CN101967164A - Ruthenium (II) complex, preparation method thereof and application thereof to preparation of antitumor medicaments - Google Patents
Ruthenium (II) complex, preparation method thereof and application thereof to preparation of antitumor medicaments Download PDFInfo
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Abstract
The invention discloses a ruthenium (II) complex, a preparation method thereof and application thereof to preparation of antitumor medicaments. The ruthenium (II) complex has a structural formula shown as a formula (I), wherein X is thiophene or indol; and N-N is bipyridyl, biimidazole or phenanthroline. The ruthenium (II) complex does not comprise readily hydrolytic chlorine (Cl) or dimethylsulfoxide (DMSO) structurally. Compared with the traditional ruthenium complex, the ruthenium (II) complex has the advantages of obviously enhancing stability, reducing toxicity and obviously improving antitumor activity, so the ruthenium (II) complex can be used for preparing medicaments for preventing or treating tumor diseases.
Description
Technical field
The present invention relates to the preparing anti-tumor medicine field, be specifically related to a kind of ruthenium (II) title complex and preparation method thereof and the application in the preparation antitumor drug.
Background technology
Cancer has become the No.1 killer who threatens human life's health, and the prevention and the treatment of cancer paid much attention in countries in the world, and exploitation is efficient, the cancer therapy drug of low toxicity, wide spectrum, highly selective becomes secular strategic objective.The beginning of the seventies, find that cis-platinum has anti-tumor activity, 1979, U.S. medicine food management board (FDA) ratified cis-platinum as the medicinal application of treatment cancer in clinical.Cis-platinum be metal complexes first is applied to clinical inorganic drug as cancer therapy drug, after this other platinum complexes go on the market in succession as antitumor drug or are applied to clinical.But the shortcoming that platinum complex exists is: toxic side effect is bigger, comprises renal toxicity, ototoxicity, neurotoxicity and gastrointestinal toxicity, easily cause patient the kidney poison, feel sick, problems such as apocleisis and neurological disorder; Water-soluble little; Make tumour cell produce acquired resistance; Must drug administration by injection.Therefore, researching and developing other metal complexess is an important topic as antitumor drug.
In having the metal complexes of anti-tumor activity, ruthenium complexe is the outstanding person in the non-platinum medicine research, generally believe in the world: the title complex of ruthenium and ruthenium belongs to hypotoxicity, absorbs easily and very fast in vivo drainage, will become one of the most promising cancer therapy drug.Ruthenium complexe is similar to cis-platinum, has different antitumor mechanism with the antitumor drug of clinical application, and the antitumor mechanism of it and cis-platinum also is not quite similar.The ratio that produces crossing drug resistant with cis-platinum is less.These mean that all ruthenium complexe has a good application prospect as antitumor drug.
The seventies, synthetic and characterized first and be used to the ruthenium complexe cis-[Ru (DMSO) of anti-tumor activity research
4Cl
2], in the later stage eighties, it is HL[RuL that Keppler etc. have designed and synthesized general formula
2Cl
4] and (HL)
2[RuLCl
5] (L is for containing N heterocycle small molecules) and better water miscible ruthenium complexe is arranged, the anti-tumor in vivo activity test has obtained amazing result.Synthesized trans precursor in 1991 in the building-up process of transforming the cis precursor, and synthesized a large amount of the type compounds subsequently on this basis, star molecule wherein surely belongs to NAMI-A.
1998, the cancer therapy drug of 8 National Laboratories of european union primary study ruthenium complexe; The further antitumor application of exploitation ruthenium complexe as antitumor drug.Calendar year 2001, first to enter clinical ruthenium complexe as antitumor drug be NAMI-A, and basic general formula is [ImH] [trans-RuCl
4(dmso-S) (Im) Im=imidazole)], structure as shown in the formula,
NAMI-A is obvious to the metastatic tumor effect of lung, and calendar year 2001, it is clinical to have entered the I phase as the effective antitumour medicine in Amsterdam of Holland, and it is clinical to enter the II phase smoothly in 2003.
Second enters clinical ruthenium complexe is KP1019, and basic general formula is [HL] [trans-Ru (III) L
2Cl
4])], structure is as follows.KP1019 works to colorectal carcinoma.Finished the I phase smoothly in 2003～2006 years clinical.Two other has ruthenium complexe ICR ([ImH] [trans-RuCl of similar structures
4(Im)
2], Im=imidazole wherein) and IndCR[IndH] [trans-RuCl
4(Ind)
2], wherein also to enter the I phase in 2003 clinical for Ind=Indazole.Later find that in succession some have the title complex of good resistance tumor promotion.As the dipolymer of Ru (III), Na
2[{ trans-RuCl
4(dmso-S) }
2(-L)], it is clinical that (L=heterocyclic bridging N-ligand) etc. also enters the I phase.The structure of described medicine is as follows.
