Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. 2. Structure-activity relationships of the 7- and 5-, 6-, 8-positions.
As a continuation of our efforts to discover and develop the apoptosis inducing 4-aryl-4H-chromenes as novel anticancer agents, we explored the SAR of 4-aryl-4H-chromenes with modifications at the 7- and 5-, 6-, 8-positions. It was found that a small hydrophobic group, such as NMe2, NH2, NHEt, and OMe, is preferred at the 7-position. Di-substitution at either the 5,7-positions or the 6,7-positions generally led to a large decrease in potency. Di-substitution at the 7,8-positions, in general, was found to result in potent compounds. 7-NMe2, 7-NHEt, 7-OMe, and 7,8-di-NH2 analogs were found to have similar SAR for the 4-aryl group, and several 7-substituted and 7,8-di-substituted analogs were found to have similar potencies as the lead compound MX58151 (2a) both as caspase activators and inhibitors of cell proliferation.
Kemnitzer
William
W
Maxim Pharmaceuticals, Inc., 6650 Nancy Ridge Drive, San Diego, CA 92121, USA.
Kasibhatla
Shailaja
S
Jiang
Songchun
S
Zhang
Hong
H
Zhao
Jianghong
J
Jia
Shaojuan
S
Xu
Lifen
L
Crogan-Grundy
Candace
C
Denis
Réal
R
Barriault
Nancy
N
Vaillancourt
Louis
L
Charron
Sylvie
S
Dodd
Jennifer
J
Attardo
Giorgio
G
Labrecque
Denis
D
Lamothe
Serge
S
Gourdeau
Henriette
H
Tseng
Ben
B
Drewe
John
J
Cai
Sui Xiong
SX
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001578:Benzopyrans / Q000138:chemical synthesis* / Q000494:pharmacology; D020169:Caspases / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D001578:Benzopyrans; D020169:Caspases