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1. Synthesis, Physicochemical Characterization, and Biological Activities of New Carnosine Derivatives Stable in Human Serum As Potential Neuroprotective Agents

Author

Valentina Carabelli, Roberta Fruttero, Gabriele Montanaro, M. Federica Buonsanti, Massimo Bertinaria, Marta Giorgis, Pier Giuseppe Daniele, Daniela Gavello, Barbara Rolando, Alberto Gasco, and Stefano Guglielmo

Subjects
Male, Serum, Cations, Divalent, Carnosine, In Vitro Techniques, Hippocampus, Neuroprotection, Antioxidants, Catalysis, Protein Carbonylation, HNE-scavenging, Mice, Structure-Activity Relationship, chemistry.chemical_compound, Copper ion sequestering, Drug Stability, carnosine, antioxidants, copper complexes, Drug Discovery, Animals, Humans, Organic chemistry, Rats, Wistar, Alkyl, Chelating Agents, Neurons, chemistry.chemical_classification, Aldehydes, Quenching (fluorescence), Primary (chemistry), Cell Death, Chemistry, Dipeptides, Free Radical Scavengers, Rats, Lipoproteins, LDL, Neuroprotective Agents, Blood-Brain Barrier, Lipophilicity, Molecular Medicine, Oxidation-Reduction, Copper
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.

Published
2010
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2. Carnosine analogues containing NO-donor substructures: Synthesis, physico-chemical characterization and preliminary pharmacological profile

Author

Barbara Rolando, Gabriele Montanaro, Pier Giuseppe Daniele, Roberta Fruttero, Elisa Benetti, Marta Giorgis, Alberto Gasco, Massimo Bertinaria, Massimo Collino, and Elisabetta Marini

Subjects
Male, Chemical Phenomena, Carnosine, Nitrooxy derivatives, Chemistry Techniques, Synthetic, Carnosine amides, In Vitro Techniques, Antioxidants, No donors, Nitric oxide, chemistry.chemical_compound, Copper ion sequestering, Drug Stability, In vivo, Drug Discovery, medicine, Animals, Humans, Pharmacology, Aldehydes, Quenching (fluorescence), Cerebral ischaemia, Organic Chemistry, General Medicine, medicine.disease, Rats, Vasodilation, chemistry, Biochemistry, Reperfusion Injury, Hydrophobic and Hydrophilic Interactions, Reperfusion injury, Copper
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.

Published
2012

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