KP1019 has wherein finished the first phase clinical experiment in 2003-2006, and prove that it can pass through plastosome approach cell death inducing, can suppress the inoperative growth of tumor of some cis-platinums, and in vivo with experiment in vitro in, all have no drug resistance, accept the patient of this pharmacological agent, also do not have very severe side effect.
Yet still there is poor stability in existing ruthenium complexe, and the shortcoming that facile hydrolysis and toxicity are big, antineoplastic activity still remain to be improved.
Summary of the invention
The objective of the invention is to determine, a kind of good stability, not facile hydrolysis, toxicity is little, anti-tumor activity is high ruthenium (II) title complex are provided according to the poor stability that exists in the existing ruthenium complexe, facile hydrolysis, toxicity are big etc.
Another purpose of the present invention is to provide the preparation method of above-mentioned ruthenium (II) title complex.
Another purpose of the present invention is to provide the application of above-mentioned ruthenium (II) title complex.
Another purpose of the present invention is to provide a kind of pharmaceutical composition that comprises above-mentioned ruthenium (II) title complex.
A further object of the invention is to provide a kind of pharmaceutical preparation that comprises above-mentioned ruthenium (II) title complex.
Above-mentioned purpose of the present invention is achieved by the following technical programs:
A kind of ruthenium (II) title complex, its structural formula is suc as formula shown in (I), and wherein, X is
Or
N-N is dipyridyl, bisglyoxaline or phenanthroline;
As a kind of preferred version, when the structure of ruthenium of the present invention (II) title complex is shown in arbitrary structure among a～f, have better properties:
The structural formula of some parts that relate in the said structure formula of the present invention (crucial pharmacophore), name and abbreviation contrast are as follows:
2,2 '-dipyridyl (bpy) 2,2 '-bisglyoxaline (biim) 1,10-phenanthroline (phen)
2-(thiophene-2-yl)-1H-imidazoles [4,5-f] [1,10]-phenanthrolines (TIP)
2-(indoles-5-yl)-1H-imidazoles [4,5-f] [1,10]-phenanthrolines (IDIP).
Found that compound of the present invention all has had strong inhibitory effects to kinds of tumor cells in experiment in vitro, its effect is better than cis-platinum, and toxicity is lower, and ruthenium complexe clearly of the present invention is useful on the application prospect of preparation treatment or preventing cancer medicine.
Therefore, the invention provides above-mentioned ruthenium complexe and treat and/or prevent application in the medicine of cancer in preparation.
Described cancer generally comprises Humanmachine tumour, liver cancer, colorectal carcinoma, mammary cancer, lung cancer etc.
Ruthenium of the present invention (II) title complex can also be the material of pharmacy acceptable salt, solvate or corresponding crystal habit (containing different crystal water) in use.Pharmacy acceptable salt comprises the salt of their basic metal, alkaline-earth metal or ammonium class material, if necessary, also can be acid salt, example hydrochloric acid, sulfuric acid, nitric acid, methylsulfonic acid, Phenylsulfonic acid, toxilic acid, tartrate, citric acid, lactic acid, lactobionic acid, perchloric acid, hexafluoro close the salt that acid commonly used on the pharmacodynamics such as phosphoric acid forms.Solvate can be a hydrate, comprises that monohydrate is to decahydrate etc.
For realizing above-mentioned application, the present invention also provides a kind of pharmaceutical composition, as long as contain the ruthenium complexe of above-mentioned any or its mixture in the said composition.Above-mentioned composition also can comprise pharmaceutically acceptable carrier, and some medicinal auxiliary agents, complementary component such as thinner.
Above-mentioned composition can be made a kind of pharmaceutical preparation and use, formulation can be any medicinal formulation, as tablet, sugar coated tablet, film tablet, enteric coated tablet, capsule and tablet, oral liquid, granule, electuary, pill, injection, sprays or sustained release preparation etc.
The application of above-mentioned ruthenium complexe can be independent application, also can be drug combination.
