Reversibility of the thia-Michael reaction of cytotoxic C5-curcuminoid and structure–activity relationship of bis-thiol-adducts thereof

Abstract

C₅-curcuminoids [a.k.a. bis(arylmethylidene)acetones] are curcumin analogues bearing a reactive cross-conjugated dienone structure essential for eliciting cytotoxicity. To gain insight into the mode of action of C₅-curcuminoids, we investigated the reversibility of the thia-Michael reaction of 1,5-bis(3,5-bis(methoxymethoxy)phenyl)-1,4-pentadiene-3-one, named GO-Y030 which is the most potent cytotoxic C₅-curcuminoid, using spectroscopic methods. A panel of GO-Y030-bis-thiol-adducts were synthesized and the structure–reactivity relationship regarding the retro thia-Michael reaction as well as the cell growth inhibitory activity against human colon cancer HCT116 were evaluated. Some C₅-curcuminoid thiol-adducts exhibited comparable cytotoxicity with GO-Y030, demonstrating their potential use as prodrugs. These results imply that C₅-curcuminoids elicit cytotoxicity by covalently interacting with various biothiols via a reversible thia-Michael reaction.