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

doi:10.6023/cjoc201910037

	Design, Synthesis, and Biological Activities of Novel Triazolothiadiazole Derivatives Linked with Amino Side Chain Containing Urea Group as DOT1L Inhibitors
	Liu Na 2; Guo Siqi 1,3; Liu Junfang 2; Chen Yantao 1; Xu Xiaoming 2; Zhang Jing 2; Kang Yaqing 2; Luo Cheng 1; Chen Shijie 1; Chen Hua 2
刊名	CHINESE JOURNAL OF ORGANIC CHEMISTRY
	2020-08-25
卷号	40 期号:8 页码:2450-2459
关键词	DOT1L inhibitor triazolothiadiazole triazolothiadiazine nucleophilic substitution
ISSN号	0253-2786
DOI	10.6023/cjoc201910037
通讯作者	Chen Shijie(shijiechen@simm.ac.cn) ; Chen Hua(hua-todd@163.com)
英文摘要	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 similar to 15k, while under the condition of strong base (NaH), the new dimeric structure analogues 22a similar to 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 mu mol.L-1. Among them, compounds 15k and 22a were the best ones with IC50 values of 25.92 and 10.59 mu mol.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
资助项目	Natural Science Interdisciplinary Research Program of Hebei University[DXK201903]
WOS关键词	ACCURATE DOCKING ; LEUKEMIA-CELLS ; POTENT ; GLIDE ; DISRUPTOR ; DISCOVERY
WOS研究方向	Chemistry
语种	英语
出版者	SCIENCE PRESS
WOS记录号	WOS:000581125800022
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/292631]
专题	中国科学院上海药物研究所
通讯作者	Chen Shijie; Chen Hua
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 2.Hebei Univ, Coll Chem & Environm Sci, Key Lab Chem Biol Hebei Prov, Baoding 071002, Hebei, Peoples R China 3.Nanchang Univ, Sch Pharm, Nanchang 330006, Jiangxi, Peoples R China
推荐引用方式 GB/T 7714	Liu Na,Guo Siqi,Liu Junfang,et al. 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.
APA	Liu Na.,Guo Siqi.,Liu Junfang.,Chen Yantao.,Xu Xiaoming.,...&Chen Hua.(2020).Design, Synthesis, and Biological Activities of Novel Triazolothiadiazole Derivatives Linked with Amino Side Chain Containing Urea Group as DOT1L Inhibitors.CHINESE JOURNAL OF ORGANIC CHEMISTRY,40(8),2450-2459.
MLA	Liu Na,et al."Design, Synthesis, and Biological Activities of Novel Triazolothiadiazole Derivatives Linked with Amino Side Chain Containing Urea Group as DOT1L Inhibitors".CHINESE JOURNAL OF ORGANIC CHEMISTRY 40.8(2020):2450-2459.