The present invention also provides the preparation method of above-mentioned ruthenium complexe,
(1) part of structure shown in the preparation formula (II):
Be with phenanthroline-5, behind 6-diketone, aldehyde, ammonium acetate and the Glacial acetic acid mixed dissolution, heating reflux reaction obtains; Described aldehyde structure is XCHO, and wherein X is
(2) preparation active intermediate Ru (L
2) Cl
2 2+, wherein L is dipyridyl, bisglyoxaline or phenanthroline; Concrete steps are as follows:
Be with ruthenium trichloride, L and lithium chloride, be dissolved in N, in the dinethylformamide, heating reflux reaction obtains under argon shield;
(3) part of structure shown in the formula (II) that step (1) is obtained mixes with Ru (L2) Cl22+ and is dissolved in ethylene glycol, and heating reflux reaction promptly obtains having the product of structure shown in the formula (I) under argon shield.
As preferably, in the step (1), the temperature of heating reflux reaction is 115-135 ℃, but more preferably 120 ℃.
As preferably, in the step (1), phenanthroline-5, the mol ratio of 6-diketone, aldehyde, ammonium acetate and Glacial acetic acid is 1: 1.2: 20: 5.
As preferably, in the step (1), after reaction finishes, obtain the part of structure shown in the formula (II) through following purification step: be chilled to room temperature, dilute with water drips strong aqua near neutral, separates out a large amount of yellow mercury oxides, suction filtration, water, washing with alcohol are dried and are promptly got product for several times.Slightly the product dissolve with methanol is crossed 60-100 order silicagel column, and methyl alcohol drip washing is collected yellow eluent to colourless, gets yellow crystals after concentrating.
As preferably, in the step (2), the mol ratio of ruthenium trichloride, L and lithium chloride is 1: (1.5-2.8): (4-5.5), but be more preferably 1: 2: 4.
As preferably, in the step (2), the temperature of heating reflux reaction is 130-150 ℃, but more preferably 140 ℃;
As preferably, in the step (2), after reaction finishes, obtain intermediate Ru (L2) Cl22+: after being chilled to room temperature, add acetone, freeze overnight through following purification step.Suction filtration, the precipitation frozen water, cold washing with acetone several, vacuum-drying obtains the atropurpureus crystallite.
As preferably, in the step (3), the mol ratio of part of structure shown in the formula (II) and Ru (L2) Cl22+ is 1: (0.8-1.5) but more preferably 1: 1.
As preferably, in the step (3), the temperature of heating reflux reaction is 115-130 ℃, but more preferably 120 ℃.
As preferably, in the step (3), after reaction finishes, obtain the product of structure shown in the formula (I) through following purification step: be chilled to room temperature, add the suitable quantity of water dilution, the saturated solution that adds NaClO4 promptly produces a large amount of red precipitates, suction filtration, water, washing with alcohol is after drying for several times.Dried thick product is dissolved with minor amounts of acetonitrile, separate, use V (toluene): V (acetonitrile)=1 with the neutral alumina post: (2.5-3.5), but more preferably 1: 3, main red component under the mixed solvent drip washing, decompression boils off solvent then, gets red crystals.
The reaction formula of above-mentioned reaction is as follows:
The preparation of ruthenium complexe shown in the formula (I):
Compare with existing ruthenium complexe, ruthenium of the present invention (II) title complex has following beneficial effect:
The anti-cancer agent that the present invention relates to has carried out structure design, synthetic, structural modification and transformation, has synthesized the ruthenium complexe of characteristic structure.Ruthenium complexe of the present invention is Ru (II) title complex, has very big difference with existing ruthenium complexe on main part and the structure.Have good stability in nature, facile hydrolysis or hydrolysis do not wait advantage very slowly.Especially we have found crucial drug activity group, can further improve its anti-tumor activity, reduce its toxicity.
Title complex of the present invention has a tangible cancer suppressing action external, and active and cis-platinum be quite or significantly better than cis-platinum, and with cis-platinum less cross resistance is arranged.
Description of drawings
Fig. 1～4th, ruthenium (II) title complex f is to the flow cytometry of HeLa cytosis 48h
Figure (because this figure is not a histogram, so with column two word deletions), wherein, Fig. 1 is the flow cytometry figure of control group; Fig. 2 is the flow cytometry figure of the concentration of ruthenium (II) title complex f when being 10ug/ml; Fig. 3 is the flow cytometry figure of the concentration of ruthenium (II) title complex f when being 20ug/ml; Fig. 4 is the flow cytometry figure of the concentration of ruthenium (II) title complex f when being 40ug/ml.
Embodiment
Further explain the present invention below in conjunction with embodiment, but embodiment does not do any type of qualification to the present invention.
