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Design, synthesis and biological evaluation of thioether-containing lenalidomide and pomalidomide derivatives with anti-multiple myeloma activity

文献类型：期刊论文

作者Wang, Yuhong4; Mi, Tian1,2; Li, Yiming4; Kan, Weijuan1,2; Xu, Gaoya1,2; Li, Jingya1,2; Zhou, Yubo1,2; Li, Jia1,2; Jiang, Xuefeng3,4
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2021
卷号209页码:13
关键词Lenalidomide Multiple myeloma MM.1S Late-stage sulfuration
ISSN号0223-5234
DOI10.1016/j.ejmech.2020.112912
通讯作者Li, Jia(jli@simm.ac.cn) ; Jiang, Xuefeng(xfjiang@chem.ecnu.edu.cn)
英文摘要Lenalidomide and its analogs are well-known for treating multiple myeloma. In this work, designed sulfide-modified lenalidomide and pomalidomide were synthesized and evaluated. The anti-proliferative activity against MM.1S cell line of 3ak (IC50 = 79 nM) was similar to lenalidomide (IC50 = 81 nM). Compared to benzylic thioether substituted lenalidomide 3a, the half-live (T-1/2) of 4-F-phenyl-thioether analogs 3ak in human liver microsomes was promoted from 3 min to 416.7 min. The corresponding metabolic factor of 3ak was increased from 2.8% to 79.5%, which was slightly lower than lenalidomide (91.5%). Moreover, the IKZF1 degradation of 3y and 3ak was well related with corresponding IC50 values, which suggested the IKZF1 degradation efficiency is correlated to the responses of MM1. S cells. Furthermore, the oral administration of compounds 3y and 3ak at dosages of 60 mg/kg could delay tumor growth in female CB-17 SCID mice. This research helped to prompt the stability of thioether lenalidomide analogs, which paved the way for developing better molecules for treating multiple myeloma. (C) 2020 Elsevier Masson SAS. All rights reserved.
WOS关键词BOND FORMATION ; THERAPY ; SULFUR ; CEREBLON ; ANALOGS ; CELLS
资助项目National Key Research and Development Program of China[2017YFD0200500] ; National Major Scientific and Technological Special Project for Significant New Drugs Development[2018ZX09711002-008004] ; NSFC[21971065] ; NSFC[21722202] ; NSFC[21672069] ; STCSM[20XD1421500] ; STCSM[20JC1416800] ; STCSM[18JC1415600] ; Shanghai Institutions of Higher Learning
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000600418500052
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/296399]  
专题新药研究国家重点实验室
通讯作者Li, Jia; Jiang, Xuefeng
作者单位1.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, 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.Chinese Acad Sci, Shanghai Inst Organ Chem, State Key Lab Organometall Chem, Shanghai, Peoples R China
4.East China Normal Univ, Dept Chem, 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		 Wang, Yuhong,Mi, Tian,Li, Yiming,et al. Design, synthesis and biological evaluation of thioether-containing lenalidomide and pomalidomide derivatives with anti-multiple myeloma activity[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2021,209:13.
APA Wang, Yuhong.,Mi, Tian.,Li, Yiming.,Kan, Weijuan.,Xu, Gaoya.,...&Jiang, Xuefeng.(2021).Design, synthesis and biological evaluation of thioether-containing lenalidomide and pomalidomide derivatives with anti-multiple myeloma activity.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,209,13.
MLA Wang, Yuhong,et al."Design, synthesis and biological evaluation of thioether-containing lenalidomide and pomalidomide derivatives with anti-multiple myeloma activity".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 209(2021):13.

入库方式： OAI收割

来源：上海药物研究所

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