Synthesis of novel α-santonin derivatives as potential cytotoxic agents

Ten novel a -santonin derivatives have been synthesized as cytotoxic agents. The in vitro antitumor activity of these compounds has been evaluated against cancer cells lines. Structure-activity relationships indicate that a -methylene- g -lactone and endoperoxide functionalities play important roles in conferring cytotoxicity. The compounds 2e4, possessing the a -methylene- g -lactone group showed IC 50 values between 5.70 and 16.40 m M. Mixture of isomers 5 and 6, with the a -methylene- g -lactone and endoperoxide functionalities, displayed the greatest activity, with IC 50 values between 1.45 and 4.35 m M. The biological assays conducted with normal cells revealed that the compounds 2, 5 and 6 are selective against cancer cells lines tested. Bioactive lactones described herein and in our previous report did not cause disruption of the cell membrane in mouse erythrocytes.