As long as it is above that the raw materials used purity of the present invention reaches chemical pure, the source all can be buied from market.
(1) phenanthroline 5,6-diketone synthetic
Mix and place 4.0g o-phenanthroline and 4.0g Potassium Bromide thoroughly round-bottomed flask, drip cold dense H then
2SO
4(40mL) with dense HNO
3Mixing acid (20mL).Holding temperature is at 80-85 ℃ of reaction 3h after dripping nitration mixture, and cooling is poured in the 500mL frozen water, uses 10mol L then
-1NaOH solution carefully is neutralized to neutrality.With 3 * 100mL chloroform this solution is extracted.After merging organic phase, it is washed, spend the night with dried over sodium sulfate at last with 50mL water.After the filtration, the pressure reducing and steaming chloroform, the solid product ethyl alcohol recrystallization must get yellow or orange-yellow needle-like crystal.Productive rate: 75%.
(2) synthetic (TIP) of 2-(thiophene-2-yl)-1H-imidazoles [4,5-f] [1,10]-phenanthroline
Phenanthroline-5,6-diketone (525mg, 2.5mmol), thiophene-2-formaldehyde (294mg, 3.5mmol), ammonium acetate (3.88g, 50mmol) and glacial acetic acid (10ml) in round-bottomed flask, refluxed 2.5 hours, be chilled to room temperature after, with the dilution of 40mL water, the careful strong aqua that drips is separated out a large amount of yellow mercury oxides near neutral.Suction filtration, successively water, ether wash for several times, and vacuum-drying promptly gets thick product.Slightly the product dissolve with ethanol is crossed 60-100 order silicagel column, and ethanol drip washing is collected yellow eluent to colourless, gets product 528mg, productive rate after concentrating: 70%, with phenanthroline-5, the 6-diketone calculates).
(3) cis-[Ru (bpy)
2Cl
2] 2H
2O's is synthetic
RuCl
3NH
2O (1.56g, about 6mmol), dipyridyl (1.87g, 12mmol) and lithium chloride (1.68g 28mmol) in three-necked bottle, adds 10mL DMF, and reflux is 8 hours under the argon shield.After being chilled to room temperature, add 50mL acetone, freeze overnight.Suction filtration, the precipitation frozen water, cold washing with acetone several, vacuum-drying obtains the atropurpureus crystallite, productive rate, 2.52g (81%, calculate with dipyridyl).
(4) [Ru (bpy)
2(TIP)] (ClO
4)
22H
2O's is synthetic
[Ru (bpy)
2Cl
2] 2H
2(0.090g, 0.17mmol), (0.051g, backflow 2h 0.17mmol) and under ethylene glycol (10mL) argon shield obtains dark red solution to 2-(thiophene-2-yl)-1H-imidazoles [4,5-f] [1,10]-phenanthrolines (TIP) to O.After the solution cooling, the dilution of 20mL water adds saturated NaClO
4Solution gets orange-yellow precipitation, filters, and solution with water, ether washing after the vacuum-drying, obtain orange red solids crude product for several times.Dissolve thick product with a small amount of second cyanogen, peroxidation aluminium post, second cyanogen: toluene (3: 1, v/v) wash-out is collected main red component, and decompression is spin-dried for, toluene: second cyanogen recrystallization, productive rate, 0.14g, (84%, with [Ru (bpy)
2Cl
2] 2H
2O calculates); Found:C:46.55; H; 3.16; N; 11.63. (Calc.for C
37H
26Cl
2N
8O
8RuS2H
2O:C:46.74; H:3.18; N:11.79);
1H NMR (400MHz, (D
6) DMSO): δ 8.98 (d, 2H), 8.87 (d, 2H), 8.83 (d, 2H), 8.22 (t, 2H), 8.11 (t, 2H), 7.93 (d, 2H), 7.82-7.87 (m, 5H), 7.64 (d, 1H), 7.59 (t, 4H), 7.37 (t, 2H), 7.24 (t, 1H) .ESI-MS (Me CN): 814.7 ([M-ClO
4]
+), 715.1 ([M-2ClO
4-H]
+), 358.3 ([M-2ClO
4]
2+) .UV-Vis (in water at pH=7.4 λ max (ε/10
4M
-1Cm
-1)): 471 (0.22), 289 (1.15); Emission spectra (in water at pH=7.4no corrected λ max): 585nm.
(1) synthetic (TIP) of 2-(thiophene-2-yl)-1H-imidazoles [4,5-f] [1,10] phenanthroline: see the step (2) in the preparation of title complex a.
