Discovery of Fuchsone Derivatives as Novel Nonpeptide Inhibitor of Caspase-3

Abstract Many degenerative diseases caused by uncontrolled cell death can be intervened pharmaceutically through inhibiting caspase-3 activity that leads to cell apoptosis. Here is presented the discovery of rosolic acid and phe- nolphthalein methyl ester, which both belong to fuchsone derivatives, as novel and potent nonpeptide inhibitors of caspase-3. They show high inhibitory potency against caspase-3 in vitro（ICso=0.28 and 0.13 ~tmol/L）. Molecular modeling study provided further an insight into the interaction of phenolphthalein methyl ester with activated cas- pase-3. The structures of the present small-molecule caspase-3 inhibitors are different from the structures of known caspase-3 inhibitors, so the inhibitors were likely to provide some information for the discovery of anti-caspase-3 in- hibitors.