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A pyrazole-functionalized nitrogen-heterocyclic carbene ruthenium compound with anticancer activity and its preparation method and application

A nitrogen-heterocyclic carbene and ruthenium compound technology, applied in ruthenium organic compounds, platinum group organic compounds, organic active ingredients, etc., can solve the problems of drug resistance and dose-limiting toxicity of cancer cells, and achieve inhibition of division and reproduction, Environmentally friendly and stable performance

Inactive Publication Date: 2018-10-30
ZHEJIANG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, cisplatin drugs have dose-limiting toxicity and make cancer cells resistant during use

Method used

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  • A pyrazole-functionalized nitrogen-heterocyclic carbene ruthenium compound with anticancer activity and its preparation method and application
  • A pyrazole-functionalized nitrogen-heterocyclic carbene ruthenium compound with anticancer activity and its preparation method and application
  • A pyrazole-functionalized nitrogen-heterocyclic carbene ruthenium compound with anticancer activity and its preparation method and application

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028]

[0029] Ethyl 5-methyl-1-hydro-pyrazolecarboxylate (30.8g, 200mmol) was dissolved in 200mL of dry tetrahydrofuran solution, and deoiled sodium hydride (4.8g, 200mmol) was added slowly under ice bath conditions, and sodium hydride was added completely Afterwards, the temperature was raised to 50° C., stirred for 1 hour, and then cooled to room temperature. Then iodomethane (28.2 g, 200 mmol) was dissolved in 100 mL of tetrahydrofuran, and slowly added dropwise to the reaction. After the dropwise addition was completed, the mixture was heated to 50° C. and continued to stir for 2 hours. After the reaction was complete, cool to room temperature, remove THF under reduced pressure, then add 100 mL of water, extract with ethyl acetate (100 mL×3), combine the organic layers, dry, and remove ethyl acetate under reduced pressure to obtain 5-methyl-1-methanol Ethyl-pyrazolecarboxylate 26.6g, 85%. Add lithium aluminum hydride (3.8g, 100mmol) and 200mL dry tetrahydrofuran into...

Embodiment 2

[0032]

[0033] Ligand HL2PF 6 Synthesized with reference to the method of Example 1, ethyl bromide replaces methyl iodide. At a temperature of 50°C, the ligand HL2PF was added 6 , 454mg (1mmol), acetonitrile 10mL, silver oxide 116mg (0.5mmol), react for 4 hours, then add [Ru(p-cymene)Cl 2 ] 2 306mg (0.5mmol) continued to react at room temperature for 2 hours, centrifuged, concentrated the filtrate to 2mL, added diethyl ether to precipitate a yellow solid, washed the yellow solid twice with diethyl ether, then dissolved it with acetonitrile, slowly added diethyl ether, and recrystallized to obtain 333 mg of nitrogen heterocycle Carbene ligand-coordinated ruthenium compound 2, yield 46%. 1 H NMR (400MHz, CD 3CN):7.54(s,1H),7.16(s,1H),7.14(s,1H),6.99(s,1H),6.36(s,1H),5.86,5.78,5.43,5.34(both d,4H ),5.31,4.96(both d,2H),4.86-4.69(m,2H),2.48(s,3H),2.36(s,3H),2.25(s,3H),2.02(s,3H),1.98 -1.96 (m, 1H), 1.60 (s, 3H), 1.40 (t, 3H), 1.14, 0.58 (both d, 6H) ppm. 13 C NMR (CD ...

Embodiment 3

[0035]

[0036] Ligand HL3PF 6 Synthesize with reference to the method of Example 1, isopropyl bromide replaces methyl iodide. At a temperature of 50°C, the ligand HL3PF was added 6 , 468mg (1mmol), acetonitrile 10mL, silver oxide 116mg (0.5mmol), react for 4 hours, then add [Ru(p-cymene)Cl 2 ] 2 306 mg (0.5 mmol) continued to react at room temperature for 2 hours, centrifuged, concentrated the filtrate to 2 mL, added diethyl ether to precipitate a yellow solid, washed the yellow solid twice with diethyl ether, then dissolved it with acetonitrile, slowly added diethyl ether, and recrystallized to obtain 353 mg of nitrogen heterocycle Carbene ligand-coordinated ruthenium compound 3, yield 53%. 1 H NMR (CD 3 CN):7.50(s,1H),7.22(s,1H),7.18(s,1H),6.80(s,1H),6.30(s,1H),5.82,5.72,5.41,5.30(both d,4H ), 5.26, 4.86 (both d, CH 2 ,2H),4.04(m,1H),2.42(s,CH 3 ,3H),2.34(s,3H),2.26(s,3H),2.12(s,3H),1.98-1.92(m,1H),1.62(s,3H),1.56(d,6H),1.16, 0.60 (both d, 6H) ppm. 13 C NMR (CD...

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Abstract

The invention discloses a pyrazole functionalized n-heterocyclic carbene ruthenium compound with anticancer activity and a preparation method and application thereof. The pyrazole functionalized n-heterocyclic carbene ruthenium compound is prepared by using 5-methyl-1-hydrogen-pyrazole ethyl formate through alkylation, reduction, chlorination, salt formation and metal exchange reaction, and the general formula of the pyrazole functionalized n-heterocyclic carbene ruthenium compound is [LRu(p-cymene)Cl](X) (L=pyrazole functionalized n-heterocyclic carbene ligand, and X is anions). In the cytotoxicity test of breast cancer cells (Bcap-37), intestinal cancer cells (LoVo), gastric cancer cells (SCG7901) and cisplatin-resistant gastric cancer cells (SCG7901-R), the n-heterocyclic carbene ruthenium compound can effectively inhibit cancer cell division and reproduction. The n-heterocyclic carbene ruthenium compound is variable in structure, convenient to synthesize, stable in performance, environmentally friendly, capable of stably existing in air for a long time, and promising in application prospect of pharmaceutical industry and fine chemical engineering industry.

Description

technical field [0001] The invention belongs to the field of anticancer drugs, in particular to a nitrogen heterocyclic carbene ruthenium compound with anticancer activity and functionalized pyrazole. Background technique [0002] Metal compounds have great application value in the field of anti-tumor drugs. For example, cisplatin-based metal compounds, which were first approved for clinical use, are now used as chemotherapy drugs to treat cancer. However, cisplatin drugs have dose-limiting toxicity and make cancer cells develop drug resistance during use. In order to overcome these shortcomings, it is necessary to find more and more novel metal compounds. [0003] Nitrocyclic carbene metal compounds have been widely used in the field of biochemistry because of their stable coordination ability, convenient synthesis and variable structure. Among them, azacyclic carbene gold, silver, platinum, and ruthenium have antitumor activity and have shown potential medicinal value. ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F15/00A61K31/555A61P35/00
CPCC07F15/0046
Inventor 王杭祥陈超
Owner ZHEJIANG UNIV
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