基于咔唑的单-/双-硫代碳酰腙衍生物的合成及Cdc25B/PTP1B抑制活性评价  

Synthesis and Cdc25B/PTP1B Inhibitory Activity Evaluation of Novel Carbazole-Based Mono-/Bis-thiocarbohydrazone Derivatives

作　　者：李英俊[1] 杨凯栋 靳焜[2] 高立信 盛丽 刘雪洁 杨鸿境 林乐弟 李佳 Li Yingjun;Yang Kaidong;Jin Kun;Gao Lixin;Sheng Li;Liu Xuejie;Yang Hongjing;Lin Ledi;Li Jia(College of Chemistry and Chemical Engineering,Liaoning Normal University,Dalian,Liaoning 116029;State Key Laboratory of Fine Chemicals,Dalian University of Technology,Dalian,Liaoning 116012;National Center for Dmg Screening,State Key Laboratory of Drag Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203)

机构地区：[1]辽宁师范大学化学化工学院,辽宁大连116029 [2]大连理工大学精细化工国家重点实验室,辽宁大连116012 [3]中国科学院上海药物研究所,国家新药筛选中心,药物研究国家重点实验室,上海201203

出　　处：《有机化学》2020年第1期162-174,共13页Chinese Journal of Organic Chemistry

基　　金：辽宁省自然科学基金(No.20102126)资助项目。

摘　　要：合成了一系列新型的基于咔唑的单-/双-硫代碳酰腙衍生物.利用IR、1H NMR、13C NMR和元素分析对其进行了结构表征.评价了目标化合物对Cdc25B和PTP1B的抑制活性,讨论了其结构与活性的关系.实验结果显示,大部分目标化合物对Cdc25B和PTP1B表现出良好的抑制活性.其中,1,5-双[(9-戊基-3-咔唑基)亚甲基]硫代碳酰腙(4d)对Cdc25B的抑制活性最高,IC50为(0.23±0.02)μg/m L.1,5-双[(9-乙基-3-咔唑基)亚甲基]硫代碳酰腙(4a)对PTP1B的抑制活性最高, IC50为(1.00±0.16)μg/m L.对目标化合物4a和4d进行分子对接研究和密度泛函理论(DFT)计算,结果表明,目标化合物4d和4a分别进入到了Cdc25B和PTP1B酶的活性位点区域,有活性作用的主要是硫代碳酰腙和咔唑基团.A series of novel carbazole-based mono-/bis-thiocarbohydrazone derivatives were synthesized. Their structures were characterized by IR, 1 H NMR, 13 C NMR spectra and elemental analysis. The inhibitory activities of the target compounds against Cdc25 B/PTP1 B were evaluated, and the relationship between structure and activity was discussed. The results showed that most of the target compounds had good inhibitory activity against Cdc25 B and PTP1 B. Among them, 1,5-bis[(9-pentyl-3-carbazolyl)methylene]thiocarbohydrazone(4 d) had the highest inhibitory activity against Cdc25 B with IC50=(0.23±0.02) μg/m L, and 1,5-bis[(9-ethyl-3-carbazolyl)methylene]thiocarbohydrazone(4 a) had the highest inhibitory activity against PTP1 B with IC50=(1.00±0.16) μg/m L. Molecular docking and density functional theory(DFT) calculations of the target compounds 4 a and 4 d were performed. Molecular docking results indicated that the target compounds 4 d and 4 a entered the active sites of Cdc25 B and PTP1 B enzymes, respectively, and thiocarbohydrazone and carbazole groups play the importent role of activity.

关 键 词：硫代碳酰腙 咔唑 合成 Cdc25B和PTP1B抑制剂 分子对接 DFT计算 

分 类 号：TQ463[化学工程—制药化工]