Discovery of New Immunomodulatory Anticancer Thalidomide Analogs: Design, Synthesis, Biological Evaluation and In Silico Studies

Abstract

New thalidomide analogs have been designed and synthesized by hybridizing the immunomodulatory gutarimide moiety with three antiproliferative nuclei: quinazolinedione, phthalazinedione, and quinoxalinone. The biological results revealed the strong impact of quinazoline derivatives 7a and 28, and phthalazine based 20a against HepG‐2, MCF‐7, PC3, and HCT‐116 cell lines, compared to thalidomide. In particular, compound 20a was the most promising as it had far better biological activity than thalidomide with regard to inhibition of TNF‐α, IL‐6, caspase 3, COX‐I/II, and VEGFR‐2, as well as cell cycle arrest, and apoptosis rate enhancement in MCF‐7 cells, the most sensitive cell line to the current new molecules. Compound 20a caused reduction in levels of TNF‐α and IL‐6 by 75.22% and 82.51%, respectively. It elevated the caspase‐3 level by 7.21‐fold. Furthermore, IC50 against COX‐I, COX‐II, and VEGFR‐2 were 0.65 μM, 0.33 μM, and 232 nM, respectively. In addition, it raised the apoptosis rate from 65.65% to 99.89%. Moreover, 20a was further examined through a docking study and a 200 ns molecular dynamics simulation for its complex with VEGFR‐2, along with computational ADME properties. This work suggests the high significance of compounds 20a, 7a and 28, as lead compounds for development of new effective immunomodulatory antitumor drugs.