CN102924527A - Ru(II) complex with anticancer activity and preparation method of complex - Google Patents
Ru(II) complex with anticancer activity and preparation method of complex Download PDFInfo
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- CN102924527A CN102924527A CN2012104205571A CN201210420557A CN102924527A CN 102924527 A CN102924527 A CN 102924527A CN 2012104205571 A CN2012104205571 A CN 2012104205571A CN 201210420557 A CN201210420557 A CN 201210420557A CN 102924527 A CN102924527 A CN 102924527A
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Abstract
The invention provides a Ru(II) complex with anticancer activity and a preparation method of the complex. The complex is [Ru(phen)2GFLX]Cl2. The preparation method of the complex comprises the following steps of: sequentially adding [Ru(phen)2Cl2].2H2O, GFLX and sodium ethoxide under the protection of argon; stirring and dissolving with absolute ethanol, refluxing, adding hydrochloric acid to remove excessive sodium ethoxide, and carrying out spin drying to recycle the solvent; dissolving the obtained solid by using acetonitrile, filtering, carrying out spin-drying on the filtrate to obtain dark brownish red solid; and dissolving the solid by using the acetonitrile, performing neutral alumina column chromatography, eluting with a mixed solution of acetonitrile and ethanol, collecting the brownish red zone, performing spin-drying, and drying in vacuum to obtain the target complex. The Ru(II) complex has a good anticancer effect, and has low injury of normal cells.
Description
Technical field
The present invention relates to metal complexes, be specially a kind of Ru (II) title complex with antitumour activity and preparation method thereof.
Background technology
Metal complexes and DNA have three kinds of modes of action, and they are respectively 1, electrostatical binding; 2, irrigation canals and ditches combination; 3, Intercalation.Electrostatical binding refers to that phosphate radical electronegative among positively charged metal complexes and the DNA combines in the mode of electrostatic attraction; Irrigation canals and ditches are in conjunction with referring to that complex-bound arrives the irrigation canals and ditches position of duplex DNA; Intercalation refers to that title complex utilizes its plane aromatic heterocycle that contains to be inserted in the base pair of DNA, and piles up with its base pair.In these three kinds of modes in the third mode as best combination, because can be inserted in the base pair of DNA, directly make base pair impaired, in the inherited diseases such as cancer because its mother causes daughter DNA also to copy with the mispairing form for the mispairing of DNA, if metal complexes can be identified such mispairing and be inserted in the base pair of mispairing, it just stops it to copy, and we just can with it as a kind of good cancer therapy drug, fundamentally treat inherited disease or molecular disease like this.At present, people's synthetic aroma ring Co title complex is arranged, but the order of magnitude of the bonding constant of aromatic nucleus Co title complex and DNA is generally 10
4M
-1About, aspect anti-tumor activity, be average in performance, thereby the difficult to the greatest extent people's will of the anti-tumor activity of this kind Co title complex.
Summary of the invention
The object of the present invention is to provide a kind of Ru (II) title complex with stronger resisting liver cancer activity and preparation method thereof.
A kind of Ru (II) title complex with antitumour activity provided by the invention, its molecular structural formula is:
A kind of preparation method with Ru (II) title complex of antitumour activity provided by the invention comprises the steps:
The first step: be the RuCl of 1:2 with mol ratio
3H
2O and 1,10-phenanthroline are dissolved in 6 times of volume N, N ˊ--in the dimethyl formamide, and under argon shield, reflux 3 ~ 4h, then rotary evaporation is removed most of solvent, and surplus solution is cooled to room temperature, adds 52 times of volume acetone, places 0 ℃ environment to spend the night; Suction filtration gained crystal, and wash with frozen water; Then thick product is dissolved in the second alcohol and water that volume ratio is 1:1, reflux 1 ~ 2h removes insolubles after the filtration, add LiCl in filtrate, itself and RuCl
3H
2The mol ratio of O is 124:1, and rotary evaporation is removed the ethanol in the solution, and remaining aqueous solution cools off in ice bath, obtains blackish green crystal [Ru (phen)
2Cl
2] 2H
2O, reaction formula:
Second step: under argon shield, in reactor, add successively [Ru (phen)
2Cl
2] 2H
2O, GFLX, sodium ethylate, its mol ratio are 2:30:5, and with 20 times of volume absolute ethyl alcohol and stirring dissolvings, 100 ℃ were refluxed 3 hours, react complete adding hydrochloric acid and remove excess ethyl alcohol sodium, be spin-dried for the recovery solvent, with acetonitrile dissolving gained solid, filter, be spin-dried for filtrate, get dark brown red solid, be thick product;
Dissolve above-mentioned thick product with acetonitrile, the neutral alumina column chromatography is the acetonitrile of 10:1 and the mixing solutions wash-out of ethanol with volume ratio, collects red-brown the second colour band, is spin-dried for, and vacuum-drying gets the target title complex.
