以均三嗪为核心的三类新型多杂环分子的合成与生物活性

doi:10.6023/cjoc201701011

摘要/Abstract

均三嗪衍生物具有优良的生物活性，在均三嗪结构中将其它杂环对接引入已成为创制新型药物分子的重要方法.首次将1，2，4-三唑、三唑并噻二唑和1，2，4-三嗪等药效基团拼合在均三嗪结构中，设计合成了三类21个新型目标分子，并通过IR、¹H NMR和HRMS等对目标分子进行了结构表征.首先为研究不同取代基团对药效活性的影响，利用4种不同的三嗪单取代化合物分别与含有苯基和正戊基的中间体缩合，合成了8个含有双1，2，4-三唑的目标分子，同时针对三唑环上的氨基进行修饰得到目标产物；其次利用7种不同的三嗪双取代化合物，首次将1，2，4-三嗪和三唑并噻二唑构筑在9个目标分子中.评价了21个目标分子对Cdc25B抑制活性.结果发现13个目标分子对Cdc25B均表现出良好的抑制活性，IC₅₀值在（3.99±0.80）～（0.44±0.07） μg/mL之间，其中6个目标分子的IC₅₀值均低于阳性参照物Na₃VO₄，有望成为潜在的抗肿瘤药物.

关键词: 均三嗪, 1,2,4-三唑, 三唑并噻二唑, 1,2,4-三嗪, Cdc25B

s-Triazine derivatives have good significant biological activities. It has been an important method to develop novel drugs by introduction of other heterocyclic rings onto s-triazine. Twenty-one novel target molecules were designed and synthesized by combination of 1,2,4-triazole, triazolo[3,4-b]thiadiazole and 1,2,4-triazine unit with s-triazine respectively. The structures of the target molecules were characterized by IR, ¹H NMR and HRMS. In order to study the effect of different substituents on the efficacy activities, first, 8 target molecules containing double 1,2,4-triazole unit were synthesized by the condensation of four different mono-substituted s-triazines with intermediates containing n-pentyl and benzyl, respectively. Meanwhile, 4 target molecules were synthesized by the modification of the amino group. 9 target molecules were also afforded by the reaction of seven disubstituted s-triazines with the intermediates. The inhibitory activities of the 21 target molecules against Cdc25B were evaluated. The results showed that 13 target molecules exhibited good inhibitory activities against Cdc25B. The IC₅₀ values were between (3.99±0.80)~(0.44±0.07) μg/mL, wherein the IC₅₀ of 5 target molecules were lower than comparison reference Na₃VO₄, which were expected to be potential anticancer drugs.

Key words: s-triazine, 1,2,4-triazole, triazolo[3,4-b]thiadiazole, 1,2,4-triazine, Cdc25B

引用此文

刘亚宁, 孙晓娜, 高然, 李传银, 王静, 李益政, 张成路. 以均三嗪为核心的三类新型多杂环分子的合成与生物活性[J]. 有机化学, 2017, 37(8): 2057-2065.

Liu Yaning, Sun Xiaona, Gao Ran, Li Chuanyin, Wang Jing, Li Yizheng, Zhang Chenglu. Synthesis and Bioactivities of Multiheteocyclic Molecules Based on s-Triazine[J]. Chin. J. Org. Chem., 2017, 37(8): 2057-2065.

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