Design, synthesis and biological evaluation of newly triazolo-quinoxaline based potential immunomodulatory anticancer molecules

It is evident that cancer is a serious disease with a growing incidence and high mortality rate. Based on the CRBN binding properties of glutarimide moiety of thalidomide molecule, and triazolo-quinoxaline cytotoxic activity, we decided to innovate new triazolo-quinoxaline based molecules hybridized with glutarimide moiety for potential immunomodulatory anticancer activity. The biological data revealed that 4-oxotriazoloquinoxaline based candidate (15) was of particular antiproliferative significance compared to doxorubicin. It showed IC50 of 9.81 +/- 0.7, 15.49 +/- 1.2, and 10.09 +/- 0.9 mu M against hepatocellular (HepG2), prostate cancer (PC3), and breast cancer (MCF-7), respectively. Meanwhile, doxorubicin revealed IC50 of 14.61 +/- 1.1, 16.32 +/- 1.1, and 12.41 +/- 0.74 mu M, respectively. Moreover, compound 15 was comparable to thalidomide in elevating the levels of caspase8 by about 8 folds in HepG-2 cells. Similarly, it showed almost the same effect as thalidomide in reducing VEGF levels in HepG-2 cells. Whereas it was superior to thalidomide in decreasing the levels of NF-kappa B P65 in HepG-2 cells from 278.1 pg/mL to 82.4 pg/mL compared to 110.5 pg/mL reported for thalidomide. At the same time, 15 and thalidomide were comparable in their significant reduction of TNF-alpha levels in HepG-2 cells by about one third. Furthermore, molecular docking studies demonstrated the binding properties of the new candidates to CRBN. Accordingly, this work suggests the significance of the triazolo-quinoxaline derivatives carrying glutarimide moiety, in particular compound 15, that showed considerable data for further consideration in order to develop new effective anticancer drugs.