CN111875643A - Novel ruthenium-arene complex, preparation method and anti-tumor application thereof - Google Patents
Novel ruthenium-arene complex, preparation method and anti-tumor application thereof Download PDFInfo
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- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
- C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System compounds of the platinum group
- C07F15/0046—Ruthenium compounds
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
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Abstract
The invention relates to the field of metal complexes, and discloses a novel ruthenium-arene complex, and a preparation method and an anti-tumor application thereof. The structure of the novel ruthenium arene complex is shown in a formula I, wherein R represents a monodentate ligand which is pyrazine, pyrimidine and pyridazine respectively. The novel ruthenium-arene complex can generate singlet oxygen (A)1O2) Ligand dissociation can be generated, namely, the photodynamic therapy and photoactivation chemotherapy dual activities are provided at the same time, and the photocatalyst can be applied to anti-tumor novel phototherapy drugs; in addition, when the novel ruthenium-arene complex reacts with DNAThe luminescence is obviously enhanced, and the optical switch can be used as a DNA optical switch.
Description
Technical Field
The invention relates to the field of metal complexes, and particularly relates to a novel ruthenium-arene complex, and a preparation method and an anti-tumor application thereof.
Background
Photodynamic therapy (PDT) and photoactivated chemotherapy (PACT) are used as tumor treatment methods, the action mechanism is controlled in time and space by virtue of illumination, and the target tissue is selectively illuminated, so that the prodrug molecules only show the drug activity in the target tissue, and the selectivity of the drug on the tumor tissue is improved.
PDT relies on singlet oxygen generated after illumination of the photosensitizer1O2) Kill cancer cells due to1O2The efficiency of production is dependent on the tumor tissue oxygen concentration and therefore has limited application in hypoxic tumors. The work mechanism of PACT is similar to that of cisplatin, but the difference is that the medicine is stable under the dark condition, and ligand dissociation can be carried out only under the illumination condition, so that the medicine and DNA basic groups or other bioactive molecules carry out coordination reaction, and further tumor cells are killed. PACT, although not limited by oxygen, produces toxic species stoichiometrically and has no efficiency advantage. Therefore, the research and development of the anti-tumor drug with the dual activities of PDT and PACT are of great significance. The drug does not depend on the oxygen concentration of cancer cells too much for PDT drugs with a single mechanism, has better cell killing efficiency for PACT drugs with a single mechanism, can inhibit the cancer cells from generating drug resistance due to multi-mode injury, and is expected to be developed into novel high-efficiency broad-spectrum phototherapy drugs.
The integration of tumor diagnosis and treatment is a new technology integrating tumor diagnosis and treatment. The implementation method is that the components with the functions of tumor diagnosis and tumor treatment are simultaneously integrated into a drug system, so that the treatment process of the drug can be monitored in real time and the treatment effect can be fed back in time while the tumor is treated, and the optimal treatment effect and the toxic and side effects of the drug can be favorably exerted.
Disclosure of Invention
It is a first object of the present invention to provide a novel ruthenium arene complex having photoligand dissociation capability and production1O2Ability to have both PDT and PACT activity; compared with other medicines with dual activities of PDT and PACT, the medicines have selective luminous response to DNA, and are expected to provide a new idea for the research and development of multi-mode diagnosis and treatment integrated medicines.
The second object of the present invention is to provide a novel method for preparing ruthenium arene complexes;
the third purpose of the invention is to provide the application of the novel ruthenium arene complex in the anti-tumor phototherapy medicine.
