CN102924525B - Synthesis method for novel ruthenium (II) polypyridyl complex - Google Patents
Synthesis method for novel ruthenium (II) polypyridyl complex Download PDFInfo
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Abstract
The present invention discloses a synthesis method for a novel ruthenium (II) polypyridyl complex. The synthesis method comprises the following steps: 1) carrying out a condensation dehydration reaction of 1,10-phenanthroline-5,6-dione and 1,2,4,5-tetraamino hydrochloride in the presence of K2CO3 and ethanol to obtain a product, and carrying out purification; 2) mixing [Ru(phen)2Cl2]2H2O and the product obtained from the step 1) in a solvent, carrying out a reflux reaction for 8-12 hours under an anaerobic condition, cooling to a room temperature, carrying out reduced pressure solvent removing, adding a saturated NaClO4 solution to obtain a precipitate, filtering, carrying out washing and drying on the precipitate, dissolving the precipitate by using acetonitrile, adopting a column to carry out elution, collecting a red component, and carrying out rotary evaporation to remove the solvent; and 3) mixing the product obtained from the step 2) and acenaphthequinone in a solvent, carrying out a reflux reaction for 6-10 hours under an anaerobic condition, cooling to a room temperature, carrying out reduced pressure solvent removing, adding a saturated NaClO4 solution to obtain a precipitate, filtering, carrying out washing and drying on the precipitate, dissolving the precipitate by using acetonitrile, adopting a column to carry out elution, collecting a red component, and carrying out rotary evaporation to obtain the product. The compound synthesized by the synthesis method provides strong inhibition effects for growths of tumor cells BEL-7402 and SKBR-3.
Description
Technical field
The present invention relates to the synthetic method of a kind of New Ruthenium (II) multi-pyridine ligand.
Background technology
Rosenberg in 1969 etc. find that cis-platinum (cis-dichloro two ammino platinum (II)) has anti-tumor activity.The 1980s, to the nineties, develop again carboplatin, circulation platinum, oxaliplatin, but due to platinum medicine poorly water-soluble, the catabasis is short, and excretion is slow, and with serious toxic side effect, life-time service can produce resistance.Generally believe that ruthenium metal complexes is one of medicine most with anticancer prospect in the world.Ruthenium Metal Drugs, compared with cis-platinum, owing to having relatively low toxicity, is easy in vivo absorb, and is easy to be gathered in tumor tissues, and in vivo the residence time short, excretion is fast, can with DNA with covalency or Non-covalent binding.
The title complex KP1019 of ruthenium system antitumor action, the general formula of this kind of title complex is [HL] [trans-Ru (III) L
2cl
4], they have obvious result for the treatment of to colorectal carcinoma, can suppress the growth of the inoperative tumour of some cis-platinums; NAMI type title complex, the metastatic tumor of this kind of title complex to muroid has restraining effect clearly, has now entered the II phase clinical.
Summary of the invention
The object of this invention is to provide the synthetic method of a kind of New Ruthenium (II) multi-pyridine ligand.
The technical solution used in the present invention is:
A kind of synthetic method of New Ruthenium (II) multi-pyridine ligand, comprises the following steps:
1) by 1,10-Phendione and 1,2,4,5-tetramino hydrochloride at K
2cO
3, solvent, water exist under carry out condensation dehydration reaction, carry out purifying after obtaining product;
2) by [Ru (phen)
2cl
2] 2H
2the product that O and step 1) obtain mixes in a solvent, and back flow reaction 8-12 hour under oxygen free condition, is cooled to room temperature, and decompression desolventizes, and adds saturated NaClO
4solution, is precipitated, filters, and washing of precipitate is dry and dissolve with acetonitrile, fills post, loading, then carries out wash-out with eluent, collect red component, except desolventizing obtains product with neutral alumina;
3) product upper step obtained and acenaphthenequinone are mixed in solvent, and back flow reaction 6-10h under anaerobic, is cooled to room temperature, and decompression desolventizes, and add saturated NaClO
4solution, must precipitate, filter, and washing of precipitate is dry and be dissolved in acetonitrile, fills post, loading, then carries out wash-out with eluent, collect red component, except desolventizing obtains product with neutral alumina.