Reaction formula:
This Ru (II) title complex has obvious antitumour activity, can be used for preparing cancer therapy drug.Experimental results show that concentration can make hepatoma cell strain HepG2 establishment rate (II%) reach 63.3% when 100ug/ml, cranial glia tumor cell strain C6 establishment rate (II%) reaches 56.2%, cervical cancer cell strain HeLa establishment rate (II%) reaches 74.9%, and stomach cancer cell line SGC7901 establishment rate (II%) reaches 89.4%
Compared with prior art, the antitumour activity of Ru of the present invention (II) title complex obviously is better than Co title complex and cisplatin medicine; Ru (II) title complex and DNA have very high affinity, and the order of magnitude of bonding constant is generally 10
5M
-1About; In the selection of inserting part be raw material owing to selecting Gatifloxacin, contain the O atom in the Gatifloxacin, the hard metal of O parent, i.e. life atoms such as Cu, Fe, Ca, simultaneously O again can with H
2O etc. form hydrogen bond.This special structure is so that Ru (II) title complex not only has good anticancer effect, and little for the normal cell damage.
Description of drawings
Fig. 1 Ru (II) title complex is to the retarding effect figure of several JEG-3
The ultra-violet absorption spectrum of Fig. 2 Ru (II) title complex and DNA
The fluorescence spectrum of Fig. 3 Ru (II) title complex and DNA
The electrochemistry figure of Fig. 4 Ru (II) title complex and DNA
Embodiment
The preparation of embodiment 1Ru (II) title complex:
The first step: with RuCl
3H
2O1g (4.82mmol); 1; 10-phenanthroline (phen) 1.91g (9.64mmol) is dissolved in 30mlN; N ˊ--in the dimethyl formamide, under argon shield, reflux 3h; then rotary evaporation is removed most of solvent; surplus solution is chilled to room temperature, adds acetone 250ml, places 0 ℃ to spend the night.Suction filtration gained crystal also washs with frozen water.Then thick product is dissolved in reflux 1h in second alcohol and water (1:1) mixed solvent, filters gained solution and remove insolubles, add 23gLiCl in filtrate, rotary evaporation is removed the ethanol in the solution, and remaining aqueous solution obtains blackish green crystal in the ice bath cooling.Dry with ether washing final vacuum;
Second step: under argon shield; the ligand L 0.0488g(0.2mmol that adds the first step gained in the 100ml there-necked flask), GFLX 1.126g(3mmol), sodium ethylate 0.034g(0.5mmol); the dissolving of 50ml absolute ethyl alcohol and stirring, 100 ℃ were refluxed 3 hours, and reacted the hydrochloric acid of complete adding equivalent and remove excess ethyl alcohol sodium; be spin-dried for the recovery solvent; with 50ml acetonitrile dissolving gained solid, filter, be spin-dried for filtrate; get dark brown red solid, be thick product.
The above-mentioned thick product of a small amount of acetonitrile (approximately 1ml) dissolving, the neutral alumina column chromatography, acetonitrile: ethanol (V:V, 10:1) mixing solutions wash-out, collect red-brown the second colour band, be spin-dried for, vacuum-drying gets target title complex [Ru (phen)
2GFLX] Cl
2
Ultimate analysis and the nuclear magnetic data of Ru (II) title complex:
Found:C,56.02;H,4.49;N,10.48％.Calc.For C42H41N7O4FRu Cl2:C,56.12;H,4.57;N,10.91％.
