2. Academic Validation
  3. Discovery of 5-(4-hydroxy-6-methyl-2-oxo-2H-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

Discovery of 5-(4-hydroxy-6-methyl-2-oxo-2H-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

  • Bioorg Med Chem Lett. 2007 Sep 1;17(17):4987-90. doi: 10.1016/j.bmcl.2007.05.098.
John Drewe 1,  Shailaja Kasibhatla,  Ben Tseng,  Emma Shelton,  David Sperandio,  Robert M Yee,  Joane Litvak,  Martin Sendzik,  Jeffrey R Spencer,  Sui Xiong Cai
Affiliations

Affiliation

  • 1 EpiCept Corporation, San Diego, CA 92121, USA.
PMID: 17562361 DOI: 10.1016/j.bmcl.2007.05.098
Abstract

We report the discovery of 5-(4-hydroxy-6-methyl-2-oxo-2H-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-2H-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 microM 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 microM in T47D cells and to function as an inhibitor of tubulin polymerization.

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