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Ruthenium complex capable of inhibiting tumor angiogenesis and preparation method and application thereof

A technology of ruthenium complexes and tumor blood vessels, which is applied in the field of ruthenium complexes that inhibit tumor blood vessel formation and its preparation, can solve problems such as poor stability, difficult hydrolysis, and high toxicity, and achieve good stability, difficult hydrolysis, and reduced toxicity Effect

Inactive Publication Date: 2012-06-27
JINAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] In order to overcome the shortcomings of existing ruthenium complexes such as poor stability, easy hydrolysis, and high toxicity, the primary purpose of the present invention is to provide a ruthenium complex that is stable, difficult to hydrolyze, low in toxicity, good in solubility, and capable of inhibiting tumor angiogenesis

Method used

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  • Ruthenium complex capable of inhibiting tumor angiogenesis and preparation method and application thereof
  • Ruthenium complex capable of inhibiting tumor angiogenesis and preparation method and application thereof
  • Ruthenium complex capable of inhibiting tumor angiogenesis and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0072] Example 1 Complex a: Ru(bpy) 2 Preparation of (ox) (wherein R is H)

[0073] (1) Synthesis of silver oxalate

[0074] Aqueous silver nitrate solution (11 mmol) was added dropwise to sodium oxalate solution (5 mmol), immediately forming a white precipitate. The reaction was stirred for 10 minutes and filtered. The white precipitate was washed with water and dried in vacuum to obtain silver oxalate (yield: 80%).

[0075] (2)cis-[Ru(bpy) 2 Cl 2 ]·2H 2 Synthesis of O

[0076] RuCl 3 ·nH 2 O (1.56g, 6mmol), bipyridine (1.87g, 12mmol) and lithium chloride (1.68g, 28mmol) were placed in a three-necked flask, 10mL of DMF was added, and heated to reflux for 8 hours under the protection of argon. After cooling to room temperature, 50 mL of acetone was added, and the mixture was kept overnight at 4°C. Suction filtration, precipitation with ice water, washing several times with acetone at 4°C, and drying in vacuo to obtain 2.52 g of purple-black microcrystals, namely cis-...

Embodiment 2

[0081] Example 2 Complex d: Ru(phen) 2 (mal) (where R 1 For the preparation of H)

[0082] (1) Synthesis of silver malonate

[0083] Aqueous silver nitrate solution (11 mmol) was added dropwise to sodium malonate solution (5 mmol), immediately forming a white precipitate. The reaction was stirred for 10 minutes and filtered. The white precipitate was washed with water and dried in vacuo to obtain silver malonate (yield: 78%).

[0084] (2)cis-[Ru(phen) 2 Cl 2 ]·2H 2 Synthesis of O

[0085] called RuCl 3 ·nH 2 O 1.56g (6mmol), with o-phenanthroline 2.40g (12mmol) and lithium chloride 1.68g (28mmol), dissolved in 10mL DMF, heated to reflux for 8h under the protection of argon. After cooling to room temperature, 50 mL of acetone was added, and it was kept overnight at 4°C. Suction filtration, precipitation with ice water, washing with acetone at 4°C, and vacuum drying to obtain purple-black microcrystals, namely cis-[Ru(phen) 2 Cl 2 ]·2H 2 O, yield 72%.

[0086] (3)...

Embodiment 3

[0090] Example 3 Complex f: Ru(bpy) 2 (mal) (where R, R 1 For the preparation of H)

[0091] (1) Synthesis of silver malonate

[0092] With embodiment 2 step (1).

[0093] (2)cis-[Ru(bpy) 2 Cl 2 ]·2H 2 Synthesis of O

[0094] With embodiment 1 step (2).

[0095] (3)Ru(bpy) 2 Synthesis of (mal)

[0096] cis-[Ru(bpy) 2 Cl 2 ]·2H 2 O (0.5 mmol) and silver malonate (0.7 mmol) were reacted at 60° C. for 12 hours in a mixed solvent of ethanol / water (V:V=1:3). The mixture was filtered through celite to remove the precipitated silver chloride. The solvent was spun off under vacuum and the solid was dissolved with methanol. The solvent was reduced to about 5% of the original capacity, diethyl ether was added, overnight at -20°C, the precipitate was filtered and recrystallized with methanol-diethyl ether (V:V=1:1).

[0097] The structural characterization data of the final product are as follows: Found: C: 53.61; H; 3.51; N; 10.85.(Calc.forC 23 h 18 N 4 o 4 Ru: C: 53....

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Abstract

The invention belongs to the field of chemical drugs, and discloses a ruthenium complex capable of inhibiting tumor angiogenesis and a preparation method and application thereof. The ruthenium complex provided by the invention has a structure shown in a formula I or II. The preparation method comprises the following steps of: dropwise adding a silver nitrate solution to a sodium salt solution, stirring and reacting, then filtering, washing and vacuum drying a precipitate, and thereby obtaining a ligand O-O; taking ruthenium chloride, L, and lithium chloride to be dissolved in N-, N-dimethyl formamide, heating and refluxing under the protection of argon atmosphere to obtain an intermeidate Ru (L2) Cl22 +; allowing the ligand O-O and the Ru (L2) Cl22 + to be dissolved in an ethanol / water mixed solvent, heating and refluxing to obtain the ruthenium complex shown in the formula I; and allowing the Ru (L2) Cl22 +, 8- hydroxyquinoline, and ammonium acetate to be dissolved in ethanol, and heating and refluxing under the protection of argon atmosphere to obtain the ruthenium complex shown in the formula II. The ruthenium complex has the advantages of good stability, uneasiness in hydrolysis, good solubility, low toxicity, and the ability to inhibit tumor angiogenesis, and is easily absorbed by the human body.

Description

technical field [0001] The invention belongs to the field of chemical drugs, and in particular relates to a ruthenium complex capable of inhibiting tumor angiogenesis, a preparation method and application thereof. Background technique [0002] In 1967, Rosenberg, a professor at Michigan State University in the United States, discovered that cisplatin had anticancer activity and passed clinical verification, thus opening up a new field of metal complex anticancer drug research. [0003] Ruthenium complexes are the best among non-platinum metal drugs. It is generally believed internationally that ruthenium complexes will become one of the most promising antitumor drugs. The advantages of ruthenium complexes as antitumor drugs are that they have little toxicity to normal cells, are easily absorbed by tumor tissues, and have obvious effects on metastatic tumors. So far, two ruthenium complexes have entered clinical trials. The first-generation ruthenium complex NAMI-A has comp...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F15/00A61K31/555A61P35/00
Inventor 刘杰袁方周艳晖孙冬冬刘亚楠
Owner JINAN UNIVERSITY
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