title: 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 Cu(2+) ions at physiological pH, displaying significant copper ion sequestering ability, and protect LDL from oxidation catalysed by Cu(2+) 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.
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via P. Giuria 9, I-10125 Torino, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Bertinaria
authors.forename: Barbara
authors.initials: B
authors.lastname: Rolando
authors.forename: Marta
authors.initials: M
authors.lastname: Giorgis
authors.forename: Gabriele
authors.initials: G
authors.lastname: Montanaro
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Marini
authors.forename: Massimo
authors.initials: M
authors.lastname: Collino
authors.forename: Elisa
authors.initials: E
authors.lastname: Benetti
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Daniele
authors.forename: Roberta
authors.initials: R
authors.lastname: Fruttero
authors.forename: Alberto
authors.initials: A
authors.lastname: Gasco
mesh_terms: D000447:Aldehydes / Q000037:antagonists & inhibitors; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002336:Carnosine / Q000031:analogs & derivatives* / Q000097:blood / Q000138:chemical synthesis / Q000494:pharmacology*; D055598:Chemical Phenomena; D060326:Chemistry Techniques, Synthetic; D003300:Copper / Q000737:chemistry; D004355:Drug Stability; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D066298:In Vitro Techniques; D008297:Male; D009569:Nitric Oxide / Q000737:chemistry*; D051381:Rats; D015427:Reperfusion Injury / Q000517:prevention & control; D014664:Vasodilation / Q000187:drug effects
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D009569:Nitric Oxide; D003300:Copper; D002336:Carnosine; C027576:4-hydroxy-2-nonenal