Studying the cytotoxicity of coumarin-chalcone hybrids by a prooxidant strategy in A549 cells

Curcumin, bearing two electrophilic ,-unsaturated ketones, is a promising anticancer agent by an electrophilicity-based prooxidant strategy (ROS-generating) due to the Michael acceptors. Considering that ROS generation depends on Michael acceptor unit, we have designed and synthesized two series coumarin-chalcone hybrids containing one or two Michael acceptor units through Claisen-Schmidt condensation, and evaluated the cytotoxicity against A549 cells as well as ROS accumulation. (E)-3-[3-(2-Hydroxyphenyl)acryloyl]-2H-chromen-2-one was identified as the strongest ROS inducer and cytotoxic agent. The structure-activity relationships (SAR) indicated that the Michael acceptor unit was more important than the position of hydroxyl to the cytotoxicity mediated by increasing the cellular lever of ROS. In addition, (E)-3-[3-(2-hydroxyphenyl)acryloyl]-2H-chromen-2-one caused S-phase cell cycle arrest in A549 cells. Therefore, this work provides an example of coumarin-chalcone scaffold as cytotoxic agent by a prooxidant (ROS-generating agent) strategy. [GRAPHICS]