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抗肿瘤氟喹诺酮C3等排衍生物——噁二唑曼尼希碱衍生物的合成和抗肿瘤活性

陈寅生1,王国强1,段楠楠1,曹铁耀1,温晓漪1,银俊1,王伟1,谢松强1,黄文龙2,胡国强1*   

  1. (1.河南大学化学生物学研究所 开封 475001;2.中国药科大学新药研究中心 南京 210009)
  • 收稿日期:2011-11-30 修回日期:2012-01-08 出版日期:2012-11-10 发布日期:2012-11-10
  • 通讯作者: 胡国强,教授; Tel/Fax:0378-3880680; E-mail:hgqxy@sina.com.cn; 研究方向：新药分子的设计与合成
  • 基金资助:
    国家自然科学基金（20872028,21072045）和河南大学科研基金(06YBZR075)资助项目

Synthesis and Antitumor Activity of Fluoroquinolone C3-Isostere Derivatives: Oxadiazole Mannich Base Derivatives

CHEN Yinsheng1, WANG Guoqiang1, DUAN Nannan1, CAO Tieyao1, WEN Xiaoyi1, YIN Jun1, WANG Wei1, XIE Songqiang1, HUANG Wenlong2, HU Guoqiang1*   

  1. (1.Institute of Chemistry & Biology,Henan University,Kaifeng 475001,China;
    2.Center of Drug Discovery,China Pharmaceutical University,Nanjing  210009,China)
  • Received:2011-11-30 Revised:2012-01-08 Published:2012-11-10 Online:2012-11-10

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摘要： 用噁二唑硫酮杂环作为培氟沙星(1)的C3羧基电子等排体，得中间体C3噁二唑硫酮4(5)，再将其与仲胺或取代苯胺及甲醛通过氨甲基化反应形成系列氟喹诺酮C3噁二唑硫酮曼尼希碱(6a~6j)目标化合物。 用元素分析、1H NMR和MS测试技术确证了目标化合物的组成和结构。 采用MTT法评价了目标化合物对体外培养人肝癌Hep-3B细胞生长的抑制活性。 结果表明，10种目标化合物活性均显著高于对照化合物1的活性，并且脂肪胺曼尼希碱的活性高于芳香胺曼尼希碱的活性。

关键词: 氟喹诺酮, 电子等排体, 噁二唑硫酮, 曼尼希碱, 抗肿瘤评价

Abstract: To further study an efficient modified route for transforming an antibacterial fluoroquinolone to an antitumor compound, an oxadiazole heterocyclic ring, 1,3,4-oxadiazole-thione, was used as an isostere of C-3 carboxylic group for pefloxacin 1, and a key intermediate, 1-ethyl-6-fluoro-7-(4-methyl-piperazin-1-yl)-3-(3H-1,3,4-oxadiazole-2-thione-5-yl)-quinolin-4(1H)-one 4(5), was designed and synthesized. The intermediate was then subjected to an aminomethylation reaction with secondary amines or substituted anilines and formaldehyde to afford the corresponding oxadiazole thione Mannch bases 6a~6j as the title compounds, respectively. The structures for ten title compounds were characterized by elemental analysis, 1H NMR and MS, and their anticancer activities in vitro against Hep-3B cancer cell lines were also evaluated. The results reveal that all the title compounds show more significant potent than that of parent compound 1, and those derived from aliphatic amines display higher activity than the aromatic amine compounds.

Key words: fluoroquinolone, isostere, oxadiazole thione, Mannich base, antitumor evaluation

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