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Pyrazolo[4,3-<i>e</i>]tetrazolo[1,5-<i>b</i>][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 (<b>MM134</b>, <b>-6</b>, <b>-7</b>, and <b>9</b>) were found to have antiproliferative activity against BxPC-3 and PC-3 cancer cell lines in micromolar concentrations (IC₅₀ 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-<i>e</i>]tetrazolo[1,5-<i>b</i>][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 IC₅₀ concentrations (except for <b>MM134</b>) and showed a dose-dependent increase in DNA damage following 24 h incubation of tested cancer cells with these agents. Furthermore, the influence of <b>MM</b> compounds on DNA damage response (DDR) factors was assessed using molecular docking and molecular dynamics simulation.