酰胺硫醚桥连1,3-硒唑和1,2,4-三唑衍生物合成及其对细胞分裂周期25磷酸酯酶B(Cdc25B)抑制活性  

Synthesis of Amide Thioether Bridged 1,3-Selenazole and 1,2,4-Triazole Derivatives and Their Inhibitory Activity against Cell Division Cycle Phosphatase B(Cdc25B)

作　　者：张成路[1] 王华玉 于向坤 杨敬怡 李传银[1] 宫荣庆 宋府璐 孙越冬 Zhang Chenglu;Wang Huayu;Yu Xiangkun;Yang Jingyi;Li Chuanyin;Gong Rongqin;Song Fulu;Sun Yuedong(School of Chemistry and Chemical Engineering,Liaoning Normal University,Dalian 116029)

机构地区：[1]辽宁师范大学化学化工学院,大连116029

出　　处：《有机化学》2020年第2期432-439,共8页Chinese Journal of Organic Chemistry

基　　金：辽宁省教育厅科学技术研究(No.2009A426)资助项目。

摘　　要：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.The cell division cycle 25 phosphatase B(Cdc25 B) is involved in carcinogenic transformation and is a potential drug target for anticancer therapy. In order to screen Cdc25 B 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 Cdc25 B 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 Cdc25 B 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 Cdc25 B 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 Na3 VO4, 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 Cdc25 B.

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 

分 类 号：TQ460.1[化学工程—制药化工] O626[理学—有机化学]