New immunomodulatory anticancer quinazolinone-based thalidomide analogs: design, synthesis and biological evaluation.

Abstract

Aim: The current work is an extension to our previous work for the development of new thalidomide analogs.Materials & methods: Quinazolinone-based molecules carrying a glutarimide moiety have been designed, synthesized and biologically evaluated for immunomodulatory and anticancer activity.Results: Compounds 7d and 12 showed considerable immunomodulatory properties in comparison to thalidomide. 7d and 12 significantly reduced TNF-α levels in HepG-2 cells from 162.5 to 57.4 pg/ml and 49.2 pg/ml, respectively, compared with 53.1 pg/ml reported for thalidomide. Moreover, they caused 69.33 and 77.74% reduction in NF-κB P65, respectively, compared with 60.26% reduction for thalidomide. Similarly, they reduced VEGF from 432.5 to 161.3 pg/ml and 132.8 pg/ml, respectively, in comparison to 153.2 pg/ml reported for thalidomide. The two new derivatives, 7d and 12 also showed about eightfold increases in caspase-8 levels in cells treated with them. These results were slightly better than those of thalidomide. The obtained results revealed that Compound 12 had better immunomodulatory properties than thalidomide, with stronger effects on TNF-α, NF-κB P65, VEGF and caspase-8.Conclusion: This work indicates that compounds 7d and 12 have interesting biological properties that should be further evaluated and modified in order to develop clinically useful thalidomide analogs.