Abstract
In continuation of our previous work on the design and synthesis of topoisomerase II (Topo II) inhibitors and DNA intercalators, a new series of quinoxaline derivatives were designed and synthesized. The synthesized compounds were evaluated for their cytotoxic activities against a panel of three cancer cell lines (Hep G-2, Hep-2, and Caco-2). Compounds 18b, 19b, 23, 25b, and 26 showed strong potencies against all tested cell lines with IC50 values ranging from 0.26 +/- 0.1 to 2.91 +/- 0.1 mu M, comparable with those of doxorubicin (IC50 values ranging from 0.65 +/- 0.1 to 0.81 +/- 0.1 mu M). The most active compounds were further evaluated for their Topo II inhibitory activities and DNA intercalating affinities. Compounds 19b and 19c exhibited high activities against Topo II (IC50 = 0.97 +/- 0.1 and 1.10 +/- 0.1 mu M, respectively) and bound the DNA at concentrations of 43.51 +/- 2.0 and 49.11 +/- 1.8 mu M, respectively, whereas compound 28b exhibited a significant affinity to bind the DNA with an IC50 value of 37.06 +/- 1.8 mu M. Moreover, apoptosis and cell-cycle tests of the most promising compound 19b were carried out. It was found that 19b can significantly induce apoptosis in Hep G-2 cells. It has revealed cell-cycle arrest at the G2/M phase. Moreover, compound 19b downregulated the Bcl-2 levels, indicating its potential to enhance apoptosis. Furthermore, molecular docking studies were carried out against the DNA-Topo II complex to examine the binding patterns of the synthesized compounds.