In step 1), the amount ratio of 1,10-Phendione, 1,2,4,5-tetramino hydrochloride, solvent, water is 1mmol:1mmol:(50-80) ml:5 ml.
In step 1), K
2cO
3quality be 135% of 1,10-Phendione.
Step 1) and step 2) in, described solvent is the one in ethanol, n-propyl alcohol, Virahol, propyl carbinol.
Step 2) in, [Ru (phen)
2cl
2] 2H
2the product that O, step 1) obtain, solvent load are than being 1mmol:1mmol:(60-100) ml.
Step 2) in, decompression desolventizes as the 60-80vol% except desolventizing.
Step 2) and step 3) in, described eluent is that acetonitrile and volume of toluene are than the mixed solution for 3:1.
In step 3), described solvent is the one in DMF, DMAC, NMP.
The invention has the beneficial effects as follows: compound on tumor cell BEL-7402 and the SKBR-3 growth synthesized by the present invention has very strong restraining effect.Its IC
50value is respectively 3.9 and 5.1 μMs, can be used as BEL-7402 and SKBR-3 anti-tumor medicine.
Accompanying drawing explanation
Fig. 1 is title complex of the present invention to the restraining effect figure of BEL-7402 cell and SKBR-3 cell proliferation.
Fig. 2 is that the fluorescent dye of blank group detects apoptosis figure (blank test does not add title complex of the present invention in culturing process).
Fig. 3 is for having added complex fluorescent staining examine apoptosis figure (adding RPMI 1640 substratum that title complex concentration is 12.5 μm of ol/L in culturing process).
Fig. 4 is for having added complex fluorescent staining examine apoptosis figure (adding RPMI 1640 substratum that title complex concentration is 25 μm of ol/L in culturing process).
Fig. 5 is the endocytosis design sketch (culturing process add RPMI 1640 substratum that title complex concentration be 12.5 μm ol/Ls) of tumour cell BEL-7402 to title complex.
Fig. 6 is the endocytosis design sketch (in culturing process add RPMI 1640 substratum that title complex concentration be 25 μm ol/Ls) of tumour cell BEL-7402 to title complex.
Fig. 7 is that title complex is to BEL-7402 cell-cycle arrest.
Fig. 8 is that title complex is to SKBR-3 cell-cycle arrest.
Embodiment
Below in conjunction with specific embodiment, the present invention is described further:
embodiment 1:
the method for making of part dadppz: be that 1, the 10-Phendione of 1:1 and 1,2,4,5-tetramino hydrochloride are at K by stoichiometric mole ratio
2cO
3under existing with ethanol and water, wherein, the amount ratio of 1,10-Phendione, ethanol and water is 1mmol:(50-80) ml:5 ml; The consumption of salt of wormwood is 1,10-phenanthroline-5,135% of 6-diketone quality, reflux 40 minutes (temperature of reaction is 80-100 DEG C), after being cooled to room temperature, filters, obtain red filtrate, removal of solvent under reduced pressure ethanol, thick product-5 DEG C of washing with alcohol, obtain red solid material (dadppz).Productive rate: 35%.
embodiment 2:
title complex [Ru (phen) 2 (dadppz)] (ClO 4 ) 2 synthesis: by [Ru (phen)
2cl
2] 2H
2o and part dadppz is 1:1 mixing in molar ratio, ([Ru (phen) under ethanol exists
2cl
2] 2H
2the amount ratio of O and ethanol is 0.5mmol:(30-50) ml), argon shield heating reflux reaction 8 hours (temperature of reaction 85-90 DEG C), is cooled to room temperature, and the ethanol of decompression removing 60-80vol%, adds saturated NaClO
4solution, obtains red precipitate (NaClO
4the consumption of solution is with till making precipitation no longer generate), filter, by the washing with alcohol of water and-5 DEG C, obtain red solid.The a small amount of acetonitrile of thick product dissolves (mass ratio of thick product and acetonitrile is 1g:3-5ml), fills post, loading with neutral alumina, acetonitrile and toluene (3:1, v/v) carry out wash-out as eluent to product, collect red component, rotary evaporation, obtains red material, productive rate: 72%.ES-MS?(CH
3CN):?m/z?873.0?([M-ClO
4]
+),?387.4?([M-2ClO
4]
2+).?
