Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high throughput screening assay. 4. Structure-activity relationships of N-alkyl substituted pyrrole fused at the 7,8-positions.
In our continuing effort to discover and develop apoptosis inducing 4-aryl-4H-chromenes as novel anticancer agents, we explored the structure-activity relationship (SAR) of alkyl substituted pyrrole fused at the 7,8-positions. A methyl group substituted at the nitrogen in the 7-position of the pyrrole ring led to a series of potent apoptosis inducers with potency in the low nanomolar range. These compounds were also found to be low nanomolar or subnanomolar inhibitors of cell growth, and they inhibited tubulin polymerization, indicating that methylation of the 7-position nitrogen does not change the mechanism of action of these chromenes. Compound 2d was identified as a highly potent apoptosis inducer with an EC50 value of 2 nM and a highly potent inhibitor of cell growth with a GI50 value of 0.3 nM in T47D cells.
Kemnitzer
William
W
Epicept Corporation, San Diego, CA 92121, USA.
Drewe
John
J
Jiang
Songchun
S
Zhang
Hong
H
Crogan-Grundy
Candace
C
Labreque
Denis
D
Bubenick
Monica
M
Attardo
Giorgio
G
Denis
Real
R
Lamothe
Serge
S
Gourdeau
Henriette
H
Tseng
Ben
B
Kasibhatla
Shailaja
S
Cai
Sui Xiong
SX
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004789:Enzyme Activation; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
C528495:2-amino-4-(3-bromo-4,5-dimethoxyphenyl)-3-cyano-4,7-dihydro-7-methylpyrano(2,3-e)indole; D000970:Antineoplastic Agents; D001578:Benzopyrans; D007211:Indoles; D011758:Pyrroles; D050257:Tubulin Modulators; D020169:Caspases