CN100577672C - Ruthenium-anthraquinone conjugates, preparation method thereof and application for the same used as optical power therapeutic photosensitizer - Google Patents
Ruthenium-anthraquinone conjugates, preparation method thereof and application for the same used as optical power therapeutic photosensitizer Download PDFInfo
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- CN100577672C CN100577672C CN200710028955A CN200710028955A CN100577672C CN 100577672 C CN100577672 C CN 100577672C CN 200710028955 A CN200710028955 A CN 200710028955A CN 200710028955 A CN200710028955 A CN 200710028955A CN 100577672 C CN100577672 C CN 100577672C
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- MVLWQUNITOZXFF-UHFFFAOYSA-N [Ru].C1=CC=C2C(=O)C3=CC=CC=C3C(=O)C2=C1 Chemical compound [Ru].C1=CC=C2C(=O)C3=CC=CC=C3C(=O)C2=C1 MVLWQUNITOZXFF-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 239000003504 photosensitizing agent Substances 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 230000003287 optical effect Effects 0.000 title description 7
- 230000001225 therapeutic effect Effects 0.000 title 1
- DGEZNRSVGBDHLK-UHFFFAOYSA-N [1,10]phenanthroline Chemical compound C1=CN=C2C3=NC=CC=C3C=CC2=C1 DGEZNRSVGBDHLK-UHFFFAOYSA-N 0.000 claims abstract description 19
- 238000002428 photodynamic therapy Methods 0.000 claims abstract description 10
- YNPNZTXNASCQKK-UHFFFAOYSA-N Phenanthrene Natural products C1=CC=C2C3=CC=CC=C3C=CC2=C1 YNPNZTXNASCQKK-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 150000002576 ketones Chemical class 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 7
- YDQWDHRMZQUTBA-UHFFFAOYSA-N Aloe emodin Chemical compound C1=CC=C2C(=O)C3=CC(CO)=CC(O)=C3C(=O)C2=C1O YDQWDHRMZQUTBA-UHFFFAOYSA-N 0.000 abstract description 4
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 abstract description 4
- 229910052707 ruthenium Inorganic materials 0.000 abstract description 4
- 238000002474 experimental method Methods 0.000 abstract description 3
- 238000000034 method Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
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- NJCKPHTYGRPUNK-UHFFFAOYSA-N 4,5-dihydroxy-9,10-dioxoanthracene-2-carbaldehyde Chemical compound O=C1C2=CC(C=O)=CC(O)=C2C(=O)C2=C1C=CC=C2O NJCKPHTYGRPUNK-UHFFFAOYSA-N 0.000 abstract 1
- 229910017673 NH4PF6 Inorganic materials 0.000 abstract 1
- 230000005907 cancer growth Effects 0.000 abstract 1
- 125000004424 polypyridyl Polymers 0.000 abstract 1
- 230000001629 suppression Effects 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 10
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 8
- ROFVEXUMMXZLPA-UHFFFAOYSA-N Bipyridyl Chemical compound N1=CC=CC=C1C1=CC=CC=N1 ROFVEXUMMXZLPA-UHFFFAOYSA-N 0.000 description 7
- 239000000243 solution Substances 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000013078 crystal Substances 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
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- 238000001035 drying Methods 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Substances OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 238000005286 illumination Methods 0.000 description 4
- 239000012535 impurity Substances 0.000 description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 description 4
- 235000015097 nutrients Nutrition 0.000 description 4
- 239000000376 reactant Substances 0.000 description 4
- 210000004881 tumor cell Anatomy 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
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- 229940076442 9,10-anthraquinone Drugs 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 239000012983 Dulbecco’s minimal essential medium Substances 0.000 description 2
- 239000012980 RPMI-1640 medium Substances 0.000 description 2
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 2
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 150000002460 imidazoles Chemical class 0.000 description 2
- 230000005764 inhibitory process Effects 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000000047 product Substances 0.000 description 2
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- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- UJKPHYRXOLRVJJ-MLSVHJFASA-N CC(O)C1=C(C)/C2=C/C3=N/C(=C\C4=C(CCC(O)=O)C(C)=C(N4)/C=C4\N=C(\C=C\1/N\2)C(C)=C4C(C)O)/C(CCC(O)=O)=C3C Chemical class CC(O)C1=C(C)/C2=C/C3=N/C(=C\C4=C(CCC(O)=O)C(C)=C(N4)/C=C4\N=C(\C=C\1/N\2)C(C)=C4C(C)O)/C(CCC(O)=O)=C3C UJKPHYRXOLRVJJ-MLSVHJFASA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
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- YAYGSLOSTXKUBW-UHFFFAOYSA-N ruthenium(2+) Chemical compound [Ru+2] YAYGSLOSTXKUBW-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a ruthenium-anthraquinone conjugate, the preparation process thereof and the application as a photo-dynamic therapy photosensitizer. The general formula of the ruthenium-anthraquinone conjugate of the invention is [Ru(L)2HAIP].(PF6)2, the general formula of the HAIP is 1,8- dihydroxy -9,10- anthraquinoneimidazole [4,5-f][1,10] phenanthroline, the general of the L is bpy or phen. The preparation process for the ruthenium-anthraquinone conjugate comprises the following procedures: 1. the synthesis of the HAIP: 1,8- dihydroxy -9,10- anthraquinone-3-aldehyde is reacted with the phenanthroline5,6-diketone to produce the HAIP; 2. Ru(L)2Cl2 is reacted with HAIP and NH4PF6 to produce the [Ru(L)2HAIP].(PF6)2. The invention takes the aloe-emodin as the raw material and the ruthenium polypyridyl complex has single chemical composition; the synthesis route is simple and the yields are higher; during the experiment, the compound shows the light suppression to the growth of cancer cells.
