Discovery of 4-aryl-2-oxo-2H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay.
As a continuation of our efforts to discover and develop the apoptosis inducing 4-aryl-4H-chromenes as potential anticancer agents, we explored the removal of the chiral center at the 4-position and prepared a series of 4-aryl-2-oxo-2H-chromenes. It was found that, in general, removal of the chiral center and replacement of the 2-amino group with a 2-oxo group were tolerated and 4-aryl-2-oxo-2H-chromenes exhibited SAR similar to 4-aryl-2-amino-4H-chromenes. The 4-aryl-2-oxo-2H-chromenes with a N-methyl pyrrole fused at the 7,8-positions were highly active with compound 2a having an EC(50) value of 13 nM in T47D cells. It was found that an OMe group was preferred at the 7-position. 7-NMe(2), 7-NH(2), 7-Cl and 7,8 fused pyrido analogs all had low potency. These 4-aryl-2-oxo-2H-chromenes are a series of potent apoptosis inducers with potential advantage over the 4-aryl-2-amino-4H-chromenes series via elimination of the chiral center at the 4-position.
Kemnitzer
William
W
Epicept Corporation, Inc. 6650 Nancy Ridge Drive, San Diego, CA 92121, USA.
Jiang
Songchun
S
Zhang
Hong
H
Kasibhatla
Shailaja
S
Crogan-Grundy
Candace
C
Blais
Charles
C
Attardo
Giorgio
G
Denis
Real
R
Lamothe
Serge
S
Gourdeau
Henriette
H
Tseng
Ben
B
Drewe
John
J
Cai
Sui Xiong
SX
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002626:Chemistry, Pharmaceutical / Q000379:methods; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D006801:Humans; D008956:Models, Chemical; D011758:Pyrroles / Q000737:chemistry; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D002867:Chromones; D011758:Pyrroles; D020169:Caspases