Design, synthesis, and biological evaluation of new challenging thalidomide analogs as potential anticancer...

Thalidomide and its analogs are immunomodulatory drugs that inhibit the production of certain inflammatory mediators associated with cancer. In the present work, a new series of thalidomide analogs was designed and synthesized to obtain new effective antitumor immunomodulatory agents. The synthesized compounds were evaluated for their cytotoxic activities against a panel of four cancer cell lines (HepG-2, HCT-116, PC3 and MCF-7). Compounds 33_h, 33_i, 42_f and 42_h showed strong potencies against all tested cell lines with IC₅₀ values ranging from 14.63 to 49.90 µM comparable to that of thalidomide (IC₅₀ values ranging from 32.12 to 76.91 µM). The most active compounds were further evaluated for their in vitro immunomodulatory activities via estimation of human tumor necrosis factor alpha (TNF-α), human caspase-8 (CASP8), human vascular endothelial growth factor (VEGF), and nuclear factor kappa-B P65 (NF-κB P65) in HCT-116 cells. Thalidomide was used as a positive control. Compounds 33_h and 42_f showed a significant reduction in TNF-α. Furthermore, compounds 33_i and 42_f exhibited significant elevation in CASP8 levels. Compounds 33_i and 42_f inhibited VEGF. In addition, compound 42_f showed significant decrease in levels of NF-κB p65. Moreover, apoptosis and cell cycle tests of the most active compound 42_f, were performed. The results indicated that compound 42_f significantly induce apoptosis in HCT-116 cells and arrest cell cycle at the G2/M phase.