| 朱周静,仝红娟,张彦民,刘斌.化学通报,2021,84(9):942-946. |
| 5-取代-2-羟甲基苯酚衍生物的合成及 体外抗肿瘤活性研究 |
| Synthesis and in Vitro Antitumor activity of 5-Substituted-2-(Hydroxymethyl)phenol Derivatives |
| 投稿时间：2021-01-18 修订日期：2021-02-16 |
| DOI： |
| 中文关键词: 5-取代-2-羟甲基苯酚 N-烷基化反应 抗肿瘤活性 合成 |
| 英文关键词:5-substituted-2-(hydroxymethyl)phenol N-alkylation reaction antimicrobial activity synthesis |
| 基金项目:陕西省自然科学基金项目(2018JM7046)、陕西国际商贸学院省级科研平台重点项目(2019XT-2-05)、陕西国际商贸学院“中药药效物质研究”创新团队项目(SSY18TD01)和陕西国际商贸学院一流专业建设项目资助 |
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| 中文摘要: |
| 以2-羟基-4-甲基苯甲酸为原料, 经过丙酮叉保护、NBS溴代制得中间体7-(溴甲基)-2,2-二甲基-4H-苯并[d][1,3]二氧六环-4-酮（4），再分别和两种杂环仲胺发生N-烷基化反应制得化合物5a-b，最后经过四氢铝锂还原得到目标化合物1a-b，其结构经1H NMR、13C NMR和ESI-MS进行表征。同时，考察了N-烷基化反应和还原反应的反应条件，确定了N-烷基化反应的最佳条件为：物料比为n（吡唑）: n（化合物4）= 1.2 : 1；K2CO3用量为n（K2CO3）: n（化合物4）= 2.0 : 1；50℃反应5 h。最佳还原反应条件为：LiAlH4用量为n（LiAlH4）: n（化合物5a）= 1.2 : 1，-75℃反应时间为1.0 h。此外，采用了MTT法测试了所合成的化合物1a-b对HepG2，HeLa，MCF-7，A5494四种肿瘤细胞以及正常宫颈上皮细胞HUCEC的体外抑制活性。结果表明，目标化合物1a-b对HeLa细胞展现出了明显的抑制作用，其IC50分别为18.4和10.6 μmol ? L-1，而对正常的HUCEC没有抑制活性。这些结果有望为进一步开发具有抗肿瘤活性的2-羟甲基苯酚衍生物提供参考。 |
| 英文摘要: |
| 7-(Bromomethyl)-2,2-dimethyl-4H-benzo[d][1,3]dioxin-4-one (4) was synthesized via acetonide protection and bromination reaction by NBS using 2-hydroxy-4-methylbenzoic acid as material, which was reacted with heterocyclic secondary amine to produce compounds 5a-b. Subsequently, 5a-b were reduced by LiAlH4 to obtain target compounds 1a-b. The structure of 1a-b was characterized by 1H NMR, 13C NMR and ESI-MS. Meanwhile, the reaction conditions for N-alkylation and reduction reactions were investigated and the optimum conditions were as follows: the mole ratio of n (pyrazole) : n (compound 4) = 1.2 : 1, the amount of K2CO3 is n (K2CO3) : n (compound 4) = 2.0 : 1, the reaction was at 50℃ for 5 h; the reduction conditions were as follows: the dosage of LiAlH4 is n (LiAlH4) : n (compound 5a) = 1.2 : 1, the reaction was at -78℃ for 1.0 h. The target compounds 1a-b were tested for their in vitro antitumor activity against HepG2，HeLa，MCF-7，A549 by MTT assay. Compounds 1a-b exhibited significant inhibitory effects on HeLa cells with IC50 of 18.4 and 10.6 ?mol ? L-1, respectively; moreover, Compounds 1a-b showed no significant toxicity to normal HUCEC cells. These results may provide the reference for the further development of 2-hydroxymethyl phenol derivatives as antitumor agents. |
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