Ruthenium complexes for restraining DNA from topologizing isomerase , preparation method and application thereof

A technology of topoisomerase and ruthenium complexes, which is applied in the field of ruthenium complexes inhibiting DNA topoisomerase and its preparation, can solve the problems of low specificity, poor solubility, complex structure, etc., and achieve simple preparation methods, The effect of improving water solubility and warming reaction conditions

Inactive Publication Date: 2009-01-07
SUN YAT SEN UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are still many problems to be further studied and discussed. For example, most organic topoisomerase inhibitors have disadvantages such as complex structure, low specificity, poor solubility, and high toxicity. At the same time, Topo I / II with good inhibitory ability Dual inhibitors are rarely reported

Method used

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  • Ruthenium complexes for restraining DNA from topologizing isomerase , preparation method and application thereof
  • Ruthenium complexes for restraining DNA from topologizing isomerase , preparation method and application thereof
  • Ruthenium complexes for restraining DNA from topologizing isomerase , preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] (1) Preparation of ligand 3-(2-pyrazinyl)-1,2,4-triazino[5,6-e]pyrene (PZPP):

[0032] 2-Pyrazine imidine (1.1 g, 8 mmol) and pyrenedione (1.8 g, 8 mmol) were heated under reflux in ethanol for 4 hours. Cooling to room temperature gave a yellow precipitate. The precipitate was collected and dried in vacuo as a yellow solid, yield 76%.

[0033] Elemental Analysis C 21 h 11 N 5 (Molecular weight 333), experimental value: C 75.69, H 3.28, N 21.03%; theoretical value: C 75.68, H 3.30, N 21.02%. FAB-MS: m / z=334 (C 21 h 11 N 5 333).

[0034] (2) Preparation of [Ru(bpy) 2 (PZPP)]Cl 2 : After bis(2,2'-bipyridine)-dichloro-ruthenium(II) dihydrate (1.0g, 2mmol) and PZPP (0.6g, 2mmol) were refluxed in ethylene glycol for 10 hours, NaClO was added 4 Aqueous solution, precipitated red solid. The crude product dried by suction filtration is separated and purified by alumina column chromatography, then dissolved in acetone, added tetrabutylammonium chloride, a red solid is...

Embodiment 2

[0037] (1) Preparation of ligand 3-(2-pyrazinyl)-1,2,4-triazino[5,6-e]pyrene (PZPP):

[0038] 2-Pyrazine imidine (1.1 g, 8 mmol) and pyrenedione (1.8 g, 8 mmol) were heated under co-flow in ethanol for 4 hours. Cooling to room temperature gave a yellow precipitate. The precipitate was collected and dried in vacuo as a yellow solid, yield 76%.

[0039] Elemental Analysis C 21 h 11 N 5 (Molecular weight 333), experimental value: C 75.69, H 3.28, N 21.03%; theoretical value: C 75.68, H 3.30, N 21.02%. FAB-MS: m / z=334 (C 21 h 11 N 5 333).

[0040] (2) Preparation of [Ru(phen) 2 (PZPP)]Cl 2 : After bis(1,10-phenanthroline)-dichloro-ruthenium dihydrate (II) (1.1g, 2mmol) and PZPP (0.6g, 2mmol) were refluxed in ethylene glycol for 10 hours, NaClO was added 4 Aqueous solution, precipitated red solid. The crude product dried by suction filtration was separated and purified by alumina column chromatography, then dissolved in acetone, added tetrabutylammonium chloride, and a ...

Embodiment 3

[0042] Example 3 Topoisomerase Inhibition Experiment of Ru(II) Complexes

[0043] According to the method of drug inhibition topoisomerase unwinding test, the inhibitory ability was judged, and the compound was reacted with pBR322 DNA and topoisomerase in an appropriate buffer, and the reaction mixture was incubated at 37°C for a certain period of time. The reaction was terminated by adding reaction termination solution. On 0.9% agar enamel (TBE) gel, electrophoresis under constant voltage condition of 75V. The gel was stained with 1 μg / mL EB solution and photographed under UV light. The complex concentration that inhibits 50% of Topo I or Topo II activity was defined as IC 50 . The experimental results show that the complex is a dual inhibitor of Topo I and Topo II, showing a very good inhibitory ability, IC 50 values ​​less than 1 µM, see figure 1 and figure 2 , in the figure, the plasmid DNA is expressed as a closed-loop supercoiled Form I band; a certain amount of T...

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Abstract

The invention discloses a ruthenium complex for inhibiting DNA topoisomerase, which has a molecular formula of [RuL2(PZPP)]Cl2, wherein L is 2,2-bipyridine or 1,10-o-phenanthroline, and PZPP is 3-(2-pyrazinyl)-1,2,4-triazolo[4,5-e]pyrene. The invention also provides the preparation method of the ruthenium complex. The invention further provides a compound 3-(2-pyrazinyl)-1,2,4-triazolo[4,5-e]pyrene obtained in the preparation process of the ruthenium complex. The invention also discloses the application of the ruthenium complex for inhibiting DNA topoisomerase in the preparation of anticancer drugs. The ruthenium complex for inhibiting DNA topoisomerase has good water solubility and has double effects on inhibiting type-I DNA topoisomerase and type-II DNA topoisomerase, and both of the IC50 values are less than 1 muM. The ruthenium complex has wide application prospect.

Description

technical field [0001] The invention relates to a topoisomerase inhibitor and a preparation method thereof, in particular to a ruthenium complex for inhibiting DNA topoisomerase and a preparation method thereof. Background technique [0002] The normal metabolism of cellular DNA plays an extremely important role throughout the life of an organism. In complex DNA metabolism, including DNA replication, recombination and transmission of genetic information, dynamic changes in DNA spatial configuration are involved. DNA topoisomerase (Topoisomerase) is the key ribozyme that regulates this reaction. [1] . According to the mechanism of topoisomerase-induced DNA fragmentation, it is mainly divided into two types: type I DNA topoisomerase (Topo I) and type II DNA topoisomerase (Topo II). [0003] DNA topoisomerase is a popular target in the research of anticancer drugs. Studies have confirmed that, unlike normal cells, topoisomerase is expressed at a high level unaffected by oth...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F15/00C07D403/04A61K31/555A61P35/00
Inventor 巢晖袁益娴计亮年
Owner SUN YAT SEN UNIV
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