Synthesis and biological evaluation of N-aryl-4-aryl-1,3-thiazole-2-amine derivatives as direct 5-lipoxygenase inhibitors.

Biological evaluation of N-aryl-4-aryl-1,3-thiazole-2-amine derivatives was examined for anti-inflammatory activity in in vitro and in vivo assays. The thiazole compounds showed direct inhibition of 5-lipoxygenase (LOX) that is a key enzyme of leukotrienes synthesis and involved in the inflammation-related diseases, including asthma and rheumatoid arthritis. To optimize biological activity, we synthesized 1,3-thiazole-2-amine derivatives and investigated for structure and activity relationship. Especially, N-(3,5-dimethylphenyl)-4-(4-chlorophenyl)-1,3-thiazole-2-amine was shown to have a potent anti-inflammatory activity as a 5-LOX inhibitor.

Synthesis and biological evaluation of 3-substituted-benzofuran-2-carboxylic esters as a novel class of ischemic cell death inhibitors.

A series of 3-substituted-benzofuran-2-carboxylic esters was synthesized and evaluated for biological activity as ischemic cell death inhibitors in H9c2 cells and rat primary cardiac myocytes under conditions of oxygen and glucose deprivation. The introduction of a sulfur atom at the three-position substituent of the benzofuran ring markedly improved ischemic cell death inhibitory potency. In particular, 3-[2-(4-nitro-phenylsulfanyl)-acetylamino]-benzofuran-2-carboxylic acid ester (10) (EC(50)=0.532 µM, cell death=6.18%) and 4-chloro-3-[3-(pyridin-2-ylsulfanyl)-propionylamino]-benzofuran-2-carboxylic ester (18) (EC(50)=0.557 µM, cell death=7.02%) were shown to be the most potent in this series of benzofuran analogs.

Negative feedback regulation of Aurora-A via phosphorylation of Fas-associated factor-1.

This study reports that Aurora-A (Aur-A) phosphorylates Fas-associated factor-1 (FAF1) at Ser-289 and Ser-291. Forced expression of a FAF1 mutant mimicking phosphorylation at Ser-289 and Ser-291 (FAF1 DD), but not phosphorylation-deficient FAF1 (FAF1 AA), reduced Aur-A expression. However, transfection of FAF1 DD failed to reduce Aur-A expression in the presence of MG132 and MG115, indicating that this decrease is proteasome-mediated. Additionally, transfection of FAF1 DD suppressed the expression of Aur-A in ts20-BALB cells lacking E1 ubiquitin (Ub) activating enzyme activity at restrictive temperatures and also reduced the expression of Aur-A S51D, a mutant resistant to Ub-dependent degradation. Our data indicate that phosphorylated FAF1 mediates the ubiquitin-independent, proteasome-dependent degradation of Aur-A. Overexpression of FAF1 DD blocked Aur-A-induced centrosome amplification and accumulated cells in G(2)/M phase, representing cellular phenotypes consistent with the anticipated loss of Aur-A. Collectively, our findings support the negative feedback regulation of Aur-A via phosphorylation of the death-promoting protein, FAF1, and disclose the presence of molecular cross-talk between constituents of the cell cycle and cell death machinery.

Cardioselective anti-ischemic ATP-sensitive potassium channel (KATP) openers: benzopyranyl indoline and indole analogues.

This paper describes the design, syntheses, and biological evaluations of novel ATP-sensitive potassium channel (K(ATP)) openers, benzopyranyl indoline and indole derivatives. Among those, two enantiomers of indoline-2-carboxylic ethyl esters (14, 18) showed the best cardioprotective activities both in vitro and in vivo, while their vasorelaxation potencies were very low (concentration for 50% inhibition of vasorelaxation >30 microM). The cardioprotective effect of 14 was completely reversed by 5-hydroxydecanoate, a selective mitochondrial K(ATP) blocker, indicating its provable protective mechanism through the mitochondrial K(ATP) opening. In addition, we performed conformational analyses using 2D-NMR, X-ray crystallography and molecular modeling to study the structure-activity relationships in this series of compounds.