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2020 , Vol. 40 >Issue 5: 1345 - 1354

DOI: https://doi.org/10.6023/cjoc201911012

研究论文

三氮唑并噻二唑类DOT1L抑制剂的结构修饰及活性

  • 徐晓明 ,
  • 郭思岐 ,
  • 张静 ,
  • 陈彦韬 ,
  • 康亚青 ,
  • 刘娜 ,
  • 刘俊芳 ,
  • 罗成 ,
  • 陈示洁 ,
  • 陈华
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  • a 河北大学化学与环境科学学院 河北省化学生物学重点实验室 河北保定 071002;
    b 中国科学院上海药物研究所 新药研究国家重点实验室 上海 201203;
    c 南昌大学药学院 南昌 330006

收稿日期: 2019-11-07

  修回日期: 2019-12-25

  网络出版日期: 2020-01-15

基金资助

河北大学自然科学多学科交叉研究计划（No.DXK201903）资助项目.

收起

Structural Modifications of the Triazolo-thiadiazole Derivatives as DOT1L Inhibitors and Their Activities

  • Xu Xiaoming ,
  • Guo Siqi ,
  • Zhang Jing ,
  • Chen Yantao ,
  • Kang Yaqing ,
  • Liu Na ,
  • Liu Junfang ,
  • Luo Cheng ,
  • Chen Shijie ,
  • Chen Hua
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  • a Key Laboratory of Chemical Biology of Hebei Province, College of Chemistry and Environmental Science, Hebei University, Baoding, Hebei 071002;
    b State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 201203;
    c School of Pharmacy, Nanchang University, Nanchang 330006

Received date: 2019-11-07

  Revised date: 2019-12-25

  Online published: 2020-01-15

Supported by

Project supported by the Natural Science Interdisciplinary Research Program of Hebei University (No. DXK201903).

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摘要

以DOT1L（Disruptor of telomeric silencing 1-like）抑制剂（8）为母体结构，对其核心骨架三氮唑并噻二唑两端的取代基进行结构修饰，设计合成了两个系列的三氮唑并噻二唑类结构衍生物，并测试了化合物在浓度为50 μmol/L时的DOT1L酶抑制活性.结果表明，所测化合物均表现出一定的酶抑制活性，其中N，N-二甲基-4-（6-甲基-[1，2，4]三唑并[3，4-b][1，3，4]噻二唑-3-基）苯胺（14b）和（R）-{1-{{3-[4-（二甲基氨基）苯基]-[1，2，4]三唑并[3，4-b][1，3，4]噻二唑-6-基叔丁基}甲基}哌啶-3-基}氨基甲酸叔丁酯（16a）具有显著的DOT1L抑制活性，IC50值分别为7.37和7.84 μmol/L，与阳性对照化合物8的酶抑制活性相当.构效分析表明，当苯基连三氮唑并噻二唑部分占据S-腺苷-L-甲硫氨酸（SAM）结合位点时，R1为4-N，N-二甲基、分子尾部R2基团为疏水基团，适宜于分子与酶的结合，且其体积对活性影响较小.

关键词： DOT1L抑制剂; 三氮唑并噻二唑; 结构改造; 疏水基团; 构效关系

本文引用格式

徐晓明 , 郭思岐 , 张静 , 陈彦韬 , 康亚青 , 刘娜 , 刘俊芳 , 罗成 , 陈示洁 , 陈华 . 三氮唑并噻二唑类DOT1L抑制剂的结构修饰及活性[J]. 有机化学, 2020 , 40(5) : 1345 -1354 . DOI: 10.6023/cjoc201911012

Abstract

A series of novel derivatives containing triazolo-thiadiazole moiety have been synthesized by structural modifications on a lead disruptor of telomeric silencing 1-like (DOT1L) inhibitor 8. All the compounds have been evaluated for their DOT1L inhibitory activities at the concentration of 50 μmol/L. The results showed that the tested compounds showed certain DOT1L inhibitory activities. Among them, N,N-dimethyl-4-(6-methyl-[1,2,4]triazolo[3,4-b] [1,3,4]thiadiazol-3-yl)aniline (14b) and (R)-tert-butyl (1-((3-(4-(dimethylamino)phenyl)-[1,2,4]triazolo[3,4-b] [1,3,4]thiadiazol-6-yl)methyl)-piperidin-3-yl)carba- mate (16a) were the best ones with IC50 values of 7.37 and 7.84 μmol/L, respectively, near that of the positive control 8. The structure-activity analysis showed that when the triazolo-thiadiazole moiety occupied the binding-site of S-adenosylmethionine (SAM) in DOT1L and R1 group was 4-N,N-dimethyl, the hydrophobic substituents as the tailed R2 groups would be accommodated into the DOT1L binding site, and the sizes of the substituents seemed no effects on their DOT1L inhibitory activities of the compounds.

Key words： DOT1L inhibitor; ttriazolo-thiadiazole; structural modification; hydrophobic substituent; structure-activity analysis

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