In order to solve the technical problems, the invention adopts the following technical scheme:
technical scheme one
A novel ruthenium arene system complex is characterized in that the molecular formula is [ (. eta.) ]6-p-cymene)Ru(dppn)(R)]2+[2PF6]2-(ii) a Wherein eta6-p-cymene is p-cymene, the structural formula is as follows:
the dppn is a bidentate ligand synthesized by 1, 10-phenanthroline-5, 6-diketone and 2, 3-diamine naphthalene, and the structural formula is as follows:
r is pyrazine, pyrimidine and pyridazine monodentate ligand respectively, and the structural formula is as follows:
the structural formula of the novel ruthenium arene system complex is shown as the formula I:
the second technical scheme is as follows:
a preparation method of a novel ruthenium arene system complex comprises the following steps:
(1) dissolving 1, 10-phenanthroline-5, 6-diketone and 2, 3-diamine naphthalene in absolute ethyl alcohol, performing reflux reaction for 3 hours, cooling, precipitating a large amount of yellow solid, and filtering to obtain a bidentate ligand dppn;
(2) weighing [ (eta ] according to the stoichiometric ratio (1:2)6-p-cymene)RuCl2]2And dppn are placed in a three-necked bottle, methanol solution is added, the mixture is fully and uniformly mixed, and reflux reaction is carried out for 4 hours;
(3) naturally cooling to room temperature, and then adding 2 times of equivalent of AgNO3Refluxing the aqueous solution for 3h, cooling and filtering to obtain filtrate;
(4) adding 4 times of equivalent of monodentate ligand such as pyrazine, pyrimidine and pyridazine into the filtrate, and carrying out reflux reaction for 4 h; cooling to room temperature, and spin-drying the reaction solution to obtain a reddish brown solid crude product;
(5) purifying the crude product by adopting a dry method through a column;
(6) ultrasonically dissolving the purified solid by using purified water, adding a saturated ammonium hexafluorophosphate aqueous solution to obtain a precipitate, performing suction filtration, washing the precipitate by using a small amount of purified water, then washing the precipitate by using ethyl ether, and finally performing vacuum drying to obtain a complex; the steps (2) to (6) are carried out under the condition of keeping out of the sun;
and (4) performing steps (2) to (4) under the protection of inert gas.
As a further improvement of the invention, the step (5) comprises the following specific processes: separating and purifying with silica gel column to obtain eluate CH3CN、H2O, saturated KNO3Mixture of aqueous solutions in a volume ratio of CH3CN：H2O：KNO3＝80：8：1。
As a further improvement of the invention, the inert gas is nitrogen.
The synthetic route of the invention is as follows:
the third technical scheme is as follows:
an application of a novel ruthenium aryl complex in the anti-tumor phototherapy medicine.
The invention has the following technical effects:
the complex of the invention can generate under illumination conditions1O2And ligand dissociation occurs, and the DNA optical switch function is realized. DNA electrophoresis experiments show that the complex 1-3 has photodamage capability to DNA, wherein1O2The DNA is broken by oxidation, and the dissociated ligand coordinates and crosslinks the DNA, and the DNA is not damaged under dark conditions. In vitro cytotoxicity experiments show that the complex has low dark toxicity and high phototoxicity, and can effectively kill tumor cells under illumination. When the medicine acts with DNA, the luminescence is obviously enhanced, and the selective photoresponse behavior to the DNA is expected to provide a new idea for the research and development of multi-mode diagnosis and treatment integrated medicines.
Drawings
The following describes embodiments of the present invention in further detail with reference to the accompanying drawings.
FIG. 1 is a graph showing the changes of UV-visible absorption spectra of complexes 1(a), 2(b) and 3(c) (20. mu.M) in PBS buffer solution with different times of illumination.
Fig. 2 shows that complex 1-3 quenches the absorption of DPBF at 410nm under emitted light (λ ═ 500nm) illumination (solvent acetonitrile, [ DPBF ] ═ 40 μ M).
FIG. 3 is a diagram showing the results of gel electrophoresis of pUC19DNA photodamaged by complex 1-3 (30. mu.M).
FIG. 4 shows the fluorescence spectrum changes of the complexes 1(a), 2(b) and 3(c) (20. mu.M) under the action of CT-DNA.
Detailed Description
In order to more clearly illustrate the present invention, the present invention will be further described with reference to the following examples and the accompanying drawings. Similar parts in the figures are denoted by the same reference numerals. It is to be understood by persons skilled in the art that the following detailed description is illustrative and not restrictive, and is not to be taken as limiting the scope of the invention.
