Chinese Journal of Organic Chemistry ›› 2020, Vol. 40 ›› Issue (5): 1345-1354.DOI: 10.6023/cjoc201911012 Previous Articles     Next Articles


徐晓明a, 郭思岐b,c, 张静a, 陈彦韬b, 康亚青a, 刘娜a, 刘俊芳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:2019-11-07 修回日期:2019-12-25 发布日期:2020-01-15
  • 通讯作者: 陈示洁, 陈华;
  • 基金资助:

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

Xu Xiaominga, Guo Siqib,c, Zhang Jinga, Chen Yantaob, Kang Yaqinga, Liu Naa, Liu Junfanga, 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:2019-11-07 Revised:2019-12-25 Published:2020-01-15
  • Supported by:
    Project supported by the Natural Science Interdisciplinary Research Program of Hebei University (No. DXK201903).

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