Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based HTS assay. Part 5: modifications of the 2- and 3-positions.
As a continuation of our efforts to discover and develop apoptosis inducing 4-aryl-4H-chromenes as novel anticancer agents, we explored modifications at the 2- and 3-positions. It was found that replacement of the 3-cyano group by an ester, including methyl and ethyl ester, resulted in >200-fold reduction of activity. Conversion of the 2-amino group into an amide or urea resulted in 4- to 10-fold drop of activity. Similarly, converting the 2-amino group into a hydrogen resulted in 4- to 10-fold reduction of activity. Compound 3d was highly active with an EC(50) value of 29 nM and a GI(50) value of 6 nM in T47D cells. Importantly, the 2-H analog 3d was found to be much more stable under acidic conditions compared to the 2-NH(2) analog 3b, suggesting that 2-H analogs might have better bioavailability than the 2-NH(2) analogs.
Kemnitzer
William
W
EpiCept Corporation, 6650 Nancy Ridge Drive, San Diego, CA 92121, USA.
Jiang
Songchun
S
Wang
Yan
Y
Kasibhatla
Shailaja
S
Crogan-Grundy
Candace
C
Bubenik
Monica
M
Labrecque
Denis
D
Denis
Real
R
Lamothe
Serge
S
Attardo
Giorgio
G
Gourdeau
Henriette
H
Tseng
Ben
B
Drewe
John
J
Cai
Sui Xiong
SX
D017209:Apoptosis / Q000187:drug effects*; D001578:Benzopyrans / Q000737:chemistry / Q000494:pharmacology*; D020169:Caspases / Q000378:metabolism*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D006801:Humans; D013329:Structure-Activity Relationship
D001578:Benzopyrans; D020169:Caspases