1H?NMR?(DMSO-d
6,?ppm):?δ?9.45?(d,?2H,?
J?=?7.0?Hz),?8.77?(dd,?4H,?
J?=?7.0,?
J?=?6.5?Hz),?8.39?(s,?4H),?8.23?(d,?2H,?
J?=?5.5?Hz),?8.08?(d,?2H,?
J?=?5.0?Hz),?8.03?(d,?2H,?
J?=?5.5?Hz),?7.75-7.79?(m,?6H),?7.20?(s,?2H),?6.61?(s,?4H).
embodiment 3:
title complex [Ru (phen) 2 (adadppz)] (ClO 4 ) 2 synthesis: [Ru (phen)
2(dadppz)] (ClO
4)
2(0.5 mmol) and acenaphthenequinone (0.5 mmol) mix, and add 20 mLDMF, and 6 hours (temperature of reaction is 140-160 DEG C) of refluxing under argon shield, is cooled to room temperature, and decompression removing DMF is 5 mL to solution, adds saturated NaClO
4solution (NaClO
4the consumption of solution is with till making precipitation no longer generate), obtain red precipitate, filter, precipitation distilled water wash, drying.Thick product is dissolved in a small amount of acetonitrile (mass ratio of thick product and acetonitrile is 1g:3-5ml), fills post with neutral alumina, loading, acetonitrile and toluene (3:1, v/v), as eluent, collect red component, rotary evaporation, obtains red material, productive rate: 70%.ES-MS?(CH
3CN,?m/z):?1049.5?[(M-ClO
4)]
+,?948.8?[(M-2ClO
4-H)]
+,?474.5?[(M-2ClO
4)]
2+.?Anal.?Calc?for?C
56H
36N
10Cl
2O
8Ru:?C,?58.54;?H,?3.16;?N,?12.19%.?Found:?C,?58.36;?H,?3.25;?N,?12.44%.?
1H?NMR?δ
H?(DMSO-d
6):?9.34?(s,?2H),?8.90?(d,?2H,?
J?=?8.5?Hz),?8.43?(d,?4H,?
J?=?8.5?Hz),?8.45?(s,?4H),?8.30?(d,?2H,?
J?=?8.5?Hz),?8.21?(d,?2H,?
J?=?5.0?Hz),?8.13?(d,?2H,?
J?=?5.0?Hz),?7.94-7.87?(m,?6H),?7.83?(t,?4H,?
J?=?5.0?Hz),?7.70?(d,?2H,?
J?=?6.0?Hz).?
13C?NMR?δ
C?(DMSO-d
6):?155.25,?154.42,?153.22,?152.84,?150.88,?147.33,?140.69,?140.21,?139.29,?137.29,?137.15,?133.26,?130.65,?130.19,?129.73,?128.95,?128.42,?127.77,?126.53,?126.36,?122.31。
Building-up process of the present invention is schematically as follows:
embodiment 4:
cell toxicity test:mtt assay is adopted to have studied the vitro cytotoxicity of compound.First by being trained the target cell of individual layer after trysinization, utilizing cell counter to count, adding and making cell count reach 10
5individual every milliliter, get nutrient solution 0.1 mL containing target cell (BEL-7402 cell and SKBR-3 cell) in 96 porocyte culture plates, then by the cell plate inoculated at 37 DEG C, 5% CO
224 h are cultivated in incubator.To cover with the RPMI-1640 substratum added after liquid abandoned by monolayer cell culture plate containing title complex, wherein, the concentration of title complex is from 10
-6to 10
-4mol/L, puts into 37 DEG C, 5% CO
2incubator in cultivate 48 h after, suck nutrient solution, with PBS(pH=7.2) washing once.Every hole adds the MTT dye solution of 20 μ L 5 mg/mL, at 37 DEG C, and 5%CO
2incubator in cultivate 4 h after, add 0.1 mlDMSO, the first a ceremonial jade-ladle, used in libation formed in dissolved cell.Each hole OD value is detected at 490 nm places by microplate reader.Calculate viable count, the concentration (IC of compound when can calculate 50% cell survival by logarithmic curve method
50).
