title: Synthesis, physicochemical characterization, and biological activities of new carnosine derivatives stable in human serum as potential neuroprotective agents.
abstract: The synthesis and the physicochemical and biological characterization of a series of carnosine amides bearing on the amido group alkyl substituents endowed with different lipophilicity are described. All synthesized products display carnosine-like properties differentiating from the lead for their high serum stability. They are able to complex Cu(2+) ions at physiological pH with the same stoichiometry as carnosine. The newly synthesized compounds display highly significant copper ion sequestering ability and are capable of protecting LDL from oxidation catalyzed by Cu(2+) ions, the most active compounds being the most hydrophilic ones. All the synthesized amides show quite potent carnosine-like HNE quenching activity; in particular, 7d, the member of the series selected for this kind of study, is able to cross the blood-brain barrier (BBB) and to protect primary mouse hippocampal neurons against HNE-induced death. These products can be considered metabolically stable analogues of carnosine and are worthy of additional investigation as potential neuroprotective agents.
authors.affiliation: Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Via Pietro Giuria 9, 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: Stefano
authors.initials: S
authors.lastname: Guglielmo
authors.forename: M Federica
authors.initials: MF
authors.lastname: Buonsanti
authors.forename: Valentina
authors.initials: V
authors.lastname: Carabelli
authors.forename: Daniela
authors.initials: D
authors.lastname: Gavello
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 / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000378:metabolism; D002336:Carnosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002413:Cations, Divalent; D016923:Cell Death / Q000187:drug effects; D002614:Chelating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D003300:Copper / Q000378:metabolism; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004355:Drug Stability; D016166:Free Radical Scavengers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D006801:Humans; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000378:metabolism; D008297:Male; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction; D050050:Protein Carbonylation; D051381:Rats; D017208:Rats, Wistar; D044967:Serum; D013329:Structure-Activity Relationship
chemical_list: D000447:Aldehydes; D000975:Antioxidants; D002413:Cations, Divalent; D002614:Chelating Agents; D004151:Dipeptides; D016166:Free Radical Scavengers; D008077:Lipoproteins, LDL; D018696:Neuroprotective Agents; C556314:beta-alanyl-N-propylhistidinamide; D003300:Copper; D002336:Carnosine; C027576:4-hydroxy-2-nonenal