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Chinese Journal of Organic Chemistry >

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

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

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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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

Cite this article

Xu Xiaoming , Guo Siqi , Zhang Jing , Chen Yantao , Kang Yaqing , Liu Na , Liu Junfang , Luo Cheng , Chen Shijie , Chen Hua . Structural Modifications of the Triazolo-thiadiazole Derivatives as DOT1L Inhibitors and Their Activities[J]. Chinese Journal of Organic Chemistry, 2020 , 40(5) : 1345 -1354 . DOI: 10.6023/cjoc201911012

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