1HNMR(ppm,DMSO-d
6):7.76(m,4H),6.44(dd,6H),6.00(d,2H),5.30(m,4H),4.15(dd,4H),3.99(s,2H),3.75(d,2H),3.35(dd,4H),3.18(d,2H),2.40(m,2H),2.10(s,1H),1.37(m,2H),1.08(d,2H),0.30(m,4H),(m,multiplet).
The experiment of embodiment 2Ru (II) title complex antitumour activity
Antitumour activity experiment realizes by cytotoxicity, is by utilizing tetrazolium salts 3-(4,5-dimethylthiazole)-2, and 5-phenylbenzene bromination tetrazolium (MTT) carries out for dyestuff.Title complex rushes the liquid preparation with phosphoric acid and places 4 ℃ of refrigerators for subsequent use.Get ready in the substratum of series stock solution in 96 micropore titration dishes.Title complex joins in the cell culture fluid in the mode of concentration gradient (1nM-1 μ M), and need not change medium in 24 hours.Setting the reaction times when finishing, substratum is moved in the medium of the 200 μ L that contain 0.5mg/mlMTT simultaneously micropore titration dish and is placed in the incubator 37 ℃ of constant temperature 4 hours.Add 100 μ lDMSO in the medium to increase the solubleness of this purple dye.At last, product is by measuring the optical density(OD) value in each hole under 595nm fluorescence.Inhibiting rate (II%) calculates by following formula: II(%)=(1-T/C) * 100%, and the optical density value of the part processed through title complex of representative and untreated part respectively wherein.Repeat above experiment three times.
This experiment utilizes four kinds of JEG-3 (hepatoma cell strain HepG2; Cranial glia oncocyte C6; The cervical cancer cell HeLa cell; Stomach cancer cell line SGC-7901) finishes, experimental results show that concentration can make hepatoma cell strain HepG2 establishment rate (II%) reach 63.3% when 100ug/ml; Cranial glia tumor cell strain C6 establishment rate (II%) reaches 56.2%; Cervical cancer cell strain HeLa establishment rate (II%) reaches 74.9%; Stomach cancer cell line SGC7901 establishment rate (II%) reaches 89.4%.As shown in Figure 1.These results show very establishment cancer cell multiplication of Ru (II) title complex, and this can be the medicine preparation some valuable information are provided.
The interaction experiment of embodiment 3Ru (II) title complex and DNA
Absorption Spectrum Research
Fig. 2 curve 1 is the ultra-violet absorption spectrum of Ru (II) title complex, and curve 2-17 is the ultra-violet absorption spectrum behind the adding DNA in Ru (II) title complex, and the absorption peak strength of title complex reduces after adding DNA as seen from the figure.According to bibliographical information
[10], when small molecules was incorporated between the CT-DNA duplex base pair with embedded mode, its absorption spectrum showed hypochromic effect; When small molecules was incorporated into CT-DNA with electrostatic means, its absorption spectrum showed hyperchromic effect; Therefore, the interaction between Ru (II) title complex this moment and the CT-DNA should be take intercalation as main.
Title complex is on the impact of DNA fluorescence spectrum
Fig. 3 curve 1 is the fluorescence spectrum of Ru (II) title complex, and curve 2-12 is the fluorescence spectrum behind the adding DNA in Ru (II) title complex, and the fluorescence of title complex strengthens after adding DNA as seen from the figure.Fluorescent spectrometry is a kind of desirable method of research small molecules and nucleic acid interaction, after the small molecules title complex inserts the DNA base pair, so that the rigidity of DNA increases, shows fluorescence and strengthens.Therefore, we judge that this Ru (II) title complex is with the inserted mode Interaction with DNA.
The thermally denature experiment of CTDNA
By measuring the thermal denaturation temperature (t of DNA
m) can distinguish the binding mode (intercalation, outside bonding) of title complex and DNA.Insertion reaction occurs in title complex and DNA, with the duplex structure of stabilized DNA, and makes t
mSharply rise; And outside bonding is when only occuring with DNA in title complex, then t
mAscensional range is less or do not rise.Under this experiment condition, the t of DNA
mIt is 67 ℃.After DNA and the effect of Ru (II) title complex, its t
mIt is 71 ℃.This shows that Ru (II) title complex combines in the intercalation mode with DNA.
