Design, synthesis and biological evaluation of the thioether-containing lenalidomide analogs with anti-proliferative activities

doi:10.1016/j.ejmech.2019.05.035

	Design, synthesis and biological evaluation of the thioether-containing lenalidomide analogs with anti-proliferative activities
	Xiao, Donghuai 1; Wang, Yu-jie 2,3; Hu, Xiao-bei 2,3; Kan, Wei-juan 2,3; Zhang, Qiumeng 1,2; Jiang, Xuefeng 4; Zhou, Yu-bo 2,3; Li, Jia 2,3; Lu, Wei 1
刊名	EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
	2019-08-15
卷号	176 页码:419-430
关键词	Lenalidomide Thioether Anti-Tumor Structural modification
ISSN号	0223-5234
DOI	10.1016/j.ejmech.2019.05.035
通讯作者	Li, Jia(jii@simm.dc.cn) ; Lu, Wei(wiu@chem.ecnu.edu.cn)
英文摘要	Lenalidomide and its analogs have exhibited extensive anti-tumor, anti-inflammatory and immunomodulatory properties in pharmaceutical research. In this work, a series of novel thioether-containing lenalidomide analogs were designed and synthesized for biological evaluation. Lenalidomide showed significant anti-proliferative activity against the MM.1S cell line (IC50 = 50 nM) while it displayed no anti proliferative activity against other treated tumor cell lines. Compared with lenalidomide, compound 3j exhibited preferable anti-proliferative activity against the MM.1S (IC50= 1.1 nM), Mino (IC50 = 2.3 nM) and RPMI 8226 cell lines (IC50= 5.5 nM). In addition, compound 3j displayed selective anti-proliferative activity against several tumor cell lines, including various B-NHL, MM and AML cell lines, and showed no cytotoxicity on the normal human cell line PBMC, suggesting a good safety profile. Following oral administration, compound 3j achieved a C-max of 283 ng/mL at 0.83 h, and had a higher relative oral bioavailability value (F = 39.2%) than that of CC-220 (F = 22.8%), but its oral exposure in vivo was somewhat low (AUC = 755 h ng/mL). Furthermore, it was found that oral administration of compound 3j at dosages of 60 mg/kg could delay RPMI 8226 tumor growth in the female CB-17 SCID mice. The current work confirmed that installing thioether moiety at the 4-position of isoindolinone is an effective strategy for identifying new promising lenalidomide analogs with anti-tumor activities in preclinical study. (C) 2019 Elsevier Masson SAS. All rights reserved.
资助项目	Shanghai Science and Technology Council[16DZ2280100] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program[2018ZX09711002-008-004]
WOS关键词	NATURAL-KILLER-CELL ; POTENT INHIBITORS ; T-CELLS ; THALIDOMIDE ; DEGRADATION ; POMALIDOMIDE ; MODULATION ; SULFONE ; IDENTIFICATION ; DEXAMETHASONE
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
WOS记录号	WOS:000472686100029
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/289519]
专题	中国科学院上海药物研究所
通讯作者	Li, Jia; Lu, Wei
作者单位	1.East China Normal Univ, Shanghai Engn Res Ctr Mol Therapeut & New Drug De, Sch Chem & Mol Engn, 3663 North Zhongshan Rd, Shanghai 200062, Peoples R China 2.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China 4.East China Normal Univ, Sch Chem & Mol Engn, Shanghai Key Lab Green Chem & Chem Proc, 3663 North Zhongshan Rd, Shanghai 200062, Peoples R China
推荐引用方式 GB/T 7714	Xiao, Donghuai,Wang, Yu-jie,Hu, Xiao-bei,et al. Design, synthesis and biological evaluation of the thioether-containing lenalidomide analogs with anti-proliferative activities[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2019,176:419-430.
APA	Xiao, Donghuai.,Wang, Yu-jie.,Hu, Xiao-bei.,Kan, Wei-juan.,Zhang, Qiumeng.,...&Lu, Wei.(2019).Design, synthesis and biological evaluation of the thioether-containing lenalidomide analogs with anti-proliferative activities.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,176,419-430.
MLA	Xiao, Donghuai,et al."Design, synthesis and biological evaluation of the thioether-containing lenalidomide analogs with anti-proliferative activities".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 176(2019):419-430.