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

Eur J Med Chem. 2021 Jan 1:209:112912. doi: 10.1016/j.ejmech.2020.112912.

Yuhong Wang ¹, Tian Mi ², Yiming Li ¹, Weijuan Kan ², Gaoya Xu ², Jingya Li ², Yubo Zhou ², Jia Li ³, Xuefeng Jiang ⁴

Affiliations

1 Shanghai Key Laboratory of Green Chemistry and Chemical Process, Department of Chemistry, East China Normal University, 3663 North Zhongshan Rd., Shanghai, 200062, PR China.
2 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, PR China.
3 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China; University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing, 100049, PR China. Electronic address: jli@simm.ac.cn.
4 Shanghai Key Laboratory of Green Chemistry and Chemical Process, Department of Chemistry, East China Normal University, 3663 North Zhongshan Rd., Shanghai, 200062, PR China; State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, PR China. Electronic address: xfjiang@chem.ecnu.edu.cn.

PMID: 33328101 DOI: 10.1016/j.ejmech.2020.112912

Abstract

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.

Keywords

Late-stage sulfuration; Lenalidomide; MM.1S; Multiple myeloma.

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