细胞分裂周期25磷酸酯酶B抑制剂双1,2,4-三唑多杂环分子的设计合成

doi:10.11944/j.issn.1000-0518.2018.02.170004

摘要/Abstract

摘要：

以1,2,4-三唑为核心结构的杂环分子,因其优良而广泛的生物活性,已成为药物筛选中重要的研究对象。本文为了研究其构效关系,针对1,2,4-三唑结构中3个位点分别进行不同的结构修饰,并将其与哌嗪和均三嗪分别偶联,首次合成了两类共28个双三唑多杂环目标分子[TM1TM3(af)]和[TM4TM5(ae)]。为了比较三唑中4-氨基对生物活性的影响,还与化合物6-吗啉-2,4-(5-硫醚基-4-氨基-3-正戊基1,2,4-三唑)-1,3,5-三嗪(C)和6-吡咯-2,4-(5-巯基-4-氨基-3-正戊基-1,2,4-三唑)-1,3,5-三嗪(D)进行了比较。通过傅里叶变换红外光谱仪(IR)、核磁共振谱(¹H NMR)和高分辨率质谱仪(HRMS)等技术手段对28个目标分子进行了结构表征,研究了其对细胞分裂周期25磷酸酯酶B(Cdc25B)的抑制活性。结果表明,21个目标分子表现出优良的抑制活性,9个目标分子的抑制活性优于阳性参照物,有望成为抗肿瘤药物先导物。

关键词: 1,2,4-三唑, 哌嗪, 三嗪, 细胞分裂周期25磷酸酯酶B抑制剂

Abstract:

Heterocyclic molecules containing 1,2,4-triazole motif are important for drug screening due to their better broad spectrum of bioactivities. For structure-activity relationship study, twenty-eight novel multi-heterocyclic molecules [TM1TM3(af)] and [TM4TM5(ae)] containing duo 1,2,4-triazole motifs were synthesized by the conjugation with piperazine and s-triazine, respectively. The structures of target molecules were confirmed via infrared(IR), proton nuclear magnetic resonance(¹H NMR) and high resolution mass spectrometry(HRMS). In order to investigate the effect of 4-amino substituent on 1,2,4-triazole for bioactivities, the comparison between compounds 6-morpholine-2,4-(5-thioether-4-amino-3-n-pentyl-1,2,4-triazole)-1,3,5-triazine(C), 6-pyrrole-2,4-(5-mercapto-4-amino-3-n-pentyl-1,2,4-triazole)-1,3,5-triazine(D) and target molecules were also performed. The inhibitory activities against cell division cycle protein 25B(Cdc25B) phosphatases of synthesized molecules were evaluated. Twenty one molecules exhibit good activities, and nine among them are more potent than the positive control Na₃VO₄.

Key words: 1,2,4-triazole, piperazine, s-triazine, cell division cycle protein 25B inhibitor

张成路, 王静, 李益政, 李传银, 孙晓娜. 细胞分裂周期25磷酸酯酶B抑制剂双1,2,4-三唑多杂环分子的设计合成[J]. 应用化学, 2018, 35(2): 154-164.

ZHANG Chenglu, WANG Jing, LI Yizheng, LI Chuanyin, SUN Xiaona. Synthesis and Design of Multi-Heterocyclic Molecules with Duoble 1,2,4-Triazole Motifs as Inhibitors of Cell Division Cycle Protein 25B Phosphatases[J]. Chinese Journal of Applied Chemistry, 2018, 35(2): 154-164.

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