(2)cis-[Ru(biim)
2Cl
2]·2H
2O
Claim RuCl
3NH
2O 1.56g (about 6mmol) with bisglyoxaline 1.61g (12mmol) and lithium chloride 1.68g (28mmol), is dissolved in it among 10mL DMF reflux 8h under the argon shield.After being chilled to room temperature, add 50mL acetone, freeze overnight.Suction filtration, the precipitation frozen water, after cold acetone was cleaned, vacuum-drying got the atropurpureus crystallite.Productive rate, 72%.
(3) [Ru (biim)
2(TIP)] (ClO
4)
22H
2O's is synthetic
[Ru (biim)
2Cl
2] 2H
2(0.080g, 0.17mmol), (0.051g, backflow 2h 0.17mmol) and under ethylene glycol (10mL) argon shield obtains dark red solution to 2-(thiophene-2-yl)-1H-imidazoles [4,5-f] [1,10] phenanthroline (TIP) to O.After the solution cooling, the dilution of 20mL water adds saturated NaClO
4Solution gets orange-yellow precipitation, filters, and solution with water, ether washing after the vacuum-drying, obtain orange red solids crude product for several times.Dissolve thick product with a small amount of second cyanogen, peroxidation aluminium post, second cyanogen: toluene (3: 1, v/v) wash-out is collected main red component, and decompression is spin-dried for, toluene: second cyanogen recrystallization, productive rate, 0.13g, (83%, with [Ru (biim)
2Cl
2] 2H
2O calculates); Found:C:38.51; H; 3.01; N; 18.39. (Calc.for C
29H
22Cl
2N
12O
8RuS2H
2O:C:38.42; H:2.89; N:18.54); ESI-MS (MeCN): 671.7 ([M-2ClO
4-H]
+), 336.3 ([M-2ClO
4]
2+) .UV-Vis (in water at pH=7.4 λ max (ε/10
4M
-1Cm
-1)): 455 (0.32), 289 (1.27); Emission spectra (in water at pH=7.4no corrected λ max): 582nm.
Embodiment 3 title complex c:[Ru (phen)
2(TIP)]
2+Preparation
(1) synthetic (TIP) of 2-(thiophene-2-yl)-1H-imidazoles [4,5-f] [1,10] phenanthroline: referring to the step in the preparation of title complex a (2).
(2)cis-[Ru(phen)
2Cl
2]·2H
2O
Claim RuCl
3NH
2O 1.56g (about 6mmol) with phenanthroline 2.40g (12mmol) and lithium chloride 1.68g (28mmol), is dissolved in it among 10mL DMF reflux 8h under the argon shield.After being chilled to room temperature, add 50mL acetone, freeze overnight.Suction filtration, the precipitation frozen water, after cold acetone was cleaned, vacuum-drying got the atropurpureus crystallite.Productive rate, 72%.
(3) [Ru (phen)
2(TIP)] (ClO
4)
22H
2O's is synthetic
[Ru (phen)
2Cl
2] 2H
2(0.096g, 0.17mmol), (0.051g, backflow 2h 0.17mmol) and under ethylene glycol (10mL) argon shield obtains dark red solution to 2-(thiophene-2-yl)-1H-imidazoles [4,5-f] [1,10] phenanthroline (TIP) to O.After the solution cooling, the dilution of 20mL water adds saturated NaClO
4Solution gets orange-yellow precipitation, filters, and solution with water, ether washing after the vacuum-drying, obtain orange red solids crude product for several times.Dissolve thick product with a small amount of second cyanogen, peroxidation aluminium post, second cyanogen: toluene (2: 1, v/v) wash-out is collected main red component, and decompression is spin-dried for, toluene: second cyanogen recrystallization, productive rate, 0.14g, (82%, with [Ru (phen)
2Cl
2] 2H
2O calculates); Found:C:49.25; H; 3.10; N; 11.32. (Calc.for C
41H
26Cl
2N
8O
8RuS2H
2O:C:49.30; H:3.03; N:11.22);
1H NMR (400MHz, (D
6) DMSO): δ 8.94 (d, 2H), 8.76 (d, 4H), 8.39 (s (singlet), 4H), 8.10-8.12 (m, 4H), 7.89 (d, 3H), 7.75-7.79 (m, 4H), 7.70 (t, 2H), 7.65 (d, 1H), 7.24 (t, 1H) .ESI-MS (MeCN): 864.9 ([M-ClO
4]
+), 763.2 ([M-2ClO
4-H]
+), 382.3 ([M-2ClO
4]
2+) .UV-Vis (in water at pH=7.4 λ max (ε/10
4M
-1Cm
-1)): 465 (0.22), 265 (0.92); Emission spectra (in water at pH=7.4no corrected λ max): 584nm.
