2. Academic Validation
  3. Design, synthesis and biological evaluation of the thioether-containing lenalidomide analogs with anti-proliferative activities

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

  • Eur J Med Chem. 2019 Aug 15:176:419-430. doi: 10.1016/j.ejmech.2019.05.035.
Donghuai Xiao 1,  Yu-Jie Wang 2,  Xiao-Bei Hu 2,  Wei-Juan Kan 2,  Qiumeng Zhang 3,  Xuefeng Jiang 4,  Yu-Bo Zhou 2,  Jia Li 5,  Wei Lu 6
Affiliations

Affiliations

  • 1 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, 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 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, PR China; National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, PR China.
  • 4 Shanghai Key Laboratory of Green Chemistry and Chemical Process, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, PR China.
  • 5 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.
  • 6 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai, 200062, PR China. Electronic address: wlu@chem.ecnu.edu.cn.
PMID: 31125896 DOI: 10.1016/j.ejmech.2019.05.035
Abstract

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 Cmax 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.

Keywords

Anti-Tumor; Lenalidomide; Structural modification; Thioether.

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