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

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.