 and 14.25 ± 1.64 μMs, activity improves more than 3.4～10.9 times compared with ligand L; And its activity is also significantly greater than cisplatin, relative to cisplatin, coordination compound 1 has been respectively increased about 1.4 and 1.3 times. On the other hand, coordination compound 1 is still less to the cytotoxicity of people normal liver cell HL-7702, suitable with ligand L, and is substantially less than cisplatin, it is shown that the toxicity selectivity that tumor cell is good.
Two, coordination compound 1 inhibitory action to telomerase in Hep-G2 cell:
1, cell is cultivated and dosing method
Selected cell strain is Hep-G2 cell, and drug treating time is 24 hours, final concentration of 10 μMs of medicine, and cell is cultivated and other steps such as dosing method carry out with reference to abovementioned steps.
2, telomerase extracts and Inhibition test
Telomerase extracts box and adopts the telomerase of the long-range company in Chinese and Western, Beijing to extract box, article No. NKJ15DLM ,-20 DEG C of preservations.
2.1, telomerase extracts
After coordination compound 1 effect, from Hep-G2 Cell Aspiration telomerase extracting solution, silver dye experiment (TRAP-silverstainingassay) of telomerase is with reference to Reed et al. (Reed, J.E.; Etal.J.Am.Chem.Soc., 2006,128:5992 5993.) method reported carries out. Detailed step is as follows:
(1) collect no less than 1 × 106Individual cell (is about the 1-2 porocyte amount of 6 orifice plates), centrifugal 2000rpm, 5min, centrifugal collecting cell, grinds homogenate after the PBS washing of pre-cooling on ice bath;
(2) add Washbuffer (adding the DTT of 1 μ L (1mol/L) before using in every milliliter of PBS) ice-cold for 1mL, resuspended above-mentioned sample, put 5min on ice, 4 DEG C centrifugal (3,000rpm, 5min), abandon supernatant;
(3) add 40 Lysisbuffer (with adding 0.5 μ LPMSF and 0.5 μ L beta-mercaptoethanol in front every 1mLLysisbuffer) suspension precipitations ice-cold for μ L, vortex oscillation 10s, put 45min on ice, 4 DEG C, centrifugal (13,000rpm, 30min) take supernatant;
(4) supernatant is transferred in new EP pipe and (measures total protein concentration if desired) with Lysisbuffer degree of thickening 10 μ g/ μ L, save backup in-20 DEG C;
2.2, pcr amplification
(1) 5 μ L10 × TRAPbuffer is drawn, another addition 1 μ LdNTPs, 1 μ LTaq-DNApolymerase, 1 μ LTSprimer, 2 μ L telomerase extract, it is subsequently adding 39 μ L sterilizing ultra-pure waters, in incubated at room temperature 30min;
(2) add 1 μ LCXprimer mixing, amplification instrument carries out 30 circulations, 94 DEG C of preheating 5min, it is as follows that loop parameter is set: 94 DEG C of degeneration 30s; 50 DEG C of annealing 30s; 72 DEG C extend 90s; Last 72 DEG C extend 5min, 4 DEG C of preservation products as early as possible electrophoresis.
2.3, polyacrylamide gel electrophoresis
(1) 12% non-denaturing polyacrylamide gel (10mL) is prepared: include 30%Acr-Bis (29:1) 4mL, H2The TEMED of O (4.92mL), 10 × TBE (1mL), 10%APS (70 μ L) and 10 μ L.
(2) taking 9 μ LPCR products plus 1 μ L10 × sample-loading buffer, in voltage 180V, 12% non-denaturing polyacrylamide gel vertical electrophoresis runs 45min in advance, at voltage 220V, 12% non-denaturing polyacrylamide gel vertical electrophoresis 2h;
2.4, cma staining
(1) gel is put the fixing 30min of 10% acetic acid, rinsed with deionized water 3 times, each 5min;
(2) gel is placed in 0.2g/L sodium thiosulfate and soaks 1min, rinsed with deionized water 3 times, each 30s;
(3) gel is placed in silver nitrate dye liquor dyeing 30min, rinsed with deionized water 30s;
(4) gel is placed in nitrite ion and develops the color about 10-15min until band colour developing is complete;
(5) finally gel is placed in 10% acetic acid and soaks 5min termination reaction.
