Discovery of 4-aryl-2-oxo-2H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay

Abstract As a continuation of our efforts to discover and develop the apoptosis inducing 4-aryl-4 H -chromenes as potential anticancer agents, we explored the removal of the chiral center at the 4-position and prepared a series of 4-aryl-2-oxo-2 H -chromenes. It was found that, in general, removal of the chiral center and replacement of the 2-amino group with a 2-oxo group were tolerated and 4-aryl-2-oxo-2 H -chromenes exhibited SAR similar to 4-aryl-2-amino-4 H -chromenes. The 4-aryl-2-oxo-2 H -chromenes with a N -methyl pyrrole fused at the 7,8-positions were highly active with compound 2a having an EC 50 value of 13 nM in T47D cells. It was found that an OMe group was preferred at the 7-positon. 7-NMe 2 , 7-NH 2 , 7-Cl and 7,8 fused pyrido analogs all had low potency. These 4-aryl-2-oxo-2 H -chromenes are a series of potent apoptosis inducers with potential advantage over the 4-aryl-2-amino-4 H -chromenes series via elimination of the chiral center at the 4-position.