Novel hydroxyphenylurea dual inhibitor against acyl-CoA: cholesterol acyltransferase (ACAT) and low density lipoprotein (LDL) oxidation as antiatherosclerotic agent.

Novel hydroxyphenylurea derivatives were synthesized and their inhibitory potency evaluated against acyl-CoA: cholesterol acyltransferase (ACAT). Quantitative structure activity relationship analysis revealed that their ACAT inhibitory activities were controlled by the hydrophobicity of the whole molecule. the substitution pattern of urea moiety, and the existence of carboxylic acid. The derivatives with strong activities inhibited foam cell formations. Moreover, these compounds showed antioxidative effects against low density lipoprotein (LDL), owing to their characteristic 3-lert-butyl-2-hydroxy-5-methoxyphenyl substructure. Based on the mechanism of atherosclerosis generation, this hydroxyphenylurea-type dual inhibitor against both ACAT and LDL oxidation is expected to be a promising drug for atherosclerosis.

Antioxidative property of T-0970, a new ureidophenol derivative.

We investigated the antioxidative property of T-0970, a newly synthesized ureidophenol derivative. The inhibitory effect of T-0970 on spontaneous lipid peroxidation in rat brain was 10 times greater than those of well-known antioxidants such as butylhydroxytoluene (BHT), probucol and alpha-tocopherol. T-0970 also showed dose-dependent free radical scavenging activities in vitro for both superoxide anions and hydroxyl radicals. The radical-scavenging potencies of T-0970 were about 10-30 times stronger than those of BHT. We evaluated the in vivo antioxidative ability of T-0970 in the animal model of acute oxidative tissue injury in rats. Intraperitoneal injection of ferric nitrilotriacetate (Fe/NTA) caused an acute and remarkable increase in the level of thiobarbituric acid-reactive substances (TBARS) in both plasma and the liver, and also resulted in a considerable elevation of the plasma levels of GOT and GPT indicative of hepatic injury. Both oral and intravenous administration of T-0970 dose-dependently depressed these diagnostic parameters. These results indicate that T-0970 may have a therapeutic potential in various diseases associated with oxidative tissue injury.

Quantitative structure-activity analyses of novel hydroxyphenylurea derivatives as antioxidants.

A series of substituted hydroxyphenylureas was synthesized, the chemical structure of which was designed based on structures of natural antioxidants, vitamin E (alpha-tocopherol) and uric acid. They exhibited high inhibitory activity against lipid peroxidation. In order to gain an insight into the mechanism of the inhibition reaction, we analyzed their structure-activity relationships quantitatively. Electronic and steric effects of substituents on the phenolic hydroxyl group were shown to be of importance in governing the inhibitory potency. An increase in the electron donating property of substituents toward the phenolic hydroxyl group enhanced the antioxidative activity by the stabilization of an electron-deficient radical-type transition state. The steric shielding by ortho-substituents stabilized the phenoxy radicals formed following the transition state. Derivatives having the carboxyl group were only weakly active presumably because of an intermolecular ion-dipole interaction of the phenolic hydroxyl group with the carboxylate anion which could retard the formation of the transition state.

Inhibitory effect of a new ureidophenol derivative T-2591 on LDL oxidation and ACAT activity.

We investigated the effects of T-2591, a new ureidophenol derivative, on low density lipoprotein (LDL) oxidation, acyl CoA: cholesterol acyltransferase (ACAT) and foam cell formation of macrophages in vitro. T-2591 inhibited both copper ion--and endothelial cell--induced LDL oxidation with higher potencies than probucol did. It inhibited ACAT from rabbit intestine, liver and aorta, the respective IC50 values being 0.26, 4.6 and 4.1 microM. It also inhibited ACAT from the mouse macrophage cell line J774 A.1, and its IC50 value (0.067 microM) was much lower than that of CI-976 (4.1 microM). This probably accounts for the inhibition of foam cell formation measured as cholesteryl ester formation in both mouse peritoneal macrophages and J774 A.1 cells at low concentrations (IC50; 0.06 and 0.44 microM, respectively). These observations suggest that T-2591 should be evaluated as a potential tool to retard atherosclerosis in animal models.

2,2'-Disubstituted biphenyls: synthesis and suppressive effect against carbon tetrachloride-induced liver injury.

2,2'-Disubstituted biphenyl compounds (1-15) were synthesized by using the Ullmann coupling reaction as a key step. The suppressive effect of these compounds against CCl4-induced liver injuries in mice was evaluated. An unsymmetrical biphenyl (14f) exhibited the most potent activity. The structure-activity relationship is discussed.

Major proteins released by a protein-producing bacterium, Bacillus brevis 47, are derived from cell wall protein.

B. brevis 47 secretes a vast amount of protein consisting mainly of two kinds with approximate molecular weights of 130,000 and 150,000. The two major extracellular proteins were indistinguishable from those of cell wall protein by SDS-polyacrylamide gel electrophoresis. Based on the results of analysis of amino acid composition, limited proteolysis followed by electrophoresis, and the cross-reactivity of antisera, we conclude that the 130K and 150K extracellular proteins are derived from the respective cell wall proteins. Furthermore, the NH2-terminal amino acid analysis suggests that the two major extracellular proteins are released from the cell wall without any modification of the NH2-terminal portion.