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

Abstract As a continuation of our studies of apoptosis inducing 9-oxo-9 H -fluorene-1-carboxamides as potential anticancer agents, we explored modification of the 9-oxo-9 H -fluorene ring. SAR studies showed that most changes to the 9-oxo-9 H -fluorene ring were not well tolerated, except the 9 H -fluorene ( 2b ) and dibenzothiophene ( 2d ) analogs, which were about twofold less active than the 9-oxo-9 H -fluorene analog 2a . Significantly, introduction of substitutions at the 7-position of the 9-oxo-9 H -fluorene ring led to compounds 5a – 5c with improved activity. Compound 5a was found to have EC 50 values of 0.15–0.29 μM 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.