LAUSR

In view of their DNA intercalation activities as anticancer agents, novel twenty four [1,2,4]triazolo[4,3-a]quinoxaline derivatives have been designed, synthesized and evaluated against HepG2, HCT-116 and MCF-7 as DNA intercalators and Top II enzyme inhibitors. The data obtained from molecular modeling studies revealed that, our small aromatic molecules were concluded to act through two ways firstly, through non-covalent interaction with the directly bound proteins to DNA hence inhibit topoisomerase-II enzyme. The second is through non-covalently binding to double helical structures of DNA either by intercalating binder as in compounds 10a and 11d or by minor groove binding as in compounds 8e and 8c. Cytotoxic activity indicated that MCF-7 and HepG2 were the most sensitive cell lines to the influence of the new derivatives respectively. In particular, compounds 10a, 11d and 8e were found to be the most potent derivatives overall the tested compounds against the three HepG2, HCT116 and MCF-7 cancer cell lines with IC50 = (4.55 ± 0.3, 6.18 ± 0.8 and 3.93 ± 0.6 µM), (5.61 ± 0.5, 6.49 ± 0.5and 3.71 ± 0.3 µM) and (4.66 ± 0.3, 8.08 ± 0.8 and 5.11 ± 0.7 µM) respectively. The three derivatives exhibited higher activities than doxorubicin, (IC50 = 7.94 ± 0.6, 8.07 ± 0.8 and 6.75 ± 0.4 µM respectively), against HepG2 and MCF-7 but 8e exhibited nearly the same activity against HCT116 cancer cell lines respectively. The most active derivatives 8a-e, 10a,b, 11b-e, 13a and 14b,c were evaluated for their DNA binding activities. The tested compounds displayed very good to moderate DNA-binding affinities. Compounds 10a 11d, 8e, 8c, 8a and 8b displayed the highest binding affinities. These compounds potently intercalate DNA at decreased IC50 values of 25.27 ± 1.2, 27.47 ± 2.1, 27.54 ± 3.2, 27.78 ± 1.3, 29.15 ± 1.8 and 30.23 ± 3.7 µM respectively, which were less than that of doxorubicin (31.27 ± 1.8). Furthermore, the most active cytotoxic compounds 8a, 8b, 8c, 8e, 10a and 11d were selected to evaluate their inhibitory activities against Topo II enzyme. All the tested compounds could interfere with the Topo II activity. They exhibited very good inhibitory activities with IC50 values ranging from 0.379 ± 0.07 to 0.813 ± 0.14 µM that were lower than that of doxorubicin (IC50 = 0.94 ± 0.4 µM). For a great extent, the reported results were in agreement with that of in vitro cytotoxicity activity, DNA binding and molecular modeling studies.