Citation: Liu Na, Guo Siqi, Liu Junfang, Chen Yantao, Xu Xiaoming, Zhang Jing, Kang Yaqing, Luo Cheng, Chen Shijie, Chen Hua. Design, Synthesis, and Biological Activities of Novel Triazolothiadiazole Derivatives Linked with Amino Side Chain Containing Urea Group as DOT1L Inhibitors[J]. Chinese Journal of Organic Chemistry, ;2020, 40(8): 2450-2459. doi: 10.6023/cjoc201910037 shu

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

Liu Na ^a,† ,
Guo Siqi ^b,c,† ,
Liu Junfang ^a ,
Chen Yantao ^b ,
Xu Xiaoming ^a ,
Zhang Jing ^a ,
Kang Yaqing ^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: 29 October 2019
Revised Date: 13 January 2020
Available Online: 25 May 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(8)

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.
- DOT1L inhibitor,
- triazolothiadiazole,
- triazolothiadiazine,
- nucleophilic substitution
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沈阳化工大学材料科学与工程学院沈阳 110142

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

南开大学师唯/华北电力大学（保定）刘景维：二维配位聚合物中有序的亲锂冠醚位点用于无枝晶锂沉积

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通讯作者: 陈斌, bchen63@163.com