2.5, result judges to process with data:
Pcr amplification product, with cma staining, occurs that the trapezoid-shaped strips of 6bp or interval 6bp integral multiple is positive findings, measures band with gel imaging software, show that the Relative Absorbance IOD value of each specimen represents telomerase activation. Positive band is analyzed with Gelpro4.0 version gel photodensitometry software, surveys its IOD (integratedopticaldensity) accumulation optical density, is equipped with blank group every time. Computing formula is as follows:
The computerized compound suppression ratio to Hep-G2 tumor cell telomerase, its experimental result is such as shown in figure 3 below.
From telomerase experimental result it can be seen that among human liver cancer cell Hep-G2, coordination compound 1 (10 μMs) is to the inhibitory action of telomerase up to 56.97%, and its inhibitory action is far longer than the cisplatin (suppression ratio is 17.89) under comparable sodium; With the applicant it have been reported that 1-azepine benzanthrone (suppression ratio respectively 40.28% and 43.96%) compared with the inhibition of telomerase of the platinum of the different aporphine of 6-hydroxyl oxidize (II) coordination compound, also significantly improve, absolutely prove that telomerase is provided with higher targeting by coordination compound 1, be a kind of telomerase inhibitor preferably.
In sum, coordination compound 1 of the present invention shows anti tumor activity in vitro and the selectivity of excellence, the cytotoxicity of tumor cell is better than ligand L, has good potential medical value, is a kind of telomerase inhibitor preferably.
Claims (9)
1. compound or its pharmaceutically acceptable salt shown in following formula (I):
2. the synthetic method of compound described in claim 1, it is characterised in that: take the different aporphine of 9-amino group and dichloro two (dimethyl sulfoxide) closes platinum (II), be dissolved in polar solvent, carry out complexation reaction, namely obtain target product.
3. synthetic method according to claim 2, it is characterised in that comprise the following steps:
1) take the different aporphine of 9-amino group and dichloro two (dimethyl sulfoxide) closes platinum (II), be dissolved in polar solvent, obtain mixed solution;
2) gained mixed solution carries out complexation reaction in the reflow temperature range of room temperature to polar solvent;
3) the dense filtration of solution after reacting, isolates solid, namely obtains target product.
4. the synthetic method according to Claims 2 or 3, it is characterised in that: described polar solvent is the combination of methanol and acetonitrile, or methanol and acetonitrile and one or both the combination in acetone and dimethyl sulfoxide; The concentration of described methanol is 50～90v/v%; In the composition of polar solvent, described methanol ratio shared by polar solvent is 0.5～99.5v/v%, acetonitrile ratio shared by polar solvent is 0.5～99.5v/v%, acetone ratio shared by polar solvent is 0～99v/v%, and dimethyl sulfoxide ratio shared by polar solvent is 0～99v/v%.
5. the synthetic method according to Claims 2 or 3, it is characterised in that: complexation reaction carries out in the reflow temperature range of 60 DEG C to polar solvent.
6. compound described in claim 1 or the application in preparing antitumor drug of its pharmaceutically acceptable salt.
7. the antitumor drug prepared with compound described in claim 1 or its pharmaceutically acceptable salt for effective ingredient.
8. compound described in claim 1 or the application in preparing telomerase inhibitor of its pharmaceutically acceptable salt.
9. the telomerase inhibitor prepared with compound described in claim 1 or its pharmaceutically acceptable salt for effective ingredient.
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| CN106496280A (en) * | 2016-09-29 | 2017-03-15 | 广西师范大学 | One species specificity suppresses platinum (II) metal complex of proliferation of lung cancer cells and its synthetic method and application |
| CN108383880A (en) * | 2018-05-07 | 2018-08-10 | 玉林师范学院 | Target cumarin-platinum (II) complex and its synthetic method and the application of ovarian cancer drug-resistant strain |
| CN108456231A (en) * | 2018-05-07 | 2018-08-28 | 玉林师范学院 | A kind of pair of halogenated cumarin-platinum (II) complex and its synthetic method and application |
| CN108623638A (en) * | 2018-07-05 | 2018-10-09 | 桂林医学院 | 12- chloro benzimidazoles -1,8- naphthalimides-platinum complex and its preparation method and application |
| CN108659051A (en) * | 2018-05-07 | 2018-10-16 | 玉林师范学院 | A kind of high activity cumarin targeting oophoroma-platinum (II) complex and its synthetic method and application |
| CN108727435A (en) * | 2018-07-05 | 2018-11-02 | 桂林医学院 | 12- fluorobenzimidazoles -1,8- naphthalimides-platinum complex and its preparation method and application |
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| CN108997436A (en) * | 2018-07-20 | 2018-12-14 | 玉林师范学院 | A kind of novel Rui Gefeini anti-tumor platinum (II) complex and the preparation method and application thereof |
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