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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.