Embodiment 4 title complex d:[Ru (bpy)
2(IDIP)]
2+Preparation
(1) synthetic (IDIP) of 2-(indoles-5-yl)-1H-imidazoles [4,5-f] [1,10]-phenanthroline
Phenanthroline-5,6-diketone (525mg, 2.5mmol), indoles-5-formaldehyde (507mg, 3.5mmol), ammonium acetate (3.88g, 50mmol) and glacial acetic acid (10ml) in round-bottomed flask, refluxed 2.5 hours, be chilled to room temperature after, with the dilution of 40mL water, the careful strong aqua that drips is separated out a large amount of yellow mercury oxides near neutral.Suction filtration, successively water, ether wash for several times, and vacuum-drying promptly gets thick product.Slightly the product dissolve with ethanol is crossed 60-100 order silicagel column, and ethanol drip washing is collected yellow eluent to colourless, gets product 586mg, productive rate after concentrating: 70%, with phenanthroline-5, the 6-diketone calculates).
(2) [Ru (bpy)
2Cl
2] 2H
2The preparation process (3) of the synthetic participation title complex a of O.
(3) [Ru (bpy)
2(IDIP)] (ClO
4)
22H
2O's is synthetic
Referring to the preparation process (4) of title complex a, just 2-(thiophene-2-yl)-1H-imidazoles [4,5-f] [1,10]-phenanthrolines (TIP) are replaced with 2-(indoles-5-yl)-1H-imidazoles [4,5-f] [1,10]-phenanthrolines (IDIP).Found：C：49.95；H；3.50；N；12.76.(Calc.for?C
41H
29Cl
2N
9O
8Ru·2H
2O：C：50.06；H：3.38；N：12.81)；ESI-MS(MeCN)：848.4([M-ClO
4]
+)，748.4([M-2ClO
4-H]
+)，374.1([M-2ClO
4]
2+).UV-Vis(in?water?at?pH＝7.4λmax(ε/10
4M
-1cm
-1))：456(0.18)，263(0.82)；emission?spectra(in?water?at?pH＝7.4no?corrected?λmax)：585nm。
Embodiment 5 title complex e:[Ru (biim)
2(IDIP)]
2+Preparation
(1) synthetic (IDIP) of 2-(indoles-5-yl)-1H-imidazoles [4,5-f] [1,10]-phenanthroline: referring to the step in the preparation of title complex d (1).
(2) [Ru (biim)
2Cl
2] 2H
2O's is synthetic: referring to (2) in the preparation process of title complex b
(3) [Ru (biim)
2(IDIP)] (ClO
4)
22H
2O's is synthetic
Referring to the preparation process (3) of title complex b, just 2-(thiophene-2-yl)-1H-imidazoles [4,5-f] [1,10]-phenanthrolines (TIP) are replaced with 2-(indoles-5-yl)-1H-imidazoles [4,5-f] [1,10]-phenanthrolines (IDIP).Found：C：42.01；H；3.22；N；19.49.(Calc.for?C
33H
25Cl
2N
13O
8Ru·2H
2O：C：42.18；H：3.11；N：19.38)；ESI-MS(MeCN)：703.3([M-2ClO
4-H]
+)，352.9([M-2ClO
4]
2+).UV-Vis(in?water?at?pH＝7.4λmax(ε/10
4M
-1cm
-1))：456(0.23)，263(1.34)；emission?spectra(in?water?at?pH＝7.4no?corrected?λmax)：583nm。
Embodiment 6 title complex f:[Ru (phen)
2(IDIP)]
2+Preparation
(1) synthetic (IDIP) of 2-(indoles-5-yl)-1H-imidazoles [4,5-f] [1,10]-phenanthroline: referring to the step in the preparation of title complex d (1).
