Genotoxicity of Novel Pyrazolo[4,3- e ]tetrazolo[1,5- b ][1,2,4]triazine Sulfonamides in Normal and Cancer Cells In Vitro.

Pyrazolo[4,3- e ]tetrazolo[1,5- b ][1,2,4]triazine sulfonamides constitute a novel group of heterocyclic compounds with broad biological activities including anticancer properties. The compounds investigated in this study ( MM134 , -6 , -7 , and 9 ) were found to have antiproliferative activity against BxPC-3 and PC-3 cancer cell lines in micromolar concentrations (IC 50 0.11-0.33 µM). Here, we studied the genotoxic potential of the tested compounds with alkaline and neutral comet assays, accompanied by immunocytochemical detection of phosphorylated γH2AX. We found that pyrazolo[4,3- e ]tetrazolo[1,5- b ][1,2,4]triazine sulfonamides induce significant levels of DNA damage in BxPC-3 and PC-3 cells without causing genotoxic effects in normal human lung fibroblasts (WI-38) when used in their respective IC 50 concentrations (except for MM134 ) and showed a dose-dependent increase in DNA damage following 24 h incubation of tested cancer cells with these agents. Furthermore, the influence of MM compounds on DNA damage response (DDR) factors was assessed using molecular docking and molecular dynamics simulation.