摘要/Abstract
细胞分裂周期25磷酸酯酶B（Cdc25B）与致癌转化有关，是潜在的抗癌疗法的药物靶标.为筛选Cdc25B抑制剂，以1，3-硒唑为核心组块，利用酰胺硫醚键与1，2，4-三唑席夫碱活性组块桥连成目标化合物2-（1，2，4-三唑-3-基）硫代-N-（4-苯基-1，3-硒唑-2-基）乙酰胺（TATS）.首先为验证将1，3-硒唑作为核心组块的合理性，选择了苯环未被修饰的TATS1与Cdc25B进行分子对接模拟，结果表明，1，3-硒唑能紧密地嵌入Cdc25B结构中，与Cdc25B的重要催化位点Arg492发生N-H…PI非键弱相互作用，发挥了核心作用.酰胺羰基氧原子与Arg492和Arg488形成氢键，表明酰胺硫醚键引入合理.在理论对接研究的基础上，通过对1，2，4-三唑席夫碱活性组块中两个区域用不同基团修饰，设计并合成了13个新型目标化合物TATS1~TATS13，对比测试了目标化合物和重要中间体对Cdc25B的抑制活性.结果表明，其中12个目标化合物生物活性优于阳性参照物Na3VO4，1，2，4-三唑席夫碱两个区域的不同修饰对抑制活性有明显影响，实现了活性叠加效应，表明该类结构化合物有望成为潜在的Cdc25B抑制剂.
关键词: 1,3-硒唑, 1,2,4-三唑席夫碱, 分子对接模拟, Cdc25B抑制剂
The cell division cycle 25 phosphatase B (Cdc25B) is involved in carcinogenic transformation and is a potential drug target for anticancer therapy. In order to screen Cdc25B inhibitors, 1,3-selenazole was selected as the core block, and 1,2,4-triazole Schiff base was bridged into 2-(1,2,4-triazol-3-yl)thio-N-(4-phenyl-1,3-selenazolyl-2-yl)acetamide (TATS) by the amide thioether bond. The molecular docking simulation of TATS1 with Cdc25B was first performed to identify the rationality of the core function of 1,3-selenazole. The results show that 1,3-selenazole can be tightly embedded in the Cdc25B structure and perform N-H…PI non-bond weak interaction with the important catalytic site Arg492, which indicates that 1,3-selenazole plays a central role. The amide carbonyl oxygen atom forms a hydrogen bond with Arg492 and Arg488, indicating that the introduction of the amide thioether bond is reasonable. Based on the theoretical docking study, thirteen new target compounds TATS1~TATS13 were designed and synthesized through modification in two regions of 1,2,4-triazole Schiff base. The inhibition against Cdc25B of target molecules and important intermediates was tested respectively. As a result, the inhibitory activities of the intermediates are not good, 12 target compounds have better biological activity than the positive reference substance Na3VO4, the modifications of two regions of 1,2,4-triazole also have a significant effect, which suggests that these compounds are expected to be a potential inhibitor of Cdc25B.
Key words: 1,3-selenazole, 1,2,4-triazole Schiff base, molecular docking simulation, Cdc25B inhibitor
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