Design, synthesis and anti leukemia cells proliferation activities of pyrimidylaminoquinoline derivatives as DOT1L inhibitors

doi:10.1016/j.bioorg.2018.07.022

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	Design, synthesis and anti leukemia cells proliferation activities of pyrimidylaminoquinoline derivatives as DOT1L inhibitors
	Zhang, Li 2; Chen, Yantao 3,4; Liu, Na 2; Li, Linjuan 1,3,4; Xiao, Senhao 1,3,4; Li, Xiaoliu 2; Chen, Kaixian3,4 ; Luo, Cheng3,4 ; Chen, Shijie 3,4; Chen, Hua 2
刊名	BIOORGANIC CHEMISTRY
	2018-10
卷号	80 页码:649-654
关键词	Pyrimidylaminoquinoline Nonnucleoside DOT1L inhibitors Amino side chains Mixed-linage leukemia Histone lysine methyltransferase
ISSN号	0045-2068
DOI	10.1016/j.bioorg.2018.07.022
文献子类	Article
英文摘要	A series of novel pyrimidylaminoquinoline derivatives 8(a-i) and 9(a-i) containing amino side chain, and the bisaminoquinoline analogs 3(b-e) have been designed and synthesized by structural modifications on a lead DOT1L inhibitor, 3a. All the compounds have been evaluated for their DOT1L inhibitory activities. The results showed that most of the compounds have strong anti DOT1L activities. Compounds 3e, 8h and 9e are the most potential ones from each category with the IC50 values of 1.06 +/- 0.35 mu M, 5.72 +/- 1.56 mu M and 3.55 +/- 1.28 mu M, respectively. Such inhibitors expressed significant binding interactions with DOT1L by surface plasmon resonance (SPR)-based binding assay. The results of molecular docking experiments suggested that they could occupy the SAM binding pocket of DOT1L. Compounds 8h and 9e exhibited better inhibitory activities but poor selectivities against the both MLL-rearranged MV4-11 cells and the non MLL-rearranged Kasumi-1 cells than those of 3a and 3e, which suggested that the introduction of the amino side chain would be beneficial for their anti leukemia cells proliferation activities, possibly due to the improvement of the fat solubility. Additionally, the direct cellular inhibition activities were found that compound 9e could effectively down-regulate both the level of H3k79 methylation and MLL-rearranged leukemia gene expression of Hoxa9 and Meisl in MV4-11 in the qRT-PCR and western blot studies. These observations suggested DOT1L was one of the potential targets but perhaps not the most pivotal one for these compounds, which made their poor selectivities against leukemia cells proliferation.
资助项目	National Natural Science Foundation of China[21472208] ; National Natural Science Foundation of China[81625022] ; National Natural Science Foundation of China[81703415] ; National Natural Science Foundation of China[81430084] ; Shanghai Sailing Program[17YF1423100] ; Hebei Province Natural Science Fund[B2016201031]
WOS关键词	HISTONE METHYLTRANSFERASE DOT1L ; H3K79 METHYLATION ; ACCURATE DOCKING ; POTENT ; DISCOVERY ; GLIDE ; DISRUPTOR
WOS研究方向	Biochemistry & Molecular Biology ; Chemistry
语种	英语
出版者	ACADEMIC PRESS INC ELSEVIER SCIENCE
WOS记录号	WOS:000441537800068
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279565]
专题	药物发现与设计中心中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Chen, Shijie; Chen, Hua
作者单位	1.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai 200031, Peoples R China 2.Hebei Univ, Key Lab Chem Biol Hebei Prov, Coll Chem & Environm Sci, Baoding 071002, Peoples R China; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China;
推荐引用方式 GB/T 7714	Zhang, Li,Chen, Yantao,Liu, Na,et al. Design, synthesis and anti leukemia cells proliferation activities of pyrimidylaminoquinoline derivatives as DOT1L inhibitors[J]. BIOORGANIC CHEMISTRY,2018,80:649-654.
APA	Zhang, Li.,Chen, Yantao.,Liu, Na.,Li, Linjuan.,Xiao, Senhao.,...&Chen, Hua.(2018).Design, synthesis and anti leukemia cells proliferation activities of pyrimidylaminoquinoline derivatives as DOT1L inhibitors.BIOORGANIC CHEMISTRY,80,649-654.
MLA	Zhang, Li,et al."Design, synthesis and anti leukemia cells proliferation activities of pyrimidylaminoquinoline derivatives as DOT1L inhibitors".BIOORGANIC CHEMISTRY 80(2018):649-654.