Discovery of N-aryl-9-oxo-9H-fluorene-1-carboxamides as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. 2. Structure-activity relationships of the 9-oxo-9H-fluorene ring.
As a continuation of our studies of apoptosis inducing 9-oxo-9H-fluorene-1-carboxamides as potential anticancer agents, we explored modification of the 9-oxo-9H-fluorene ring. SAR studies showed that most changes to the 9-oxo-9H-fluorene ring were not well tolerated, except the 9H-fluorene (2b) and dibenzothiophene (2d) analogs, which were about twofold less active than the 9-oxo-9H-fluorene analog 2a. Significantly, introduction of substitutions at the 7-position of the 9-oxo-9H-fluorene ring led to compounds 5a-5c with improved activity. Compound 5a was found to have EC(50) values of 0.15-0.29 microM against T47D, HCT116, and SNU398 cells, about fivefold more potent than the original lead 2a. As opposed to the original lead compound 2a, compounds 5a-5b were active in a tubulin inhibition assay, indicating a change of mechanism of action. The potent azido analog 5c could be utilized for target identification.
Kemnitzer
William
W
Epicept Corporation, 6650 Nancy Ridge Drive, San Diego, CA 92121, USA.
Sirisoma
Nilantha
N
Jiang
Songchun
S
Kasibhatla
Shailaja
S
Crogan-Grundy
Candace
C
Tseng
Ben
B
Drewe
John
J
Cai
Sui Xiong
SX
D000577:Amides / Q000737:chemistry* / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D020169:Caspases / Q000737:chemistry*; D055808:Drug Discovery / Q000379:methods*; D005449:Fluorenes / Q000737:chemistry* / Q000494:pharmacology; D045325:HCT116 Cells; D057166:High-Throughput Screening Assays / Q000379:methods*; D006801:Humans; D013329:Structure-Activity Relationship
D000577:Amides; D000970:Antineoplastic Agents; D005449:Fluorenes; C041509:fluorene; C099448:fluorene-1-carboxylic acid; D020169:Caspases