Description
Technical field
The present invention relates to the optical dynamic therapy technical field, specifically, relate to a kind of ruthenium-anthraquinone conjugates and preparation method thereof and application as photosensitizer for photodynamic therapy.
Background technology
Optical dynamic therapy is a kind of minimal invasive methods of treatment that results from nineteen seventies, its ultimate principle is to after the venous patient injection photosensitizers certain hour, rayed lesions position with certain wavelength, in the presence of biological tissue's oxygen, photosensitizers excites the generation active oxygen, and the focus zone is produced damage.Because it is strong that optical dynamic therapy has selectivity, stable curative effect, wound is little and can Synergistic treatment, but remarkable advantages such as palliative treatment, be widely used in tumor disease and non-tumor disease such as the yellowish-brown macle of skin clinically, the treatment of ophthalmic diseases and virus disease etc.
Photosensitizers of Shi Yonging such as hematoporphyrin derivative etc. all are mixture basically clinically, and photosensitive activity is relatively poor relatively, and the light toxic side effect is relatively large, patient is after carrying out optical dynamic therapy, often want the lucifuge long period, and the treatment degree of depth is more shallow, limited to the intracavity tumor cure effect.
Ruthenium (II) title complex has abundant spectroscopy feature, and very strong MLCT transition (metal is to the charge transfer between part) is particularly arranged at the 400-600nm place; And ruthenium complexe is easy to absorb in vivo, also be easy to metabolism, it is the compound of a class low toxicity, the what is more important ruthenium complexe has long lifetime of excited state, can be with insert, ditch combination and electrostatic interaction mode combine with dna molecular, and the conformation of dna molecular is produced perturbation, and to its biological function exert an influence (it is generally acknowledged that dna molecular is the biology target spot of optical dynamic therapy).In photosensitizer for photodynamic therapy research, has the potential application prospect.
Summary of the invention
The objective of the invention is to overcome the deficiency that existing photosensitizer for photodynamic therapy exists, a kind of ruthenium-anthraquinone conjugates that can be used for preparing photosensitizer for photodynamic therapy is provided.
Another object of the present invention provides the preparation method of above-mentioned ruthenium-anthraquinone conjugates.
Further purpose of the present invention provides the application of above-mentioned ruthenium-anthraquinone conjugates in the preparation photosensitizer for photodynamic therapy.
Ruthenium-anthraquinone conjugates of the present invention, its composition formula are [Ru (L)
2HAIP] (PF
6)
2, HAIP is 1,8-dihydroxyl-9, and 10-anthraquinone imidazoles [4,5-f] [1,10] phenanthroline, L is bpy or phen.
The preparation method of above-mentioned ruthenium-anthraquinone conjugates comprises the steps:
(1) synthetic HAIP:1,8-dihydroxyl-9,10-anthraquinone-3-aldehyde and phenanthroline 5,6-two reactive ketones obtain HAIP;
(2) Ru (L)
2Cl
2With HAIP, NH
4PF
6Reaction obtains [Ru (L)
2HAIP] (PF
6)
2
Ruthenium-anthraquinone conjugates of the present invention to the inhibiting rate height of tumour, can be used for preparing photosensitizer for photodynamic therapy under illumination.
Compared with prior art, the present invention has following beneficial effect: the present invention uses rhabarberone as raw material, and the synthetic ruthenium complexe that obtains has single chemical constitution; Synthetic route is simple, and productive rate is higher; In the experiment in vitro, the light that compound all shows growth of tumour cell suppresses.