(2) [Ru (phen)
2Cl
2] 2H
2O's is synthetic: referring to (2) in the preparation process of title complex c
(3[Ru (phen)
2(IDIP)] (ClO
4)
22H
2O's is synthetic
Referring to the preparation process (3) of title complex c, just 2-(thiophene-2-yl)-1H-imidazoles [4,5-f] [1,10]-phenanthrolines (TIP) are replaced with 2-(indoles-5-yl)-1H-imidazoles [4,5-f] [1,10]-phenanthrolines (IDIP).Found：C：53.67；H；3.12；N；11.97.(Calc.for?C
45H
29Cl
2N
9O
8Ru·2H
2O：C：53.38；H：3.22；N：12.22)；ESI-MS (MeCN)：896.4([M-ClO
4]
+)，796.4([M-2ClO
4-H]
+)，398.1([M-2ClO
4]
2+).UV-Vis(in?water?at?PH＝7.4λmax(ε/10
4M
-1cm
-1))：456(0.19)，263(1.04)；emission?spectra(in?water?at?pH＝7.4no?correctedλmax)：584nm。
The following data declaration antitumor drug that can be used as of the present invention by experiment
Embodiment 7
Cell strain: the multiple tumor cell line of this experimental selection, people's malignant melanoma cell (A375), human liver cancer cell (HepG2), human prostata cancer (PC-3), human breast cancer cell (MDA-MB-231), human lung adenocarcinoma cell (A549), cervical cancer cell (HeLa) available from ATCC company.Institute's test agent is numbered: a, b, c, d, e, f and cis-platinum.
(1) MTT testing method
Get the tumour cell that is in logarithmic phase, adjusting viable cell concentrations is 2 * 10
4/ ml is added on 96 well culture plates, every hole 100 μ l, in incubator, cultivate 24h treat adherent after, add different concns given the test agent 100 μ l more respectively, negative control is an equal-volume physiological saline, and positive control is a cis-platinum, application of sample group and control group are all established 3 multiple holes, put 37 ℃, 5%CO2 cultivates 48h, adds MTT (5mg/ml) 20 μ l/ holes then, the centrifugal supernatant liquor of abandoning behind the 5h, add dimethyl sulfoxide (DMSO) (DMSO) 150 μ l/ holes, about vibration 10min, under the 570nm wavelength, measure the OD value with microplate reader.Calculate cell survival rate, by its half-inhibition concentration of computed in software IC50.
The OD value of the actual OD value/negative control hole in cell survival rate (%)=dosing hole;
Cell inhibitory rate (%)=100%-cell survival rate;
Experimental result sees Table 1.
The anti tumor activity in vitro of table 1 ruthenium complexe
(2) flow cytometry
The flow cytometry cell cycle, the cell after the centrifugal collection and treatment cleans twice with PBS, adds 70% ethanol, and-20 ℃ of placements are fixedly spent the night, and are centrifugal, after PBS cleans twice, carries out cell PI dyeing.Dna content is measured and is utilized the Beckman stream type cell analyzer.Cell cycle distribution utilize software Multi Cycle (Phoenix Flow Systems, San Diego, CA).With DNA histogram graph representation cell at each distribution proportion mutually of G0/G1, S and G2/M.Apoptotic cell hypodiploid dna content is measured and is recorded by sub-G1 peak among the quantitative figure.10000 cells of each sample analysis.
Experimental result is seen Figure of description 1～4.
Title complex of the present invention has certain fat-soluble and water-soluble, is absorption of human body easily, in vitro tests tumour cell is had certain restraining effect, therapeutic equivalence with cis-platinum, and toxicity is lower than cis-platinum, shows excellent application value, is particularly suitable for being prepared into antitumor drug.
The foregoing description is a preferred implementation of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification done under spirit of the present invention and the principle, substitutes, combination, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (10)
1. a ruthenium (II) title complex, its structural formula is suc as formula shown in (I), and wherein, X is
Or
N-N is dipyridyl, bisglyoxaline or phenanthroline;
2. ruthenium according to claim 1 (II) title complex, the structure that it is characterized in that described title complex is shown in arbitrary structure among a～f:
3. the preparation method of claim 1 or 2 described ruthenium (II) title complexs is characterized in that comprising the steps:
(1) with phenanthroline-5,6-diketone, aldehydes, ammonium acetate and Glacial acetic acid mixed dissolution, heating reflux reaction;
(2) ruthenium trichloride, part and lithium chloride are dissolved in N, in the dinethylformamide, heating reflux reaction under argon shield;
(3) product of step (1) is mixed with the product of step (2) be dissolved in ethylene glycol, heating reflux reaction under argon shield obtains ruthenium complexe.
4. according to the preparation method of the described ruthenium of claim 3 (II) title complex, it is characterized in that in the step (1), described aldehydes is XCHO, wherein, X is
5. according to the preparation method of the described ruthenium of claim 3 (II) title complex, it is characterized in that in the step (2), described part is dipyridyl, bisglyoxaline or phenanthroline.
