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.
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 44nM in T47D, HCT116 and SNU398 cells, respectively. Compound 2a also was highly active in a growth inhibition assay with an GI(50) value of 34nM in T47D cells. Functionally, compound 2a arrested HCT116 cells in G(2)/M followed by induction of apoptosis and inhibited tubulin polymerization.
Jiang
Songchun
S
EpiCept Corporation, San Diego, CA 92121, USA.
Crogan-Grundy
Candace
C
Drewe
John
J
Tseng
Ben
B
Cai
Sui Xiong
SX
D017209:Apoptosis / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D055808:Drug Discovery; D004789:Enzyme Activation; D006801:Humans; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology*
D009281:Naphthalenes; D020169:Caspases