New immunomodulatory anticancer quinazolinone based thalidomide analogs: Design, synthesis and biological evaluation

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Abstract As an extension to our previous work for the development of new thalidomide analogs, the current work offers new insights into the immunomodulatory and anticancer activities of quinazolinone based molecules carrying a glutarimide moiety. The findings confirmed some previous findings and revealed some new information. Among the newly synthesized compounds, 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 pg/mL to 57.4 pg/mL and 49.2 pg/mL, respectively compared to 53.1 pg/mL reported for thalidomide. Moreover, they caused 69.33% and 77.74% reduction in NF-κB P65, respectively, compared to 60.26% reduction for thalidomide. Similarly, they reduced VEGF from 432.5 pg/mL 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 8-fold 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-B P65, VEGF, and caspase-8. Accordingly, this work indicates that compound 12 has interesting biological properties that should be further evaluated and modified in order to develop clinically useful thalidomide analogs.

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