Synthesis and biological evaluation of novel pyrazole derivatives with anticancer activity

Abstract: We synthesized thirty-six novel pyrazole derivatives and studied their antiproliferative activity in human ovarian adenocarcinoma A2780 cells, human lung carcinoma A549 cells, and murine P388 leukemia cells. Four of these substances were selected because of their higher antiproliferative activity and further analyses showed that they were all able to induce apoptosis, although to a different extent. The expression of p53 and p21waf1, which induce apoptosis and cell cycle arrest, was evaluated by western blot analysis in cells treated with compound 12d. The analysis of the cell cycle showed that all the selected compounds cause a partial G2/M block and the formation of polyploid cells. Furthermore, the four selected compounds were tested for their interaction with the microtubular cytoskeletal system by docking analysis, tubulin polymerization assay and immunofluorescence staining, demonstrating that the compound 12d, unlike the other active derivatives, was able to significantly bind dimers of α- and β-tubulin, probably causing a molecular distortion resulting in the disassembly of microtubules. [Copyright &y& Elsevier]