Embodiment
Embodiment 11,8-dihydroxyl-9,10-anthraquinone) preparation of imidazoles [4,5-f] [1,10] phenanthroline (HAIP):
Phenanthroline and KBr mixture are joined in the 125ml three-necked bottle, stir, the ice bath cooling dropwise adds dense H down
2SO
4With dense HNO
3Nitration mixture (v/v, 40: the 20) 60mL that forms.Drip the back and continue to reflux 3 hours, add the frozen water cooling, the pH value is transferred to 6-7 with NaOH.Compound CHCl
3Extract 3 times, water is removed organic phase, Na
2SO
4Drying with the solvent elimination, obtains orange-yellow thick product.Thick product ethyl alcohol recrystallization obtains phenanthroline 5, the 6-diketone.
Get phenanthroline 5, and the 6-diketone (525mg, 2.5mmol), ammonium acetate (3.88g, 50mmol) and 1,8-dihydroxyl-9, (938mg's 10-anthraquinone-3-aldehyde 3.5mmol), refluxed 2 hours in the 10ml Glacial acetic acid.Add 25ml distilled water in the dark red solution that after cooling, obtains, transfer to neutrality with ammoniacal liquor.Compound is filtered solid water and acetone rinsing, drying.60-80 order silicagel column is crossed column purification, is eluent with the dehydrated alcohol, productive rate 63%.1,8-dihydroxyl-9,10-anthraquinone) structural formula of imidazoles [4,5-f] [1,10] phenanthroline sees (I).ESI-MS：459.4(M+H)。
Embodiment 2[Ru (bpy)
2HAIP] (PF
6)
2Preparation
Cis-Ru (bpy)
2Cl
22H
2The preparation of O:
RuCl
3NH
2(1.56g, 6mmol), (1.87g, 12mmol), (1.68g 28mmol), adds DMF (10ml) to LiCl to dipyridyl to O, refluxes 8 hours under argon shield.Reactant is cooled to room temperature, adds acetone (50ml).Compound was placed 24 hours at 0 ℃, obtained the red-purple crystal.With cold water and acetone drip washing crystal, vacuum-drying, productive rate 81%.
[Ru (bpy)
2HAIP] (PF
6)
2Synthetic:
[Ru (bpy)
2Cl
2] 2H
2O (0.106g, 0.20mmol) and HAIP (0.095g 0.20mmol), adds 10cm
3Ethylene glycol.Under argon shield, refluxed 2 hours.After the cooling, add entry (20cm
3), solids removed by filtration impurity.Add NH
4PF
6Remove dissolved impurity in the solution.With the crystal drying of separating out, with the small amount of methanol dissolving, (10:1 v/v) is eluent alumina column chromatography purifying, productive rate: 67% with methyl alcohol-acetonitrile.[Ru (bpy)
2HAIP] (PF6)
2Structural formula see (II).ESI-MS：436.1[M-2PF
6]
2+。
Embodiment 3[Ru (phen)
2HAIP] (PF
6)
2Preparation
Cis-Ru (phen)
2Cl
22H
2O's is synthetic:
RuCl
3NH
2(1.56g, 6mmol), (2.16g, 12mmol), (1.68g 28mmol), adds DMF (10mi) to LiCl to phenanthroline to O, refluxes 8 hours under argon shield.The question response thing is cooled to room temperature, adds acetone (50ml) to reactant.Reactant was placed 24 hours at 0 ℃, obtained purple crystals.With cold water and acetone drip washing crystal, vacuum-drying, productive rate 72%.
[Ru (phen)
2HAIP] (PF
6)
2Synthetic:
[Ru (phen)
2Cl
2] 2H
2O (0.114g, 0.20mmol) and HAIP (0.095g 0.20mmol) adds 10cm
3Ethylene glycol, argon shield refluxed 2 hours down.Add entry (20cm to the refrigerative reactant
3) solids removed by filtration impurity.Add NH
4PF
6Remove dissolved impurity in the solution.With the crystal drying of separating out, with small amount of methanol dissolving, with methyl alcohol-acetonitrile (10: 1, v/v) be eluent alumina column chromatography purifying, productive rate: 64%.[Ru (phen)
2HAIP] (PF
6)
2Structural formula see (III).ESI-MS：460.3[M-2PF
6]
2+.
