基于咔唑的新型碳酰腙衍生物的合成及蛋白酪氨酸磷酸酶1B(PTP1B)抑制活性评价  

Synthesis and Protein Tyrosine Phosphatase 1B(PTP1B) Inhibitory Activity Evaluation of Novel Carbazole-Based Carbohydrazone Derivatives

作　　者：李英俊[1] 刘雪洁 刘季红[2] 高立信 靳焜[4] 盛丽 杨鸿境 林乐弟 李佳 Li Yingjun;Liu Xuejie;Liu Jihong;Gao Lixin;Jin Kun;Sheng Li;Yang Hongjing;Lin Ledi;Li Jia(College of Chemistry and Chemical Engineering,Liaoning Normal University,Dalian 116029;Chemistry Analysis and Inspection Center,Dalian University of Technology,Dalian 116023;National Center for Drug Screening,State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai 201203;State Key Laboratory of Fine Chemicals,Dalian University of Technology,Dalian 116012)

机构地区：[1]辽宁师范大学化学化工学院,大连116029 [2]大连理工大学化学分析测试中心,大连116023 [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 [4]大连理工大学精细化工国家重点实验室,大连116012

出　　处：《有机化学》2020年第2期478-488,共11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：合成出了一系列新型基于咔唑的单-/双-碳酰腙衍生物3和4.利用1H NMR、13C NMR、IR和元素分析对其进行了结构表征.评价了目标化合物对蛋白酪氨酸磷酸酶1B(PTP1B)的抑制活性,讨论了结构与活性的关系.实验结果显示,大部分化合物对PTP1B具有良好的抑制活性,其中1,5-双[(9-丁基-3-咔唑基)亚甲基]碳酰腙(4c)的抑制活性最高,IC50=(4.81±0.41)mmol/L,且活性高于对照药物齐墩果酸.对目标化合物1-[(9-庚基-3-咔唑基)亚甲基]碳酰腙(3f)和4c进行分子对接研究和密度泛函理论(DFT)计算.分子对接结果表明,化合物3f和4c结合到PTP1B酶由螺旋α3和α6形成的活性位点,与PTP1B酶通过氢键、极性、疏水和p-p等相互作用形成了稳定的复合物.A series of novel carbazole-based mono-/bis-carbohydrazone derivatives 3 and 4 were synthesized. Their structures were characterized by 1 H NMR, 13 C NMR, IR spectra and elemental analysis. The inhibitory activities of all synthesized compounds against protein tyrosine phosphatase 1 B(PTP1 B) were evaluated, and the structure-activity relationship was discussed.The results indicated that most of the compounds had good inhibitory activity against PTP1 B, and 1,5-bis[(9-butyl-3-carbazolyl)methylene]carbohydrazone(4 c) showed the highest inhibitory activity against PTP1 B with IC50=(4.81±0.41) mmol/L and the activity was higher than that of the control drug oleanolic acid. Molecular docking and density functional theory(DFT)calculations of 3 f and 4 c were carried out. The results of molecular docking indicated that 1-[(9-heptyl-3-carbazolyl)methylene]carbohydrazone(3 f) and 4 c bind to an active site of PTP1 B enzyme formed by the helices α3 and α6, and formed a stable complex respectively with PTP1 B enzyme by hydrogen bonds, polar, hydrophobic and p-p interactions.

关 键 词：碳酰腙 咔唑 合成 PTP1B抑制剂 分子对接 DFT计算 

分 类 号：TQ460.1[化学工程—制药化工]