Discovery of (naphthalen-4-yl)(phenyl)methanones and N-methyl- N-phenylnaphthalen-1-amines as new apoptosis inducers using a cell- and caspase-based HTS assay

The discovery and SAR studies of (naphthalen-4-yl)(phenyl)methanones and N-methyl- N-phenylnaphthalen-1-amines as novel and potent apoptosis inducers is reported. We report the discovery of a series of (naphthalen-4-yl)(phenyl)methanones as potent inducers of apoptosis using our proprietary cell- and caspase-based ASAP HTS assay. Through SAR studies, a group of N-methyl- N-phenylnaphthalen-1-amines also were identified as potent inducers of apoptosis. (1-(Dimethylamino)naphthalen-4-yl)(4-(dimethylamino)phenyl)methanone ( 2a), one of the most potent analogs, had EC 50 values of 37, 49 and 44 nM in T47D, HCT116 and SNU398 cells, respectively. Compound 2a also was highly active in a growth inhibition assay with an GI 50 value of 34 nM in T47D cells. Functionally, compound 2a arrested HCT116 cells in G 2/M followed by induction of apoptosis and inhibited tubulin polymerization.