4′-氯-7-\[2-(哌嗪-l-基)乙氧基\]异黄酮的合成及分析方法的建立
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国家自然科学基金(81274005)


Synthetic and analytical method establishment of 3-(4-chlorophenyl)-7-[JP]\[2-(piperazin-l-yl)ethoxy\]-4H-chromen-4-one
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    摘要:

    为解决天然大豆苷元(daidzein,DAI)抗肿瘤活性不足的问题,对DAI的4′位和7位进行结构修饰。首先,以间苯二酚和对氯苯乙酸为起始原料,经傅克酰基化、增碳关环反应制备4′-氯-7-羟基-异黄酮,将4′-氯-7-羟基异黄酮依次与二溴乙烷、哌嗪通过取代反应制备目标化合物4′-氯-7-\[2-(哌嗪-l-基)乙氧基\]异黄酮(3-(4-chlorophenyl)-7-\[2-(piperazin-l-yl)ethoxy\]-4H-chromen-4-one,CPEO-43),采用柱层析方法实现目标产物与杂质的分离。其次,通过FT-IR,MS,1H-NMR及13C-NMR确证结构。再次,通过MTT实验评价化合物CPEO-43对A549肺癌细胞和HCT116结肠癌细胞的抑制作用。最后,建立CPEO-43血浆样品的超高效液相色谱(ultra high performance liquid chromatography,UPLC)分析方法。结果表明,通过FT-IR,MS,1H-NMR及 13C-NMR确证了所合成的化合物与目标化合物结构一致。10 μmol/L DAI对A549肺癌和HCT116结肠癌细胞的抑制率分别为4.421%和5.601%;而相同浓度的CPEO-43对A549肺癌细胞和HCT116结肠癌细胞抑制率分别为58.43%和72.03%,IC50值分别为2.51 μmol/L和0.87 μmol/L。建立的UPLC方法无内源性物质干扰,在0.5~10 μg/mL范围内线性关系良好,日内精密度及日间精密度均小于10%,化合物CPEO-43的低、中、高浓度的血浆样品的回收率为92.98%~100.10%。化合物CPEO-43的抗肿瘤活性显著高于DAI,UPLC分析方法能简便快速地测定血浆中CPEO-43的含量,结果准确可靠,可为提高DAI的抗肿瘤效果提供理论依据,为药物临床检测提供方法基础。

    Abstract:

    In order to solve the problem of insufficient antitumor activity of natural daidzein (DAI),the 4 'and 7 positions of DAI were modified.Firstly,3-(4-chlorophenyl)-7-hydroxy-4H-chromen-4-one was prepared from resorcinol and p-chlorophenylacetic acid by friedel crafts acylation,carbonization and ring closing reaction.The 3-(4-chlorophenyl)-7-\[2-(piperazin-l-yl)ethoxy\]-4H-chrome-4-one (CPEO-43) was synthesized by substitution reaction of 3-(4-Chlorophenyl)-7-hydroxy-4H-chromen-4-one with dibromoethane and piperazine.Column chromatography was used to separate the target product from impurities.Secondly,FT-IR,1H-NMR,13C-NMR and MS were used to identify the compounds.Thirdly,MTT assay was used to detect the inhibitory effect of compound CPEO-43 on A549 lung cancer cells and HCT116 colon cancer cells.Finally,an ultra high performance liquid chromatography (UPLC) method was established for the analysis of CPEO-43 plasma samples.The results show that the structure of the synthesized compound is consistent with that of the target compound confirmed by FT-IR,MS,1H-NMR and 13C-NMR.The inhibitory rates of DAI (10 μmol/L) on A549 lung cancer and HCT116 colon cancer cells are 4.421% and 5.601%,respectively.The inhibitory rates of the same concentration of CPEO-43 on A549 lung cancer cells and HCT116 colon cancer cells are 58.43% and 72.03%,respectively.The IC50 values of CPEO-43 are 2.51 μmol/L and 0.87 μmol/L,respectively.The established UPLC method has no interference from endogenous substances.The linear relationship is good in the range of 0.5~10 μg/mL.The intra-day precision and inter-day precision are less than 10%.The average recoveries of low,medium and high plasma samples of compound CPEO-43 are in the range of 92.98%~100.1%.The antitumor activity of compound CPEO-43 is significantly higher than that of DAI.The established UPLC assay method can easily and rapidly determine the content of CPEO-43 in plasma,and the results are accurate and reliable,provide a theoretical basis for improving the antitumor activity of DAI,and provide method basis for drug clinical testing.

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连孟强,刘娅琛,郭春燕.4′-氯-7-\[2-(哌嗪-l-基)乙氧基\]异黄酮的合成及分析方法的建立[J].河北科技大学学报,2022,43(3):300-307

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  • 收稿日期:2022-04-01
  • 最后修改日期:2022-05-05
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  • 在线发布日期: 2022-07-08
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