Electronic Properties of Triazoles. Experimental and Computational Determination of Carbocation and Radical-Stabilizing Properties.

Three fluorobenzenes substituted with meta-triazole groups have been prepared, and 19F chemical shifts indicate that these triazole groups are all inductively electron-withdrawing in character, with the 1,5-triazole being the most electron-withdrawing. σ+ values for these three triazoles have also been determined from solvolysis rates of substituted cumyl trifluoroacetates. When substituted in the para-position, the 1,4 and the 2,4-triazoles are cation-stabilizing, whereas the 1,5-triazole is carbocation-destabilizing. γ+ values indicate that the 1,4 triazole group is cation-stabilizing relative to the phenyl group, albeit the 1,5 triazole is significantly destabilizing relative to phenyl. These studies all suggest that the 1,5-triazole group exerts a strong electron-withdrawing effect on carbocations that is not offset by a resonance effect. The three triazole groups all enhance the methylenecyclopropane rearrangement rate and are therefore radical stabilizers. The smallest stabilizing effect is seen for the 1,5-triazole, and this is attributed to the triazole group being twisted out of conjugation in the developing benzylic radical. Finally, the anionic triazole group is the most effective radical-stabilizing group. Computational studies indicate that these triazole groups all stabilize benzylic radicals by a spin delocalization mechanism.

Autophagic receptor p62 protects against glycation-derived toxicity and enhances viability.

Diabetes and metabolic syndrome are associated with the typical American high glycemia diet and result in accumulation of high levels of advanced glycation end products (AGEs), particularly upon aging. AGEs form when sugars or their metabolites react with proteins. Associated with a myriad of age-related diseases, AGEs accumulate in many tissues and are cytotoxic. To date, efforts to limit glycation pharmacologically have failed in human trials. Thus, it is crucial to identify systems that remove AGEs, but such research is scanty. Here, we determined if and how AGEs might be cleared by autophagy. Our in vivo mouse and C. elegans models, in which we altered proteolysis or glycative burden, as well as experiments in five types of cells, revealed more than six criteria indicating that p62-dependent autophagy is a conserved pathway that plays a critical role in the removal of AGEs. Activation of autophagic removal of AGEs requires p62, and blocking this pathway results in accumulation of AGEs and compromised viability. Deficiency of p62 accelerates accumulation of AGEs in soluble and insoluble fractions. p62 itself is subject to glycative inactivation and accumulates as high mass species. Accumulation of p62 in retinal pigment epithelium is reversed by switching to a lower glycemia diet. Since diminution of glycative damage is associated with reduced risk for age-related diseases, including age-related macular degeneration, cardiovascular disease, diabetes, Alzheimer's, and Parkinson's, discovery of methods to limit AGEs or enhance p62-dependent autophagy offers novel potential therapeutic targets to treat AGEs-related pathologies.