Structure-activity relationship study of a series of nucleoside derivatives bearing sulfonamide scaffold as potent and selective PRMT5 inhibitors

doi:10.1016/j.bioorg.2022.106228

	Structure-activity relationship study of a series of nucleoside derivatives bearing sulfonamide scaffold as potent and selective PRMT5 inhibitors
	Chen, Yuting 1,3; Shi, Qiongyu 4; Yang, Hong 2; Li, Jiayi 3,5; Zhou, Kaixin2,3,6 ; Zhang, Junjie 1,3; Wang, Zekun 2,3; Shi, Huanyu 1,3; Xiong, Bing 1,3; Liu, Jia 1,5; Huang, Xun 3,4,5; Liu, Tongchao 1
	2023
发表期刊	BIOORGANIC CHEMISTRY (IF:4.5[JCR-2023],4.7[5-Year])
ISSN	0045-2068
EISSN	1090-2120
卷号	130
发表状态	已发表
DOI	10.1016/j.bioorg.2022.106228
摘要	Protein arginine methyltransferase 5 (PRMT5) is a promising target for the treatment of malignant tumors. The discovery of nucleoside-derived inhibitors against PRMT5 with novel scaffold has been challenging. Herein, we report our effort on the design and synthesis of nucleoside derivatives bearing sulfonamide scaffold as potent PRMT5 inhibitors. The representative compound 23n was identified as a potent and selective PRMT5 inhibitor with an IC value of 8 nM. Molecular docking study demonstrated the binding mode of compound 23n and illustrated its inhibitory activity to PRMT5. The Trimethyl Lock prodrug strategy was used to afford prodrug 36 with lower polarity which could rapidly release the active compound 23n after entering the tumor cells. Cell-based assays revealed that the prodrug 36 restrained the proliferation of Z-138 and MOLM-13 cells and suppressed methylation of PRMT5 substrate more potently than 23n. Additionally, both compound 23n and 36 exerted antiproliferative effects against Z-138 cells mainly by inducing apoptosis effectively rather than arresting cell cycle. Thus, compounds 23n and 36 represent a series of potent PRMT5 inhibitor with novel scaffold.
关键词	Epigenetic Nucleoside derivatives PRMT5 inhibitor Structure-activity Relationship, Prodrug
URL	查看原文
收录类别	SCOPUS
语种	英语
Scopus 记录号	2-s2.0-85141391741
来源库	Scopus
引用统计	正在获取...
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/251407
专题	生命科学与技术学院_博士生
通讯作者	Xiong, Bing
作者单位	1.Department of Medicinal Chemistry,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,555 Zuchongzhi Road,201203,China 2.Division of Antitumor Pharmacology,State Key Laboratory of Drug Research,Shanghai Institute of Materia Medica,Chinese Academy of Sciences,Shanghai,555 Zuchongzhi Road,201203,China 3.University of Chinese Academy of Sciences,Beijing,NO.19A Yuquan Road,100049,China 4.Lingang Laboratory,Shanghai,200031,China 5.Hangzhou Institute for Advanced Study,UCAS,Hangzhou,310024,China 6.School of Life Science and Technology,ShanghaiTech University,Shanghai,201210,China
推荐引用方式 GB/T 7714	Chen, Yuting,Shi, Qiongyu,Yang, Hong,et al. Structure-activity relationship study of a series of nucleoside derivatives bearing sulfonamide scaffold as potent and selective PRMT5 inhibitors[J]. BIOORGANIC CHEMISTRY,2023,130.
APA	Chen, Yuting.,Shi, Qiongyu.,Yang, Hong.,Li, Jiayi.,Zhou, Kaixin.,...&Liu, Tongchao.(2023).Structure-activity relationship study of a series of nucleoside derivatives bearing sulfonamide scaffold as potent and selective PRMT5 inhibitors.BIOORGANIC CHEMISTRY,130.
MLA	Chen, Yuting,et al."Structure-activity relationship study of a series of nucleoside derivatives bearing sulfonamide scaffold as potent and selective PRMT5 inhibitors".BIOORGANIC CHEMISTRY 130(2023).