Synthesis and structure-activity relationships of thioflavone derivatives as specific inhibitors of the ERK-MAP kinase signaling pathway.
Condensation of nitrobenzaldehydes 3 and alpha-[o-(p-methoxybenzylthio)benzoyl] sulfoxide 4 gave alpha-sulfinyl enones 5. Treatment of 5 with formic acid caused cyclization followed by debenzylation to afford 3-(methylsulfinyl)thioflavanones 6. Double-bond formation with elimination of methanesulfenic acid was performed by refluxing 6 in benzene, and, finally, the nitro group of 2-phenyl-4H-1-benzothiopyran-4-one (thioflavones) 7 was reduced with tin in tetrafluoroboric acid. Various 2'-aminothioflavones 8 thus prepared were evaluated for their inhibitory effects on the ERK-MAP kinase pathway. In a cell-based assay, 2-(2'-amino-3'-methoxyphenyl)-4H-1-benzothiopyran-4-one (8b) showed a more potent inhibitory effect than the corresponding oxygen compound (PD98059, 1) on the Raf-induced activation of the ERK-MAP kinase pathway as well as cell proliferation. Furthermore, compound 8b selectively and potently inhibited the proliferation of tumor cells in which the ERK-MAP kinase pathway is constitutively activated.
Kataoka
Tadashi
T
Laboratory of Pharmaceutical Chemistry, Gifu Pharmaceutical University, 6-1, Mitahora-higashi 5-chome, Gifu 502-8585, Japan. kataoka@gifu-pu.ac.jp
Watanabe
Shin-ichi
S
Mori
Eiji
E
Kadomoto
Ryoji
R
Tanimura
Susumu
S
Kohno
Michiaki
M
D000818:Animals; D047309:Flavones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D041681:NIH 3T3 Cells; D013057:Spectrum Analysis; D013329:Structure-Activity Relationship
D047309:Flavones