Example 1: the synthesis method of the complex 1 comprises the following steps:
dissolving 1, 10-phenanthroline-5, 6-diketone and 2, 3-diamine naphthalene in absolute ethyl alcohol, performing reflux reaction for 3 hours, cooling and filtering to obtain the bidentate ligand dppn. Accurately weighing 122.5mg of [ (. eta.) ]6-p-cymene)RuCl2]2And 132.8mg of dppn, mixing in a reaction vessel, adding 10mL of methanol solution to dissolve the mixture, refluxing for 4h, cooling the reaction solution, and adding 10mL of AgNO3(136mg) of an aqueous solution, refluxing for 3 hours, and filtering to obtain a filtrate. Adding 4 times of equivalent of monodentate ligand pyrazine into the filtrate, and carrying out reflux reaction for 4 h. The above reactions are all in N2Under protection. And (4) spin-drying the reaction liquid to obtain a red brown solid crude product. Separating and purifying with silica gel column, eluting with a mixture of acetonitrile, water and saturated potassium nitrate water solution at a volume ratio of CH3CN：H2O：KNO380: 8: 1; the obtained solid is dissolved by using a small amount of water through ultrasonic treatment, and then saturated ammonium hexafluorophosphate aqueous solution is added to obtain yellow precipitate. And (3) carrying out suction filtration, washing the precipitate with a small amount of water, then washing with a small amount of diethyl ether, drying in vacuum to obtain a complex 1, and weighing after drying to calculate the yield.
Wherein the structural formula of the complex 1 is as follows:
[(η6-p-cymene)Ru(dppn)(pyrazine)](PF6)2(1) yield: 19.52%. nuclear magnetic data:1HNMR(600MHz,in[D6]CD3COCD3) 1.04(d,6H, J is 7.2Hz),2.16(s,3H),2.76 to 2.80(m,1H)6.68(d,2H, J is 6.6Hz),7.03(d,2H, J is 6.6Hz),7.82 to 7.84(m,2H),8.42 to 8.45(m,2H),8.59 to 8.61(m,2H),8.67(d,2H, J is 4.2Hz),8.97(d,2H, J is 4.2Hz),9.19(s,2H),10.02(d,2H, J is 7.8Hz),10.54(d,2H, J is 5.4Hz), and high-resolution peaks obtained by mass spectrometry: ESI-MS: M/z 324.08067(M-2 PF)6)2+.
Example 2: the synthesis method of the complex 2 comprises the following steps:
the synthesis of the repetitive complex 1 differs in that the monodentate ligand pyrazine is replaced by pyrimidine.
The structural formula of the complex 2 is as follows:
[(η6-p-cymene)Ru(dppn)(pyrimidine)](PF6)2(2) yield 36.56%. nuclear magnetic data:1H NMR(600MHz,in[D6]CD3COCD3) 1.03(d,6H, J6.6 Hz),2.13(s,3H),2.75-2.79(m,1H),6.68(d,2H, J6.6 Hz),7.03(d,2H, J6.6 Hz),7.63(t,1H, J5.4 Hz),7.81-7.82(m,2H),8.42-8.44(m,2H),8.57-8.59(m,2H),8.87(d,1H, J4.8 Hz),9.13(d,1H, J6.6 Hz),9.18(s,2H),9.52(s,1H),9.99(d,2H, J7.8 Hz),10.56(d,2H, J4.5 Hz), high-resolution cation peaks: ESI-MS: M/z 324.08022(M-2 PF)6)2+.
Example 3: the synthesis method of the complex 3 comprises the following steps:
the synthesis of complex 1 was repeated, with the difference that the monodentate ligand pyrazine was replaced by pyridazine.
The structural formula of the complex 3 is as follows:
[(η6-p-cymene)Ru(dppn)(pyridazine)](PF6)2(3) yield 40.93%. nuclear magnetic data:1H NMR(600MHz,in[D6]CD3COCD3) 1.05(d,6H, J ═ 7.2Hz),2.08(s,3H),2.72 to 2.76(m,1H),6.55(d,2H, J ═ 6.6Hz),6.87(d,2H, J ═ 6.6Hz),7.78 to 7.79(m,2H),7.87 to 7.89(m,2H),8.40 to 8.41(m,2H),8.50 to 8.53(m,2H),9.14 to 9.16(m,3H),9.61 to 9.62(m,1H),9.93(d,2H, J ═ 6.6Hz),10.41(d,2H, J ═ 5.4Hz), cationic ion peaks obtained by high-mass spectrometry: ESI-MS: M/z 324.07991(M-2 PF)6)2+.
