Design, synthesis, and biological evaluation of new celecoxib analogs as apoptosis inducers and cyclooxygenase-2 inhibitors.

Series of new celecoxib analogs were synthesized to assess their anticancer activity against the MCF-7 cell line. Four compounds, 3a, 3c, 5b, and 5c, showed 1.4-9.2-fold more potent anticancer activity than celecoxib. The antiproliferative activity of the most potent compounds, 3c, 5b, and 5c, seems to be associated well with their ability to induce apoptosis in MCF-7 cells (18-24-fold). This evidence was supported by an increase in the expression of the tumor suppressor gene p53 (4-6-fold), the elevation in the Bax/BCL-2 ratio, and a significant increase in the level of active caspase-7 (4-7-fold). Moreover, compounds 3c and 5c showed significant cyclooxygenase-2 (COX-2) inhibitory activity. They were also docked into the crystal structure of the COX-2 enzyme (PDB ID: 3LN1) to understand their mode of binding.