Carnosine analogues containing NO-donor substructures: Synthesis, physico-chemical characterization and preliminary pharmacological profile

Abstract

The synthesis, physico-chemical, and biological characterisation of a short series of carnosine amides bearing NO-donor nitrooxy functionalities are described. The NO-donor carnosine analogues and their des-NO derivatives display carnosine-like properties, differing from the lead for their high serum stability. The newly-synthesised compounds are able to complex Cu2+ ions at physiological pH, displaying significant copper ion sequestering ability, and protect LDL from oxidation catalysed by Cu2+ ions. All products show moderately-potent HNE quenching activity. The NO-donor compounds 7c–f relaxed rat aorta strips via an NO-dependent mechanism. In vivo evaluation of organ protection in a model of cerebral ischaemia/reperfusion injury, using the selected NO-donor 7e and its des-NO analogue 7a, showed that both derivatives protect from hypoxia-induced brain damage, at lower concentrations than carnosine; 7e also decreased serum TNF-α levels. This class of NO-donor carnosine amides is worthy of further study as potential tools for treating a wide range of chronic vascular and neurodegenerative diseases in which NO-bioavailability is reduced.