- Synthesis and structure-activity relationships of thioflavone derivatives as specific inhibitors of the ERK-MAP kinase signaling pathway
-
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.
- Kataoka, Tadashi,Watanabe, Shin-Ichi,Mori, Eiji,Kadomoto, Ryoji,Tanimura, Susumu,Kohno, Michiaki
-
p. 2397 - 2407
(2007/10/03)
-
- Structure-activity relationship of N-[2-(dimethylamino)-6-[3-(5-methyl-4- phenyl-1H-imidazol-1-yl)propoxy]phenyl]-N'-pentylurea and analogues. Novel potent inhibitors of acyl-CoA:cholesterol O-acyltransferase with antiatherosclerotic activity
-
We have discovered N-butyl-N'-[2-(dimethylamino)-6-[3-(4-phenyl-1H- imidazol-1-yl)propoxy]phenyl]urea (4), a novel, potent, and systemically bioavailable inhibitor of ACAT (acylCoA:cholesterol O-acyltransferase). The structure-activity relationships (SARs) of this lead compound 4 were investigated by systematic modification of four regions in the molecule. The compounds prepared in this study were tested for in vitro inhibitory activity toward both aortic and intestinal ACATs, and selected compounds were further tested for in vivo hypocholesterolemic activity. The studies not only resulted in the discovery of N-[2-(dimethylamino)-6-[3-(5-methyl-4-phenyl- 1H-imidazol-1-yl)propoxy]phenyl]-N'-pentylurea (24), with potent activity and moderate plasma level after oral administration, but also revealed the SAR in each modified region. Four compounds (4, 13, 14, 24) were further selected for testing of in vivo antiatherosclerotic activity; 4, 13, and 24 reduced atherosclerotic plaque development to 38-45% of the control value in terms of area, while 14 did not have a significant antiatherosclerotic effect.
- Kimura,Takase,Hayashi,Tanaka,Ohtsuka,Saeki,Kogushi,Yamada,Fujimori,Saitou,Akasaka
-
p. 1630 - 1640
(2007/10/02)
-