Carnoquinolines Target Copper Dyshomeostasis, Aberrant Protein–Protein Interactions, and Oxidative Stress

• Published in: Chemistry : a European journal Vol. 26; no. 70; pp. 16690 - 16705
• Main Authors: Bellia, Francesco, Grasso, Giuseppa Ida, Ahmed, Ikhlas Mohamed Mohamud, Oliveri, Valentina, Vecchio, Graziella
• Format: Journal Article
• Language: English
• Published: Germany Wiley Subscription Services, Inc 15-12-2020
• Subjects: Agglomeration; aggregation; Amyloid; amyloid beta-peptides; Amyloid beta-Peptides - chemistry; Amyloid beta-Peptides - metabolism; Antioxidants; Antioxidants - chemistry; Antioxidants - pharmacology; Carbonyl compounds; Carbonyls; Carnosine; Carnosine - chemical synthesis; Carnosine - chemistry; Carnosine - pharmacology; Chemistry; Circular dichroism; Coordination compounds; Copper; Copper - chemistry; Copper - pharmacology; Copper compounds; Dichroism; Free radicals; Hybrids; Hydroxyquinoline; Imidazole; Neurodegeneration; Neurodegenerative diseases; NMR; Nuclear magnetic resonance; Oxidative stress; Oxidative Stress - drug effects; Phenolic compounds; Phenols; Protein Binding - drug effects; Protein interaction; Proteins; protein–protein interactions; Spectroscopy; neurodegeneration; copper; aggregation; amyloid beta-peptides; protein-protein interactions
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202001591

Metal dysregulation, oxidative stress, protein modification, and aggregation are factors strictly interrelated and associated with neurodegenerative pathologies. As such, all of these aspects represent valid targets to counteract neurodegeneration and, therefore, the development of metal‐binding compounds with other properties to combat multifactorial disorders is definitely on the rise. Herein, the synthesis and in‐depth analysis of the first hybrids of carnosine and 8‐hydroxyquinoline, carnoquinolines (CarHQs), which combine the properties of the dipeptide with those of 8‐hydroxyquinoline, are reported. CarHQs and their copper complexes were characterized through several techniques, such as ESI‐MS and NMR, UV/Vis, and circular dichroism spectroscopy. CarHQs can modulate self‐ and copper‐induced amyloid‐β aggregation. These hybrids combine the antioxidant activity of their parent compounds. Therefore, they can simultaneously scavenge free radicals and reactive carbonyl species, thanks to the phenolic group and imidazole ring. These results indicate that CarHQs are promising multifunctional candidates for neurodegenerative disorders and they are worthy of further studies.
Combining strengths: Carnoquinolines (CarHQs), the first carnosine–8‐hydroxyquinoline hybrids, combine the properties of the natural dipeptide (carnosine) with those of a known copper ionophore (8‐hydroxyquinoline). Conjugation provides multitargeted directed ligands that can target albumin, β‐amyloid (Aβ), copper ions, the copper–Aβ system, and radical and glycating agents. These findings indicate that CarHQs could provide lead compounds for neurodegenerative diseases.