Discovery of 4-aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based HTS assay. Part 5: modifications of the 2- and 3-positions |
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Authors: | Kemnitzer William Jiang Songchun Wang Yan Kasibhatla Shailaja Crogan-Grundy Candace Bubenik Monica Labrecque Denis Denis Real Lamothe Serge Attardo Giorgio Gourdeau Henriette Tseng Ben Drewe John Cai Sui Xiong |
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Affiliation: | EpiCept Corporation, 6650 Nancy Ridge Drive, San Diego, CA 92121, USA. |
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Abstract: | As a continuation of our efforts to discover and develop apoptosis inducing 4-aryl-4H-chromenes as novel anticancer agents, we explored modifications at the 2- and 3-positions. It was found that replacement of the 3-cyano group by an ester, including methyl and ethyl ester, resulted in >200-fold reduction of activity. Conversion of the 2-amino group into an amide or urea resulted in 4- to 10-fold drop of activity. Similarly, converting the 2-amino group into a hydrogen resulted in 4- to 10-fold reduction of activity. Compound 3d was highly active with an EC(50) value of 29 nM and a GI(50) value of 6 nM in T47D cells. Importantly, the 2-H analog 3d was found to be much more stable under acidic conditions compared to the 2-NH(2) analog 3b, suggesting that 2-H analogs might have better bioavailability than the 2-NH(2) analogs. |
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