Discovery of a potent, highly selective, and orally efficacious small-molecule activator of the insulin receptor.

A series of 3,6-diaryl-2,5-dihydroxybenzoquinones were synthesized and evaluated for their abilities to selectively activate human insulin receptor tyrosine kinase (IRTK). 2, 5-Dihydroxy-6-(1-methylindol-3-yl)-3-phenyl-1,4-benzoquinone (2h) was identified as a potent, highly selective, and orally active small-molecule insulin receptor activator. It activated IRTK with an EC(50) of 300 nM and did not induce the activation of closely related receptors (IGFIR, EGFR, and PDGFR) at concentrations up to 30 000 nM. Oral administration of the compound to hyperglycemic db/db mice (0.1-10 mg/kg/day) elicited substantial to nearly complete correction of hyperglycemia in a dose-dependent manner. In ob/ob mice, the compound (10 mg/kg) caused significant reduction in hyperinsulinemia. A structurally related compound 2c, inactive in IRTK assay, failed to affect blood glucose level in db/db mice at equivalent exposure levels. Results from additional studies with compound 2h, aimed at evaluating classical quinone-related phenomena, provided sufficient grounds for optimism to allow more extensive toxicologic evaluation.

Stimulation of binding of benzo[a]pyrene metabolites to DNA by diet-induced peroxidative stress.

To investigate the influence of unsaturation of dietary fat on the oxidation of benzo[a]pyrene-7,8-dihydrodiol to DNA binding products, we fed diets containing 10% by weight of either safflower oil or lard to weanling rats. Compared with the group fed lard, the group fed safflower oil had 2.0- to 2.5-fold higher levels of unstimulated and peroxidation-stimulated activation of benzo[a]pyrene-7,8-dihydrodiol to DNA-binding metabolites, respectively, in hepatic nuclei. The rats fed safflower oil had a significant 75% higher level of lipid peroxidation as measured by the thiobarbituric acid assay. Rats fed safflower oil also showed 30% greater binding of (-)-benzo[a]pyrene-7,8-dihydrodiol oxidation products to DNA compared with animals fed lard, following administration of this dihydrodiol enantiomer through the hepatic portal vein. Significant diet-dependent differences were not apparent in DNA binding of the (+)-isomer, or in the tetrol production from either isomer; however, rats fed safflower oil showed a trend towards production of higher levels of anti-benzo[a]pyrene diol epoxide-derived tetrols. Activities of hepatic nuclear and microsomal aryl hydrocarbon hydroxylase and of cytosolic and microsomal glutathione S-transferases were not significantly affected by diet, nor was the activity of microsome-mediated binding of (+)- or (-)-benzo[a]pyrene-7,8-dihydrodiol to DNA in vitro. The results indicate that polyunsaturated fat in quantities as low as 10% by weight of the diet is sufficient to increase significantly the extent to which DNA-binding metabolites of benzo[a]pyrene are produced, and that this increased metabolism is likely to be independent of mixed-function oxidases.