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

doi:10.6023/cjoc201911012

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

三氮唑并噻二唑类DOT1L抑制剂的结构修饰及活性

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

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 E-mail:shijiechen@simm.ac.cn;hua-todd@163.com
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.

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

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).

1. 201345S.pdf(1493KB)

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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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.

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三氮唑并噻二唑类DOT1L抑制剂的结构修饰及活性

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

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