含1-[4-二(4-氟苯)甲基]哌嗪基团的异噁唑的设计合成及抗肿瘤活性研究
收稿日期: 2017-07-02
修回日期: 2017-08-19
网络出版日期: 2017-09-15
基金资助
四川省科技厅科技支撑计划（No.2015NZ0033）资助项目.
Design, Synthesis and Anti-tumor Activity Evaluation of a Novel Series of Isoxazoles Bearing (1-Bi(4-fluorophenyl)methyl)-piperazine Unit
Received date: 2017-07-02
Revised date: 2017-08-19
Online published: 2017-09-15
Supported by
Project supported by the Sichuan Provincial Department of Science and Technology Support Program (No. 2015NZ0033).
以1-[二（4-氟苯）甲基]哌嗪、溴丙炔及氯代肟为原料以21%~76%的收率制得了12个含有1-[4-二（4-氟苯）甲基哌嗪单元的异噁唑衍生物5a~5l.合成的12个目标化合物通过熔点测定和质谱、红外光谱、元素分析及核磁共振氢谱和碳谱分析对其结构进行确证.经体外抗肿瘤活性测试表明，在20 μg/mL的浓度下，有10个化合物对细胞周期分裂蛋白25B（CDC25B）具有较好的抑制活性，其抑制率为64.15%~97.96%，IC50为35.62~13.67 μg/mL.在40 μmol/L的浓度下，其中四个化合物对白血病HL-60细胞的IC50为36.51~15.25μg/mL，2-（2-氟苯基）-5-（1-（二（4-氟苯）甲基）哌嗪）甲基异噁唑（5g），2-（2-氟苯基）-5-（1-（二（4-氟苯）甲基）哌嗪）甲基异噁唑（5h）对肺癌A-549肿瘤细胞的IC50分别为21.09和35.36 μg/mL.
关键词： 1-[二(4-氟苯)甲基]哌嗪; 异噁唑; 有机合成; 抗肿瘤活性
丁勇 , 李清寒 , 赵志刚 , 杨学军 , 陈峰 . 含1-[4-二(4-氟苯)甲基]哌嗪基团的异噁唑的设计合成及抗肿瘤活性研究[J]. 有机化学, 2017 , 37(12) : 3282 -3288 . DOI: 10.6023/cjoc201707001
Twelve novel isoxazoles containing (1-bi(4-fluorophenyl)methyl)piperazine unit were prepared in two steps starting from propargyl bromide, (1-bi(4-fluorophenyl)methyl)piperazine and hydroxymoyl chlorides with moderate yield (21%~76%). The structures of the new compounds were characterized by IR, MS, 1H NMR, 13C NMR and elemental analysis, and their in vitro anti-tumor activity was screened. The bioactive assay for the newly prepared compounds manifested that ten newly isoxazole derivatives exhibited good to excellent inhibitory activity against CDC25B in 20 μg/mL with inhibition of 64.15%~95.87% and IC50 of 35.62~13.67 μg/mL. Four isoxazoles exhibited good to excellent inhibitory activity against Leukemia cell HL-60 in 40 μmol/L (IC50:36.51~15.25 μg/mL), 2-(2-fluorophenyl)-5-(1-(bi-(4-fluorophenyl)methyl)-piperazine)methylisoxazole (5g) and 2-(4-fluorophenyl)-5-(1-(bi-(4-fluorophenyl)methyl)piperazine)methylisoxazole (5h) exhibited good to excellent inhibitory activity against Lung cancer cell A-549 (IC50 value up to 21.09 and 35.36 μg/mL, respectively).
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