Fig. 1 is title complex of the present invention to the restraining effect figure of BEL-7402 cell and SKBR-3 cell proliferation, and title complex is to the IC of BEL-7402 and SKBR-3 cell
50be respectively 3.9 ± 0.4 and 5.1 ± 0.6, visible title complex has very strong restraining effect to cell BEL-7402 and SKBR-3.
embodiment 5:
cell apoptosis assay:in six orifice plates, (BEL-7402 cell density is 2 × 10
5) add RPMI 1640 substratum containing title complex, wherein, the concentration of title complex is respectively 12.5 μm of ol/ L and 25 μm ol/L, by BEL-7402 cell in 37 DEG C, 5% CO
2lower cultivation 24 hours, removing nutrient solution, the PBS(pH=7.2 with 0 DEG C) washing, then fix with the formalin of 4%, dye with the Hoechst33258 of 10mg/mL, fluorescence microscopy Microscopic observation.
Simultaneously arrange control group in this experiment, nutrient solution is that other culture condition are identical not containing the RPMI-1640 of title complex, and carry out same abandoning liquid, washing, fix, dying operation, finally in fluorescence microscopy Microscopic observation.
If Fig. 2 is that fluorescent dye detects apoptosis figure (blank test, title complex of the present invention is not added in culturing process, namely last synthetic product), Fig. 3 (adds RPMI 1640 substratum containing title complex for having added complex fluorescent staining examine apoptosis figure in culturing process, the concentration of title complex is 12.5 μm of ol/L), Fig. 4 detects apoptosis figure (add RPMI 1640 substratum containing title complex in culturing process, the concentration of title complex is 25 μm of ol/L) for having added fluorescent dye.
embodiment 6:
The present embodiment test tumour cell BEL-7402 is to the endocytosis effect of title complex
Be placed in by BEL-7402 cell on the Tissue Culture Plate in 24 holes, every hole is containing cell 4 × 10
4, at 37 DEG C, 5% CO
2lower overnight incubation, joins (title complex concentration is respectively 12.5 μm of ol/L and 25 μm ol/L) in hole by RPMI 1640 substratum containing title complex, continues at 37 DEG C of 5% CO
2lower cultivation is after 48 hours, the PBS(pH=7.2 with 0 DEG C) wash three times, removing substratum, is placed in fluorescence microscopy Microscopic observation by cell.Test-results is as Fig. 5 and Fig. 6.
embodiment 7:
This experiment adopts the cells were tested by flow cytometry cell cycle.
Experimental group: carry out BEL-7402 cell cultures by containing RPMI 1640 substratum of 10% FBS, cell with every hole density for 2 × 10
5be inoculated in 6 orifice plates, and in 37 DEG C, 5% CO
2cultivate 24 hours in the incubator of saturated humidity.Abandon original substratum, changing containing title complex concentration is that the RPMI 1640 substratum continuation cultivation of 12.5 μm of ol/L is after 24 hours, cells trypsinised, and with the PBS(pH=7.2 of 0 DEG C) wash 2 times, adding concentration is that 70vol% ethanol is fixed, add the RNAse (0.2 mg/mL) of 20 mL and the propidium iodide (PI, 0.02 mg/mL) of 20 mL again, at 37 DEG C, 5% CO
2hatch 30 min, adopt FACS Flow cytometry to analyze, the cell count that each sample need be analyzed is 10000.
This test also arranges control group, and control group is identical with the culture condition of experimental group, but does not use the nutrient solution containing title complex (namely final synthetic product) instead in cultivating; Title complex to BEL-7402 cell-cycle arrest as shown in Figure 7.
