Chinese Journal of Organic Chemistry ›› 2020, Vol. 40 ›› Issue (8): 2450-2459.DOI: 10.6023/cjoc201910037 Previous Articles     Next Articles


刘娜a, 郭思岐b,c, 刘俊芳a, 陈彦韬b, 徐晓明a, 张静a, 康亚青a, 罗成b, 陈示洁b, 陈华a   

  1. 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:2019-10-29 修回日期:2020-01-13 发布日期:2020-05-28
  • 通讯作者: 陈示洁, 陈华;
  • 基金资助:

Design, Synthesis, and Biological Activities of Novel Triazolothiadiazole Derivatives Linked with Amino Side Chain Containing Urea Group as DOT1L Inhibitors

Liu Naa, Guo Siqib,c, Liu Junfanga, Chen Yantaob, Xu Xiaominga, Zhang Jinga, Kang Yaqinga, Luo Chengb, Chen Shijieb, Chen Huaa   

  1. 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:2019-10-29 Revised:2020-01-13 Published:2020-05-28
  • Supported by:
    Project supported by the Natural Science Interdisciplinary Research Program of Hebei University (No. DXK201903).

Based on the drug design method of combination of privileged fragments, a series of novel triazolothiadiazole derivatives linked with amino side chain containing urea group were designed as potential DOT1L (disruptor of telomeric silencing 1-like) inhibitors. The intermediate 13 with benzyl chloride on triazolothiadiazole structure was synthesized from aromatic acid through five steps. Under the condition of weak base (DIPEA), the nucleophilic substitution reaction between 13 and amino chain with urea group resulted in triazolothiadiazole derivatives linked with amino side chain containing urea group 15a~15k, while under the condition of strong base (NaH), the new dimeric structure analogues 22a~22d bearing with triazolothiadiazole-triazolothiadiazine were obtained by intermolecular reaction of two molecules of 13. The inhibitory activities of compounds 15 and 22 against DOT1L were tested. The results showed that the tested compounds exhibited moderate or weak DOT1L inhibitory activities at 50 μmol·L-1. Among them, compounds 15k and 22a were the best ones with IC50 values of 25.92 and 10.59 μmol·L-1, respectively, lower than that of the positive control (E)-6-(2-(furan-2-yl)vinyl)-3-phenyl-[1,2, 4]triazolo[3,4-b] [1,3,4]thiadiazole (10). The results of docking experiments suggested that the bulky amino-urea side chain might be the main reason for the loss of the activities of the compounds, which sterically hindered the molecular from binding to the DOT1L enzyme.

Key words: DOT1L inhibitor, triazolothiadiazole, triazolothiadiazine, nucleophilic substitution