4-Aryl-4H-chromenes as a new series of apoptosis inducers using a cell- and caspase-based high throughput screening assay, structure-activity relationships of the 7, 8-positions

1129 We have recently reported the discovery of 2-amino-3-cyano-7-dimethylamino-4- (3-methoxy-4,5-methylenedioxyphenyl)-4H-chromene (1a) as potent apoptosis inducers using a novel cell- and caspase-based HTS assay and the SAR of the 4-position with a dimethylamino group in the 7-position (Kemnitzer, W. et al. J. Med. Chem. 2004, 47, 6299). These chromenes were found to be active in the HUVEC tube formation assay, suggesting that this series of compounds may have antivascular activity, and several compounds were also found to be highly active in anti-cancer in vivo tumor models. (Kasibhatla, S. et al. Mol. Cancer Ther. 2004, 3, 1365, and Gourdeau, H. et al. Mol. Cancer Ther. 2004, 3, 1375). In this presentation, we will describe the SAR of the 7-and 8-positions of 4-aryl-4H-chromenes as inducers of apoptosis, including 7,8-disubstituted analogs (Kemnitzer, W. et al. Bioorg. Med. Chem. Lett. 2005, 15, 4745), as well as analogs with a fused ring at the 7, 8-positions. We will report in detail the chemistry, in vitro and in vivo characterization of these compounds.