Synthesis and structure–activity relationships of thioflavone derivatives as specific inhibitors of the ERK-MAP kinase signaling pathway Original Research Article

Condensation of nitrobenzaldehydes 3 and α-[o-(p-methoxybenzylthio)benzoyl] sulfoxide 4 gave α-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.