Embodiment 4 ruthenium-anthraquinone conjugates are to the inhibition of lung carcinoma cell Bel-7402
Select the adherent Bel-7402 liver cancer cell in logarithmic growth cycle for use, after trysinization, be made into 2 * 10 with the RPMI1640 nutrient solution of 10% calf serum
4The cell suspension of individual/ml is seeded in 96 well culture plates, and 100 μ l are inoculated in every hole, and the cell plate that inoculation is good are put into 37 ℃, 5%CO
2Cultivate 4h in the incubator.After removing nutrient solution, experimental group adds sample 10 μ l (5mg/mL), and every hole final volume is 200 μ l, supplies with RPMI-1640 nutrient solution (Flow Laboratories, the U.S.).37 ℃, 5%CO
2Cultivate 21h.After removing nutrient solution, use Dulbecco ' s phosphate buffer solution (D-PBS) washing 3 times, in every hole, add 50 μ MD-PBS, 200 μ l, illumination 30min (650nm then, 5mW), remove D-PBS, add the DMEM (Dulbecco ' s minimal essential medium) of fresh configuration, continue to cultivate 24h, then the nutritive medium in the culture plate is discarded, every hole adds the serum-free medium of the freshly prepared 0.5mg/ml MTT of 100 μ l, puts into 37 ℃, 5%CO
2Continue to cultivate 4h in the incubator.Carefully abandon supernatant, and add 200 μ l DMSO dissolving MTT formazon precipitation,, on microplate reader, measure the optical density value at wavelength 544nm place with miniature ultrasonic vibrator mixing.
Growth of tumour cell inhibiting rate (%)=(OD
Contrast-OD
Experiment)/(OD
Contrast-OD
Blank) * 100%
The different ruthenium-anthraquinone conjugates of table 1. are to the inhibition activity of growth of tumour cell
The result shows, under illumination condition, nail-anthraquinone conjugates all is higher than under the non-illumination condition mutually the inhibiting rate of growth of tumour cell should compound, so ruthenium-anthraquinone conjugates can be used as photosensitizer for photodynamic therapy.
Claims (3)
1. ruthenium-anthraquinone conjugates, its composition formula is [Ru (L)
2HAIP] (PF
6)
2, the HAIP structural formula is suc as formula (I), and L is bpy or phen,
2. the preparation method of the described ruthenium-anthraquinone conjugates of claim 1 is characterized in that comprising the steps:
(1) synthetic HAIP:1,8-dihydroxyl-9,10-anthraquinone-3-aldehyde and phenanthroline 5,6-two reactive ketones obtain HAIP, and the HAIP structural formula is suc as formula (I);
(2) Ru (L)
2C1
2With HAIP, NH
4PF
6Reaction obtains [Ru (L)
2HAIP] (PF
6)
2, L is bpy or phen.
3. the application of the described ruthenium-anthraquinone conjugates of claim 1 in the preparation photosensitizer for photodynamic therapy.
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| CN101463048B (en) * | 2009-01-04 | 2011-06-22 | 中山大学 | Ruthenium complex inducing DNA conformation transition and preparation thereof |
| CN101851256B (en) * | 2010-04-30 | 2013-01-09 | 广东药学院 | Ruthenium (II) porphyrin complex connected by flexible carbon chain and preparation method and application thereof |
| CN101863925B (en) * | 2010-05-21 | 2012-08-29 | 广东药学院 | Aryl ruthenium (11) composition and preparation method and application thereof |
| CN102924525B (en) * | 2012-06-18 | 2015-01-07 | 广东药学院 | Synthesis method for novel ruthenium (II) polypyridyl complex |
| CN103012401B (en) * | 2012-11-22 | 2015-10-07 | 中山大学 | The preparation method and application of the many pyridine ligands of anthraquinone and ruthenium-anthraquinone title complex |
| CN103554140B (en) * | 2013-10-28 | 2015-10-07 | 中山大学 | The preparation method and application of the many pyridine ligands of anthraquinone and binuclear ruthenium thereof |
| CN103965264A (en) * | 2014-04-09 | 2014-08-06 | 广州赛哲生物科技有限公司 | Aloe emodin modified chiral polypyridyl ruthenium (II) complex and preparation method thereof |
| CN110872330B (en) * | 2019-11-19 | 2021-09-21 | 华南理工大学 | Bipyridine ruthenium phenanthroline benzimidazole complex and preparation method and application thereof |
| CN113402687A (en) * | 2021-06-09 | 2021-09-17 | 长春理工大学 | Multidentate ligand porphyrin polymer and preparation method thereof |
| CN115925617B (en) * | 2022-08-25 | 2024-10-22 | 中山大学·深圳 | Deuterated ruthenium complex, preparation method thereof and application thereof in photocatalysis anti-tumor |
| CN118027124B (en) * | 2024-02-01 | 2024-08-30 | 广东药科大学 | Uridine-modified ruthenium (II) complex, preparation method thereof and application thereof as photodynamic therapy photosensitizer |
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| 钌（II）配合物与DNA相互作用的光谱研究. 刘云军，赵豪杰，韦欣煜等.广东药学院学报，第23卷第1期. 2007 * |
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