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

doi:10.6023/cjoc201911012

	Structural Modifications of the Triazolo-thiadiazole Derivatives as DOT1L Inhibitors and Their Activities
	Xu Xiaoming 2; Guo Siqi 1,3; Zhang Jing 2; Chen Yantao 1; Kang Yaqing 2; Liu Na 2; Liu Junfang 2; Luo Cheng 1; Chen Shijie 1; Chen Hua 2
刊名	CHINESE JOURNAL OF ORGANIC CHEMISTRY
	2020-05-25
卷号	40 期号:5 页码:1345-1354
关键词	DOT1L inhibitor ttriazolo-thiadiazole structural modification hydrophobic substituent structure-activity analysis
ISSN号	0253-2786
DOI	10.6023/cjoc201911012
通讯作者	Chen Shijie(shijiechen@simm.ac.cn) ; Chen Hua(hua-todd@163.com)
英文摘要	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 mu mol/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)carbamate (16a) were the best ones with IC50 values of 7.37 and 7.84 mu mol/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 R-1 group was 4-N,N-dimethyl, the hydrophobic substituents as the tailed R-2 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.
资助项目	Natural Science Interdisciplinary Research Program of Hebei University[DXK201903]
WOS关键词	ACCURATE DOCKING ; LEUKEMIA-CELLS ; POTENT ; DESIGN ; GLIDE ; DISRUPTOR ; DISCOVERY
WOS研究方向	Chemistry
语种	英语
出版者	SCIENCE PRESS
WOS记录号	WOS:000550196500026
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/292000]
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	Xu Xiaoming,Guo Siqi,Zhang Jing,et al. Structural Modifications of the Triazolo-thiadiazole Derivatives as DOT1L Inhibitors and Their Activities[J]. CHINESE JOURNAL OF ORGANIC CHEMISTRY,2020,40(5):1345-1354.
APA	Xu Xiaoming.,Guo Siqi.,Zhang Jing.,Chen Yantao.,Kang Yaqing.,...&Chen Hua.(2020).Structural Modifications of the Triazolo-thiadiazole Derivatives as DOT1L Inhibitors and Their Activities.CHINESE JOURNAL OF ORGANIC CHEMISTRY,40(5),1345-1354.
MLA	Xu Xiaoming,et al."Structural Modifications of the Triazolo-thiadiazole Derivatives as DOT1L Inhibitors and Their Activities".CHINESE JOURNAL OF ORGANIC CHEMISTRY 40.5(2020):1345-1354.