Discovery of 1-benzoyl-3-cyanopyrrolo[1,2-a]quinolines as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. 2: Structure-activity relationships of the 4-, 5-, 6-, 7- and 8-positions.
As a continuation of our efforts to discover and develop the apoptosis inducing 1-benzoyl-3-cyanopyrrolo[1,2-a]quinolines as potential anticancer agents, we explored substitutions at the 4-, 5-, 6-, 7- and 8-positions of pyrrolo[1,2-a]quinoline. SAR studies showed that substitution at the 6-position by a small group such as Cl resulted in potent compounds. Substitutions at the 5- and 8-positions were tolerated while substitutions at the 4- and 7-position led to inactive compounds. Several compounds, including 2c, 3a, 3b and 3f, were found to be highly active against human breast cancer cells T47D with EC(50) values of 0.053-0.080microM, but much less active against human colon cancer cells HCT116 and hepatocellular carcinoma cancer cells SNU398 in the caspase activation assay. Compound 3f also was found to be highly active with a GI(50) value of 0.018microM against T47D cells in a growth inhibition assay.
Kemnitzer
William
W
EpiCept Corporation, Inc. 6650 Nancy Ridge Drive, San Diego, CA 92121, USA.
Kuemmerle
Jared
J
Jiang
Songchun
S
Sirisoma
Nilantha
N
Kasibhatla
Shailaja
S
Crogan-Grundy
Candace
C
Tseng
Ben
B
Drewe
John
J
Cai
Sui Xiong
SX
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017209:Apoptosis; D020169:Caspases / Q000378:metabolism*; D045744:Cell Line, Tumor; D055808:Drug Discovery; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D011804:Quinolines; D020169:Caspases