Discovery of 5-(4-hydroxy-6-methyl-2-oxo-2 H-pyran-3-yl)-7-phenyl-( E)-2,3,6,7-tetrahydro-1,4-thiazepines as a new series of apoptosis inducers using a cell- and caspase-based HTS assay

The discovery and SAR studies of 5-(4-hydroxy-6-methyl-2-oxo-2 H-pyran-3-yl)-7-phenyl-( E)-2,3,6,7-tetrahydro-1,4-thiazepines as a novel series of apoptosis inducers is reported. We report the discovery of 5-(4-hydroxy-6-methyl-2-oxo-2 H-pyran-3-yl)-7-(4-methylphenyl)-( E)-2,3,6,7-tetrahydro-1,4-thiazepine ( 2a) as an inducer of apoptosis using our proprietary cell- and caspase-based HTS assay. Through structure activity relationship (SAR) studies, 5-(4-hydroxy-6-methyl-2-oxo-2 H-pyran-3-yl)-7-(2-methoxy-4-(methylthio)phenyl)-( E)-2,3,6,7-tetrahydro-1,4-thiazepine ( 5d) was identified as a potent apoptosis inducer with an EC 50 value of 0.08 μM in T47D cells, which was >15-fold more potent than screening hit 2a. Compound 5d also was found to be highly active in a growth inhibition assay with a GI 50 value of 0.05 μM in T47D cells and to function as an inhibitor of tubulin polymerization.