Search

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 (IC 50 = 11.91 ± 0.9, 9.27 ± 0.7, and 18.62 ± 1.5 μM) and 21b (IC 50 = 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 (IC 50 = 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 in silico ADMET and toxicity studies showed that most of tested candidates have a good profile of drug-likeness and low toxicity potential., Competing Interests: There is no conflict of interest., (This journal is © The Royal Society of Chemistry.)

Cancer is still a dangerous disease with a high mortality rate all over the world. In our attempt to develop potential anticancer candidates, new quinazoline and phthalazine based compounds were designed and synthesized. The new derivatives were built in line with the pharmacophoric features of thalidomide. The new derivatives as well as thalidomide were examined against three cancer cell lines, namely: hepatocellular carcinoma (HepG-2), breast cancer (MCF-7) and prostate cancer (PC3). Then the effects on the expression levels of caspase-8, VEGF, NF-κB P65, and TNF-α in HepG-2 cells were evaluated. The biological data revealed the high importance of phthalazine based compounds (24a-c), which were far better than thalidomide with regard to the antiproliferative activity. 24b showed IC 50 of 2.51, 5.80 and 4.11 μg mL -1 compared to 11.26, 14.58, and 16.87 μg mL -1 for thalidomide against the three cell lines respectively. 24b raised caspase-8 level by about 7 folds, compared to 8 folds reported for thalidomide. Also, VEGF level in HepG-2 cells treated with 24b was 185.3 pg mL -1 , compared to 432.5 pg mL -1 in control cells. Furthermore, the immunomodulatory properties were proven to 24b, which reduced TNF-α level by approximately half. At the same time, NF-κB P65 level in HepG-2 cells treated with 24b was 76.5 pg mL -1 compared to 278.1 and 110.5 pg mL -1 measured for control cells and thalidomide treated HepG-2 cells respectively. Moreover, an in vitro viability study against Vero non-cancerous cell line was investigated and the results reflected a high safety profile of all tested compounds. This work suggests 24b as a promising lead compound for development of new immunomodulatory anticancer agents., Competing Interests: There is no conflict of interest., (This journal is © The Royal Society of Chemistry.)