Synthesis and evaluation of neuroprotective alpha,beta-unsaturated aldheyde scavenger histidyl-containing analogs of carnosine

alpha,beta-Unsaturated aldehydes formed upon oxidation of unsaturated lipids, like malondialdehyde (MDA, existing under physiological conditions as its unsaturated enol tautomer), 4-hydroxyalkenals, and 2-alkenals (e.g., acrolein and crotonaldehyde) are reactive species of particular interest for their direct or indirect influence in human pathologies. Among these, acrolein and 4-hydroxy-trans- 2,3-nonenal (HNE) have been extensively studied for their involvement in the pathogenesis of diseases such as atherosclerosis, diabetes, and neurodegenerative disorders. Pharmacological efforts to attenuate oxidative injury in degenerative diseases have typically focused on drugs with antioxidant properties. Such approaches provide a "first line of defence" against free radicals, but do not target secondary products of oxidative stress. A complementary strategy involves the identification of low molecular weight drugs bearing nucleophilic centers (e.g., primary amine groups) that exhibit high reactivity toward endogenous aldehydes and, acting as "aldehyde scavengers", spare cellular constituents and slow down the disease's progression. Carnosine and carnosine-related peptides are promising candidates for this new therapeutic approach. The aim of this research project is the synthesis and the neuroprotective activity studies on new histidyl-containing molecular entities that combine the imidazole ring and the L-stereochemistry of histidine with aldehyde-reactive moieties able to increase the scavenging efficiency against alpha,beta-unsaturated aldehydes. In particular, we initially considered two nucleophilic moieties known to react promptly with carbonyl species, 1,2-diols and hydrazides.