Example 4: ultraviolet-visible absorption Spectroscopy
And testing the change of the absorption spectrum of the complex after different times of illumination, and comparing whether the complex changes. Under the irradiation of a solar simulator (lambda is more than 450nm), the absorption spectrum of the complex 1-3 in a PBS buffer solution (PH is 7.4) is changed, which indicates that the complex 1-3 is unstable to light in the PBS buffer solution and ligand dissociation is easy to occur, and the result is shown in FIG. 1.
Example 5: singlet oxygen quantum yield determination
1, 3-diphenyl isobenzofuran (DPBF) is a high-efficiency singlet oxygen trapping agent. Can use DPBF and1O2reaction of (2) determination of the Complex in acetonitrile solution1O2Quantum yield. The absorption of the complex to be tested and an acetonitrile solution of DPBF was adjusted to the same value at 500nm, and the absorbance change of DPBF at λ of 410nm was monitored by irradiation with excitation light at 500 nm. Selection Ru (bpy)3 2+As a standard substance, it saturates CH in air3In CN solvent1O2The quantum yield was 0.57. Measuring co-ordination 1-31O2Quantum yield order of magnitude 1>2>>The singlet oxygen quantum yields of 3 were 0.42, 0.40, and 0.25, respectively, and the results are shown in FIG. 2.
Example 6: DNA gel electrophoresis experiment
Supercoiled pUC19 plasmid DNA was used to study the ability of the complex to photodamage DNA. A PBS mixed solution containing 20. mu.L of supercoiled pUC19DNA (25. mu.g/mL) and the complex (30. mu.M) was prepared, and the mixture was allowed to stand for 10min and then subjected to a solar simulator (. lamda.) (>450nm) for 15min, adding 4 μ L of 6 × loading buffer solution, and mixing. mu.L of each sample was placed on an agarose gel plate and separated by electrophoresis for 30 min. Analyzed using a BIO-RAD GelDoxTMXR + gel imaging system. According to the report of the literature,1O2the plasmid DNA band can be broken into a circle (NC) from a double helix (SC), and the DNA band can be slowly migrated and weakened in color by being crosslinked with the DNA after the complex is dissociated. The experimental results show (see fig. 3), after being illuminated, the complexes 1-3 not only enhance the color development of the NC band of the DNA, but also make the SC band have different degrees of slow migration and weak color development (Lane2, 3 and 4). This indicates that the complex generates under illumination1O2Ligand dissociation also occurs. I.e. the complex and DNA are simultaneously irradiatedCrosslinking and photodisruption, and has PDT and PACT dual activities. By comparing the degrees of slow migration and weak coloration of SC band, it can be seen that the order of the ability of the complex to photocrosslink with DNA after dissociation by light irradiation is 1>2>3. Since the products of ligand dissociation also reduce the color development of the NC band, it is not possible to compare the luminescence intensities of the complexes 1 to 3 by observing the NC band in the graph1O2Generating capacity. The dark control experiment is carried out simultaneously, and the complexes 1-3 basically do not react with DNA under dark conditions ( Lane 5,6 and 7), which shows that the complexes do not damage the DNA under dark conditions.
Example 7: CT-DNA titration experiment
Calf thymus DNA (CT-DNA) was used in this experiment to test the selective photoresponse of the complex to DNA. The preparation method of the CT-DNA solution comprises the following steps: the required amount was weighed and PBS (pH 7.4) buffer was added and stirred overnight at a temperature below 4 ℃ using an extinction coefficient at 260nm (═ 6600M)-1cm-1) The concentration of CT-DNA was calculated. Then adding the complex into the complex (20uM) step by step according to a certain amount, mixing uniformly, and measuring the fluorescence intensity after reaction by using a fluorescence instrument. As a result, the luminous intensity of the complexes 1-3 is enhanced along with the increase of CT-DNA, and the maximum luminescence of the complexes 1-3 can be enhanced by 3-4 times after the system is saturated. The complexes 1-3 are shown to have selective photoresponse to DNA, and the results are shown in FIG. 4.