6. claim 1 or 2 described ruthenium (II) the title complexs application in the medicine of preparation prevention or treatment tumor disease.
7. a pharmaceutical composition is characterized in that comprising in the described pharmaceutical composition claim 1 or 2 described ruthenium (II) title complexs.
8. pharmaceutical composition according to claim 7 is characterized in that described pharmaceutical composition also comprises pharmaceutically acceptable carrier.
9. a pharmaceutical preparation is characterized in that comprising in the described pharmaceutical preparation claim 7 or 8 described pharmaceutical compositions.
10. pharmaceutical preparation according to claim 9, the formulation that it is characterized in that described preparation be tablet,, oral liquid, granule, electuary, pill, injection, sprays or sustained release preparation.
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102504210A (en) * | 2011-10-20 | 2012-06-20 | 苏州纳凯科技有限公司 | Narrow-bandgap organic conjugated polymer containing metal complex in main chain and preparation method thereof |
| CN102675348A (en) * | 2012-03-13 | 2012-09-19 | 中山大学 | Selenium polypyridine ligand, ruthenium-selenium polypyridine complex, and preparation methods and applications of selenium polypyridine ligand and ruthenium-selenium polypyridine complex |
| CN102924525A (en) * | 2012-06-18 | 2013-02-13 | 广东药学院 | Synthesis method for novel ruthenium (II) polypyridyl complex |
| CN105308050A (en) * | 2013-03-20 | 2016-02-03 | 艾普托斯生物科学公司 | 2-substituted imidazo[4,5-D]phenanthroline derivatives and their use in the treatment of cancer |
| CN106866743A (en) * | 2017-01-22 | 2017-06-20 | 暨南大学 | Tumor-targeting metal complex and synthetic method and application |
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101348504A (en) * | 2008-08-29 | 2009-01-21 | 广东药学院 | Ruthenium mixed-polypyridyl complex, preparation thereof and use as antitumor drug |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101348504A (en) * | 2008-08-29 | 2009-01-21 | 广东药学院 | Ruthenium mixed-polypyridyl complex, preparation thereof and use as antitumor drug |
Non-Patent Citations (1)
| Title |
|---|
| 20071231 Li-Feng Tan et al Synthesis, DNA Binding, and DNA Photocleavage of the Ruthenium(II)Complexes [Ru(bpy)(btip)]2+ and [Ru(dmb)(btip)]2+ (bpy=2,2'-Bipyridine;btip=2-Benzo[b]thien-2-yl-1H-imidazo[4,5-f] [1,10]phenanthroline;dmb=4,4'-Dimethyl-2,2'-bipyridine) 205-215 1-10 , 2 * |
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| CN102504210A (en) * | 2011-10-20 | 2012-06-20 | 苏州纳凯科技有限公司 | Narrow-bandgap organic conjugated polymer containing metal complex in main chain and preparation method thereof |
| CN102504210B (en) * | 2011-10-20 | 2013-11-20 | 苏州纳凯科技有限公司 | Narrow-bandgap organic conjugated polymer containing metal complex in main chain and preparation method thereof |
| CN102675348A (en) * | 2012-03-13 | 2012-09-19 | 中山大学 | Selenium polypyridine ligand, ruthenium-selenium polypyridine complex, and preparation methods and applications of selenium polypyridine ligand and ruthenium-selenium polypyridine complex |
| CN102924525A (en) * | 2012-06-18 | 2013-02-13 | 广东药学院 | Synthesis method for novel ruthenium (II) polypyridyl complex |
| CN102924525B (en) * | 2012-06-18 | 2015-01-07 | 广东药学院 | Synthesis method for novel ruthenium (II) polypyridyl complex |
| CN105308050A (en) * | 2013-03-20 | 2016-02-03 | 艾普托斯生物科学公司 | 2-substituted imidazo[4,5-D]phenanthroline derivatives and their use in the treatment of cancer |
| EP2976342A4 (en) * | 2013-03-20 | 2016-08-10 | Aptose Biosciences Inc | 2-substituted imidazo[4,5-d]phenanthroline derivatives and their use in the treatment of cancer |
| CN106866743A (en) * | 2017-01-22 | 2017-06-20 | 暨南大学 | Tumor-targeting metal complex and synthetic method and application |
| CN109053809A (en) * | 2018-07-05 | 2018-12-21 | 南京邮电大学 | A kind of photosensitizer and its preparation method and application of the energy optical dynamic therapy of film targeting type |
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