Experimental group: carry out SKBR-3 cell cultures by containing RPMI 1640 substratum of 10% FBS, cell with every hole density for 2 × 10
5be inoculated in 6 orifice plates, and in 37 DEG C, 5% CO
2cultivate 24 hours in the incubator of saturated humidity.Abandon original substratum, RPMI 1640 substratum changed containing title complex 25 μm of ol/L continued cultivation after 24 hours, cells trypsinised, and with the PBS(pH=7.2 of 0 DEG C) wash 2 times, adding concentration is that 70vol% ethanol is fixed, add the RNAse (0.2 mg/mL) of 20 mL and the propidium iodide (PI, 0.02 mg/mL) of 20 mL again, at 37 DEG C, 5% CO
2hatch 30 min, adopt FACS Flow cytometry to analyze, the cell count that each sample need be analyzed is 10000.
This test also arranges control group, and control group is identical with the culture condition of experimental group, but does not use the nutrient solution containing title complex (namely final synthetic product) instead in cultivating; Title complex to SKBR-3 cell-cycle arrest as shown in Figure 8.
The ordinate zou of Fig. 7 and Fig. 8 is the percentage of cell at cell cycle different times, if 56.81 indications in Fig. 7 are 56.81%.
Claims (6)
1. a synthetic method for New Ruthenium (II) multi-pyridine ligand, is characterized in that: comprise the following steps:
1) by 1,10-Phendione and 1,2,4,5-tetramino benzene hydrochloride at K
2cO
3, solvent, water exist under carry out condensation dehydration reaction, carry out purifying after obtaining product;
2) by [Ru (phen)
2cl
2] 2H
2the product that O and step 1) obtain mixes in a solvent, and back flow reaction 8-12 hour under oxygen free condition, is cooled to room temperature, and decompression desolventizes, and adds saturated NaClO
4solution, is precipitated, filters, and washing of precipitate is dry and dissolve with acetonitrile, fills post, loading, then carries out wash-out with eluent, collect red component, except desolventizing obtains product with neutral alumina;
3) product upper step obtained and acenaphthenequinone are mixed in solvent, and back flow reaction 6-10h under anaerobic, is cooled to room temperature, and decompression desolventizes, and add saturated NaClO
4solution, must precipitate, filter, and washing of precipitate is dry and be dissolved in acetonitrile, fills post, loading, then carries out wash-out with eluent, collect red component, except desolventizing obtains product with neutral alumina;
In step 1), the amount ratio of 1,10-Phendione, 1,2,4,5-tetramino benzene hydrochloride, solvent, water is 1mmol:1mmol:(50-80) ml:5 ml; Step 1) and step 2) in, described solvent is the one in ethanol, n-propyl alcohol, Virahol, propyl carbinol.
2. the synthetic method of a kind of New Ruthenium (II) multi-pyridine ligand according to claim 1, is characterized in that: in step 1), K
2cO
3quality be 135% of 1,10-Phendione.
3. the synthetic method of a kind of New Ruthenium (II) multi-pyridine ligand according to claim 1, is characterized in that: step 2) in, [Ru (phen)
2cl
2] 2H
2the product that O, step 1) obtain, solvent load are than being 1mmol:1mmol:(60-100) ml.
4. the synthetic method of a kind of New Ruthenium (II) multi-pyridine ligand according to claim 1, is characterized in that: step 2) in, decompression desolventizes as the 60-80vol% except desolventizing.
5. the synthetic method of a kind of New Ruthenium (II) multi-pyridine ligand according to claim 1, is characterized in that: step 2) and step 3) in, described eluent is that acetonitrile and volume of toluene are than the mixed solution for 3:1.
6. the synthetic method of a kind of New Ruthenium (II) multi-pyridine ligand according to claim 1, it is characterized in that: in step 3), described solvent is the one in DMF, DMAC, NMP.
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| CN104530134B (en) * | 2014-11-06 | 2017-05-03 | 广东药学院 | Symmetric ruthenium metal compound and application thereof in preparing anti-tumor drug |
| CN105858734B (en) * | 2016-03-20 | 2017-07-14 | 北京工业大学 | Ru complexs Ru (bpy)3(NH2)2The method being combined with graphene quantum |
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