Electrochemical behavior research
Movement according to the formula weight current potential of cyclic voltammetry curve gained can be judged small molecules and DNA Interactions Mode.Usually, do the time spent when external source small molecules and DNA occur to insert, micromolecular formula weight current potential is shuffled; Otherwise if the electronegative phosphate generation electrostatic interaction on external source small molecules and the DNA skeleton, then its formula weight current potential is negative moves.
By table 1(Fig. 4) as seen, the anode spike potential (E of pure Ru (II) title complex
Pa) and negative electrode spike potential (E
Pc) be respectively 1.0905V and 1.0153V, formula weight current potential (E
1/2) be the anode spike potential (E behind 1.0529V.Ru (II) the title complex Interaction with DNA
Pa) and negative electrode spike potential (E
Pc) be respectively 1.0944V and 1.0170V, formula weight current potential (E
1/2) shuffle for 1.0557V. formula weight current potential, illustrate that Ru (II) title complex and DNA interact with classical inserted mode.
Table 1 in the presence of DNA, the cyclic voltammetric value of Ru (II) title complex
| complex | R | E pa/V | E pc/V | E 1/2/V |
| Ru(phen)
2 |
0 | 1.0905 | 1.0153 | 1.0529 |
| 5 | 1.0944 | 1.0170 | 1.0557 |
R=[DNA]/[Ru]。
Claims (2)
1. Ru (II) title complex with antitumour activity is characterized in that, structural formula is:
2. a kind of preparation method with Ru (II) title complex of antitumour activity as claimed in claim 1 is characterized in that, step comprises: under argon shield, add successively [Ru (phen) in reactor
2Cl
2] 2H
2O, GFLX, sodium ethylate, its mol ratio are 2:30:5, and with 20 times of volume absolute ethyl alcohol and stirring dissolvings, 100 ℃ were refluxed 3 hours, add hydrochloric acid and remove excess ethyl alcohol sodium, be spin-dried for the recovery solvent, with acetonitrile dissolving gained solid, filter, be spin-dried for filtrate, get dark brown red solid, be thick product; Dissolve above-mentioned thick product with acetonitrile, the neutral alumina column chromatography is the acetonitrile of 10:1 and the mixing solutions wash-out of ethanol with volume ratio, collects red-brown the second colour band, is spin-dried for, and vacuum-drying gets the target title complex.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101747382A (en) * | 2009-12-29 | 2010-06-23 | 广东药学院 | Ruthenium polypyridyl complex using quinolones compound as ligand, preparation method and application thereof |
| CN101817817A (en) * | 2010-04-09 | 2010-09-01 | 广西师范大学 | Rare earth metal complexes using orbifloxacin as ligand, method for synthesizing same and application thereof |
| CN102627642A (en) * | 2012-03-19 | 2012-08-08 | 南京洵安医药科技有限公司 | Metal complexes of moxifloxacin and pharmaceutical purpose thereof |
-
2012
- 2012-10-29 CN CN2012104205571A patent/CN102924527A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101747382A (en) * | 2009-12-29 | 2010-06-23 | 广东药学院 | Ruthenium polypyridyl complex using quinolones compound as ligand, preparation method and application thereof |
| CN101817817A (en) * | 2010-04-09 | 2010-09-01 | 广西师范大学 | Rare earth metal complexes using orbifloxacin as ligand, method for synthesizing same and application thereof |
| CN102627642A (en) * | 2012-03-19 | 2012-08-08 | 南京洵安医药科技有限公司 | Metal complexes of moxifloxacin and pharmaceutical purpose thereof |
Non-Patent Citations (2)
| Title |
|---|
| 周宝石等,: "Nd(III)-邻菲罗啉-加替沙星三元配合物的合成及与DNA的作用", 《陕西师范大学学报(自然科学版)》 * |
| 黄东纬: "氧氟沙星钌(II)配合物与DNA的相互作用", 《中国现代药物应用》 * |
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Application publication date: 20130213 |