Design, synthesis, anticancer evaluation, and <i>in silico</i> ADMET analysis of novel thalidomide analogs as promising immunomodulatory agents

Abstract

Immunomodulatory medications like thalidomide and its analogs prevent the production of some proinflammatory cytokines linked to cancer. A new series of thalidomide analogs were designed and synthesized in order to develop potential antitumor immunomodulatory agents. The antiproliferative activities of the new candidates against a panel of three human cancer cell lines (HepG-2, PC3 and MCF-7) were assessed in comparison to thalidomide as a positive control. The obtained results showed the relative significant potency of 18f (IC₅₀ = 11.91 ± 0.9, 9.27 ± 0.7, and 18.62 ± 1.5 μM) and 21b (IC₅₀ = 10.48 ± 0.8, 22.56 ± 1.6, and 16.39 ± 1.4 μM) against the mentioned cell lines, respectively. These results were comparable to thalidomide (IC₅₀ = 11.26 ± 0.54, 14.58 ± 0.57, and 16.87 ± 0.7 μM, respectively). To see to what extent the biological properties of the new candidates are relative to those of thalidomide, the effects of 18f and 21b on the expression levels of TNF-α, CASP8, VEGF, and NF-κB P65 were evaluated. Significant reductions in the proinflammatory TNF-α, VEGF, and NF-κB P65 levels in HepG-2 cells were observed after exposure to compounds 18f and 21b. Furthermore, a sharp increase in CASP8 levels was detected. The obtained results revealed that 21b is of greater significance than thalidomide in TNF-α and NF-κB P65 inhibition. The <i>in silico</i> ADMET and toxicity studies showed that most of tested candidates have a good profile of drug-likeness and low toxicity potential.