Synthesis and characterization of novel phenyl carboxamide-selenium analogs: Identification of a potent DHODH inhibitor as a potential anticancer agent.

Despite continued research efforts, cancer remains a growing public health problem. Herein, we have designed four different libraries of compounds by rationally introducing select Se moieties into the phenyl carboxamide backbone and characterized them in vitro to assess their antiproliferative activities. The identified lead compounds, A1 and C3, displayed a discerning cytotoxicity against a panel of 60 cancer cell lines in the DTP of the NCI. Their ability to induce apoptosis and ROS and modulate the cell cycle was assessed in MDA-MB-231 breast cancer cells. In addition, both A1 and C3 inhibited tumor growth with no evident toxicity signs in a syngeneic breast cancer mouse model. Notably, in concordance with the COMPARE analysis, compound A1 was found to act at the level of the de novo pyrimidine biosynthetic pathway by inhibiting in vitro the cellular dihydroorotate dehydrogenase (DHODH), which was also supported by the molecular modeling studies.