Citation: 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 shu

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

Xu Xiaoming ^a,† ,
Guo Siqi ^b,c,† ,
Zhang Jing ^a ,
Chen Yantao ^b ,
Kang Yaqing ^a ,
Liu Na ^a ,
Liu Junfang ^a ,
Luo Cheng ^b ,
Chen Shijie ^b,, ,
Chen Hua ^a,,

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

Corresponding author: Chen Shijie, shijiechen@simm.ac.cn Chen Hua, hua-todd@163.com
Received Date: 7 November 2019
Revised Date: 25 December 2019
Available Online: 15 January 2020
Fund Project: Project supported by the Natural Science Interdisciplinary Research Program of Hebei University (No. DXK201903)the Natural Science Interdisciplinary Research Program of Hebei University DXK201903

Figures(6)

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.
- DOT1L inhibitor,
- ttriazolo-thiadiazole,
- structural modification,
- hydrophobic substituent,
- structure-activity analysis
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