有机化学 ›› 2015, Vol. 35 ›› Issue (2): 439-445.DOI: 10.6023/cjoc201409008 上一篇    下一篇

研究论文

γ-烷氧基-2(5H)-呋喃酮-哌嗪-磺酰胺类化合物的合成及抗癌活性研究

魏梦雪a, 高晓慧a, 张和a, 李学强a,b   

  1. a 宁夏大学化学化工学院 银川 750021;
    b 宁夏天然药物工程技术研究中心 银川 750021
  • 收稿日期:2014-09-05 修回日期:2014-10-01 出版日期:2015-02-25 发布日期:2014-10-21
  • 通讯作者: 李学强 E-mail:lixq@nxu.edu.cn
  • 基金资助:

    国家自然科学基金(Nos. 21462032、21062014)、宁夏大学人才引进科研启动基金(No. 80020241)和宁夏大学“211”工程建设(No. ndzr09-1)资助项目.

Synthesis of New Chiral γ-Alkoxy-2(5H)-furanone-piperazine-sulfonamide Compounds and Preliminary Evaluation of in Vitro Anticancer Activity

Wei Mengxuea, Gao Xiaohuia, Zhang Hea, Li Xueqianga,b   

  1. a School of Chemistry and Chemical Engineering, Ningxia University, Yinchuan 750021;
    b Ningxia Engineering Research Center for Natural Medicines, Yinchuan 750021
  • Received:2014-09-05 Revised:2014-10-01 Online:2015-02-25 Published:2014-10-21
  • Supported by:

    Project supported by the National Natural Science Foundation of China (Nos. 21462032, 21062014), the Research Starting Funds for Imported Talents of Ningxia University (No. 80020241), and the “211” Project in Ningxia University (No. ndzr09-1).

以糠醛为原料经氧化、醚化和多次重结晶方便地得到光学纯5-(S)-5-烷氧基-3,4-二溴-2(5H)-呋喃酮, 再与哌嗪发生串联的Michael加成-消除反应, 所得粗产物与一系列不同结构的磺酰氯反应, 快速、高效地合成了12种结构新颖的呋喃酮-哌嗪-磺酰胺类化合物. 通过1H NMR,13C NMR, IR和HRMS对所有新化合物进行了结构表征; 并以四甲基偶氮唑盐(MTT)法评价了该类化合物对人宫颈癌(Hela)细胞株的细胞毒活性. 初步的生物活性研究结果表明, 该类化合物具有显著地抑制人宫颈癌细胞增殖、诱导其凋亡的细胞毒活性, 其中5-(S)-5-冰片氧基-4-(对硝基苯磺酰胺-哌嗪基)-3-溴-2(5H)-呋喃酮(7k)给药24 h, 半数抑制浓度IC50值仅为0.02 μmol/L, 有进一步优化成抗人宫颈癌候选药物的潜力.

关键词: 丁烯酸内酯, 呋喃酮-哌嗪-磺酰胺, 合成, Hela细胞, 抗癌活性

The enantiomerically pure 5-(S)-5-alkoxy-3,4-dibromo-2(5H)-furanones were readily prepared from furfural through a three-step sequence of bromine-promoted oxidation/acetalization of mucobromic acid with chiral (-)-menthol and (+)-borneol/recrystallization of the resulting γ-butenolides. Then the chiral γ-butenolides were reacted with piperazine through a one-pot two-step protocol combining Michael addition and elimination of hydrogen bromide, resulting in the crude furanone-piperazines, which were further toslated with a range of sulfonyl chlorides. 12 furanone-piperazine-sulfonamide complexs were efficiently obtained in moderate to excellent yields (45.3%~96.2%). All the new compounds were identified by 1H NMR, 13C NMR, IR and HRMS technology. The in vitro anti-tumor activities of these complexs against cervical cancer cell lines (Hela) were evaluated by thiazolylblue (MTT) assay method. Among them, 5-(S)-5-borneolyloxy-4-(p-nitrobenzene-sulfonamide-piperazinyl)-3-bromo-2(5H)-furanone (7k) exhibited the best inhibitory activity with an IC50 of 0.02 μmol/L, providing a new promising lead for further development of new anti-Hela drugs.

Key words: butenolide, furanone-piperazine-sulfonamide, synthesis, Hela cells, anti-tumor activity