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.
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.
Drewe
John
J
EpiCept Corporation, San Diego, CA 92121, USA.
Kasibhatla
Shailaja
S
Tseng
Ben
B
Shelton
Emma
E
Sperandio
David
D
Yee
Robert M
RM
Litvak
Joane
J
Sendzik
Martin
M
Spencer
Jeffrey R
JR
Cai
Sui Xiong
SX
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008956:Models, Chemical; D009369:Neoplasms / Q000188:drug therapy*; D013329:Structure-Activity Relationship; D013841:Thiazepines / Q000737:chemistry* / Q000494:pharmacology; D014404:Tubulin / Q000737:chemistry
D000970:Antineoplastic Agents; D013841:Thiazepines; D014404:Tubulin; D020169:Caspases