title: 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.
authors: Graduate School of Pharmaceutical Sciences, Tohoku University, 6-3 Aza-Aoba, Aramaki, Aoba-ku, Sendai 980-8578, Japan. y-iwabuchi@m.tohoku.ac.jp.
authors: Aki
authors: A
authors: Kohyama
authors: Michihiro
authors: M
authors: Fukuda
authors: Shunsuke
authors: S
authors: Sugiyama
authors: Hiroyuki
authors: H
authors: Yamakoshi
authors: Naoki
authors: N
authors: Kanoh
authors: Chikashi
authors: C
authors: Ishioka
authors: Hiroyuki
authors: H
authors: Shibata
authors: Yoshiharu
authors: Y
authors: Iwabuchi
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D001555:Benzene Derivatives / Q000737:chemistry* / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy; D003474:Curcumin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D045325:HCT116 Cells; D006801:Humans; D007659:Ketones / Q000737:chemistry* / Q000494:pharmacology*; D011355:Prodrugs / Q000737:chemistry / Q000494:pharmacology; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000494:pharmacology
chemical_list: C541015:1,5-bis(3,5-bis(methoxymethoxy)phenyl)penta-1,4-dien-3-one; D000970:Antineoplastic Agents; D001555:Benzene Derivatives; D007659:Ketones; D011355:Prodrugs; D013438:Sulfhydryl Compounds; D003474:Curcumin