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

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, 33, 42 and 42 showed strong potencies against all tested cell lines with IC values ranging from 14.63 to 49.90 µM comparable to that of thalidomide (IC 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 and 42 showed a significant reduction in TNF-α. Furthermore, compounds 33 and 42 exhibited significant elevation in CASP8 levels. Compounds 33 and 42 inhibited VEGF. In addition, compound 42 showed significant decrease in levels of NF-κB p65. Moreover, apoptosis and cell cycle tests of the most active compound 42, were performed. The results indicated that compound 42 significantly induce apoptosis in HCT-116 cells and arrest cell cycle at the G2/M phase.