Example 8: in vitro cytotoxicity assay
In the experiment, human lung cancer cells A549 are selected as model tumor cells, and the well-grown A549 cells are treated according to the ratio of 2 multiplied by 105Growing the strain in 96-well plate at the concentration of each well for 24h, adding the complex into A549 cells, and CO-culturing for 4h at 37 deg.C and CO2Concentration of 5%, solar simulator (lambda)>400nm) for 15min, and culturing for 20h, and determining the survival rate of the cells by using a CCK8 experiment. Dark control experiments were performed simultaneously. Finally, the absorbance at 450nm is measured by using a ThermoMK3 enzyme-linked immunosorbent assay, and IC is calculated50The results are shown in Table 1.
TABLE 1 IC of A549 cells in light and dark, respectively50Value of
As a result, complexes 1 to 3 all showed different degrees of photo-enhanced cytotoxicity. Among them, the complex 1 has the highest cytotoxicity. For example, at a drug concentration of 4. mu.M,>after 15 minutes of 400nm illumination, the cell viability was only 29% for complex 1, and 57% and 59% for complexes 2 and 3, respectively. It is speculated that phototoxicity of complexes 1-3 may result from dissociation and generation of photoligands1O2While Complex 1 has the greatest phototoxicity probably because it has the highest phototoxicity1O2Quantum yield and best photocrosslinking ability of DNA.
The embodiments of the invention described herein are given by way of illustration only and are not to be taken by way of limitation, and many other variations and modifications may be made on the invention without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (6)
1. A novel ruthenium arene complex is characterized in that the molecular formula is [ (. eta.) ]6-p-cymene)Ru(dppn)(R)]2+[2PF6]2-(ii) a Wherein eta6-p-cymene is p-cymene, dppn is a bidentate ligand synthesized from 1, 10-phenanthroline-5, 6-dione and 2, 3-diaminonaphthalene, and R is a monodentate ligand pyrazine, pyrimidine, pyridazine;
the structural formula is shown as formula I:
wherein the structural formula of dppn is as follows:
r is respectively:
2. the process for producing a novel ruthenium arene complex according to claim 1, characterized by comprising the following production steps:
(1) dissolving 1, 10-phenanthroline-5, 6-diketone and 2, 3-diamine naphthalene in absolute ethyl alcohol, performing reflux reaction for 3 hours, cooling, precipitating a large amount of yellow solid, and filtering to obtain a bidentate ligand dppn;
(2) weighing [ (eta ] according to the stoichiometric ratio (1:2)6-p-cymene)RuCl2]2And dppn are placed in a three-necked bottle, methanol solution is added, the mixture is fully and uniformly mixed, and reflux reaction is carried out for 4 hours;
(3) naturally cooling to room temperature, and then adding 2 times of equivalent of AgNO3Refluxing the aqueous solution for 3h, cooling and filtering to obtain filtrate;
(4) adding 4 times of equivalent of monodentate ligand such as pyrazine, pyrimidine and pyridazine into the filtrate, and carrying out reflux reaction for 4 h; cooling to room temperature, and spin-drying the reaction solution to obtain a reddish brown solid crude product;
(5) purifying the crude product by adopting a dry method through a column;
(6) ultrasonically dissolving the purified solid by using purified water, adding a saturated ammonium hexafluorophosphate aqueous solution to obtain a precipitate, performing suction filtration, washing the precipitate by using a small amount of purified water, then washing the precipitate by using ethyl ether, and finally performing vacuum drying to obtain a complex; the steps (2) to (6) are carried out under the condition of keeping out of the sun;
and (4) performing steps (2) to (4) under the protection of inert gas.
3. The method for preparing a novel ruthenium arene complex according to claim 2, wherein the step (5) is implemented by the following steps: separating and purifying with silica gel column to obtain eluate CH3CN、H2O, saturated KNO3Mixture of aqueous solutions in a volume ratio of CH3CN：H2O：KNO3＝80：8：1。
4. The method of claim 3, wherein the inert gas is nitrogen.
5. Use of the novel ruthenium arene complexes of claim 1 in antineoplastic phototherapy.
6. The novel ruthenium arene complex of claim 1 is expected to be applied to tumor diagnosis and treatment integration.
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