Cyclometalated ruthenium complex, and preparation method and application thereof

Abstract

The invention aims at developing a novel DNA (deoxyribonucleic acid) inserting reagent with good antitumor activity. A cyclometalated single-core ruthenium (II) complex is synthetized. The complex is stable in structure; the water-solubility is better than that of a common organic small molecular reagent at present; good DNA transcription inhibitory activity is represented. A cytotoxicity test indicates that the cyclometalated ruthenium (II) complex has significant growth inhibition effects on cancer cells of 11 different tissue parts of a human body; the inhibitory activity is much better than that of cis-platinum.

Description

technical field

[0001] The invention relates to the fields of DNA insertion reagents and anticancer drugs, in particular to a preparation method and application of a novel cyclometalated ruthenium polypyridine complex. Background technique

[0002] About 7.6 million people die of cancer every year in the world, accounting for 13% of the total death toll. Every year, 12.7 million cancer patients are diagnosed worldwide. In my country, about 1.5 million people die of cancer every year, and the trend is gradually increasing every year. Tumor treatment mainly includes three aspects: surgery, radiation therapy and chemotherapy. Chemotherapy is the method of treating diseases with chemically synthesized drugs. Chemotherapy is currently one of the main means of treating tumors and some autoimmune diseases. Chemotherapy refers to the application of drugs to treat cancer. These special drugs can kill tumor cells. There are currently more than 50 chemotherapy drugs. These anti-tumor ...

Examples

Embodiment 1

[0042] The preparation method of embodiment 1 ligand and complex

[0043] (1) Synthetic method of ligand dppz:

[0044] a) Synthesis method of 1,10-phenanthrolene-5,6-dione:

[0045] The synthesis of 1,10-phenanthroline-5,6-dione is according to (J.Am.Chem.Soc.1993,115,3448) method: stir 4.0g phenanthroline and 4.0g potassium bromide And placed in a 250mL round bottom flask, then dropwise added cold concentrated sulfuric acid (40mL) and concentrated nitric acid (20mL) mixed acid. After the dropwise addition, heat and reflux at 100°C for 3h, cool to room temperature, pour it into 500mL ice water, and then use 10molL -1 The NaOH solution was carefully neutralized to neutral, and the solution was extracted with 3×100 mL of chloroform. After combining the organic phases, they were washed with 50 mL of water, and finally dried overnight with anhydrous sodium sulfate. Filtrate, remove chloroform under reduced pressure, recrystallize the solid product from ethanol to obtain orange...

Embodiment 2

[0056] The ultraviolet-visible spectroscopic titration experiment of embodiment 2 complex

[0057] When the transition metal complex interacts with DNA, the absorption spectrum wavelength and absorption intensity change due to the change of the environment in which the complex resides, and the wavelength and absorption intensity change in different ways when the complex interacts with DNA. When small molecules are DNA-bonded in an intercalation manner, the corresponding absorption peaks produce obvious hypochromicity, accompanied by a certain degree of red shift (red shift). This is due to the π-electron stacking between the insertion ligand and the base pair of DNA, making it π * After the empty orbital is coupled with the p-electron orbital of the base pair, the energy level decreases, resulting in π→π * The transition energy decreases, resulting in a redshift. Simultaneously coupled π * Empty orbitals are partially filled with electrons, making π→π * The transition chan...

Embodiment 3

[0058] Transcription inhibition experiment of the complex of embodiment 3

[0059] Complexes with large planar ligands can be inserted into the double strands of DNA, preventing T7 RNA polymerase from binding to template DNA during DNA transcription, thus effectively preventing DNA transcription. In transcription inhibition experiments, varying the content of the complex and keeping the other components constant, the final content of RNA produced was used as a measure of repressive capacity. Depend on Figure 5 As can be seen from the figure below, the IC of the transcriptional inhibition ability of the complex 50 The value is 7.5 μM.

technical field

[0001] The invention relates to the fields of DNA insertion reagents and anticancer drugs, in particular to a preparation method and application of a novel cyclometalated ruthenium polypyridine complex. Background technique

[0002] About 7.6 million people die of cancer every year in the world, accounting for 13% of the total death toll. Every year, 12.7 million cancer patients are diagnosed worldwide. In my country, about 1.5 million people die of cancer every year, and the trend is gradually increasing every year. Tumor treatment mainly includes three aspects: surgery, radiation therapy and chemotherapy. Chemotherapy is the method of treating diseases with chemically synthesized drugs. Chemotherapy is currently one of the main means of treating tumors and some autoimmune diseases. Chemotherapy refers to the application of drugs to treat cancer. These special drugs can kill tumor cells. There are currently more than 50 chemotherapy drugs. These anti-tumor ...

Examples

Embodiment 1

[0042] The preparation method of embodiment 1 ligand and complex

[0043] (1) Synthetic method of ligand dppz:

[0044] a) Synthesis method of 1,10-phenanthrolene-5,6-dione:

[0045] The synthesis of 1,10-phenanthroline-5,6-dione is according to (J.Am.Chem.Soc.1993,115,3448) method: stir 4.0g phenanthroline and 4.0g potassium bromide And placed in a 250mL round bottom flask, then dropwise added cold concentrated sulfuric acid (40mL) and concentrated nitric acid (20mL) mixed acid. After the dropwise addition, heat and reflux at 100°C for 3h, cool to room temperature, pour it into 500mL ice water, and then use 10molL -1 The NaOH solution was carefully neutralized to neutral, and the solution was extracted with 3×100 mL of chloroform. After combining the organic phases, they were washed with 50 mL of water, and finally dried overnight with anhydrous sodium sulfate. Filtrate, remove chloroform under reduced pressure, recrystallize the solid product from ethanol to obtain orange...

Embodiment 2

[0056] The ultraviolet-visible spectroscopic titration experiment of embodiment 2 complex

[0057] When the transition metal complex interacts with DNA, the absorption spectrum wavelength and absorption intensity change due to the change of the environment in which the complex resides, and the wavelength and absorption intensity change in different ways when the complex interacts with DNA. When small molecules are DNA-bonded in an intercalation manner, the corresponding absorption peaks produce obvious hypochromicity, accompanied by a certain degree of red shift (red shift). This is due to the π-electron stacking between the insertion ligand and the base pair of DNA, making it π * After the empty orbital is coupled with the p-electron orbital of the base pair, the energy level decreases, resulting in π→π * The transition energy decreases, resulting in a redshift. Simultaneously coupled π * Empty orbitals are partially filled with electrons, making π→π * The transition chan...

Embodiment 3

[0058] Transcription inhibition experiment of the complex of embodiment 3

[0059] Complexes with large planar ligands can be inserted into the double strands of DNA, preventing T7 RNA polymerase from binding to template DNA during DNA transcription, thus effectively preventing DNA transcription. In transcription inhibition experiments, varying the content of the complex and keeping the other components constant, the final content of RNA produced was used as a measure of repressive capacity. Depend on Figure 5 As can be seen from the figure below, the IC of the transcriptional inhibition ability of the complex 50 The value is 7.5 μM.

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