title: Copper(II) complexation of tacrine hybrids with potential anti-neurodegenerative roles.
abstract: The complexity and multifactorial nature of neurodegenerative diseases turn quite difficult the development of adequate drugs for their treatment. Multi-target analogues, in conjugation with natural moieties, have been developed in order to combine acetylcholinesterase (AChE) inhibition with antioxidant properties, metal-binding capacity and inhibition of amyloid-β (Aβ) aggregation. Due to the recent interest on natural-based drugs and also the importance of studying the role of transition metal ions in the disease process, we herein evaluate the copper chelating capacity and inhibitory ability for self- and Cu-induced Aβ1-42 aggregation of two nature-base hybrid model compounds obtained from conjugation of a tacrine moiety with a S-allylcystein (1) or S-propargylcystein (2) moiety. Both compounds show a moderate chelating power towards Cu(II) (pCu 7.13-7.51, CL/CCu=10, CCu=10(-6)M, pH7.4), with predominant formation of 1:1 complex species (CuL, CuH-1L) for which the coordination sphere involves the N-amide and the NH2 amine of the cysteine derivative as well as the NH of tacrine. The compounds are able to improve the inhibition of Aβ aggregation in the presence of Cu(II) and this is slightly more relevant for the allyl derivative (1), a stronger copper chelator, than for the propargyl (2). Moreover, the presence of a chloro atom in the tacrine moiety and the size of the chain length between the two NH groups appeared also to improve the inhibition capacity for Aβ aggregation.
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal.
authors.forename: Catarina
authors.initials: C
authors.lastname: Quintanova
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal; Centre for Nano and Material Sciences, Jain University, Jain Global Campus, Bangalore, Karnataka 562112, India.
authors.forename: Rangappa S
authors.initials: RS
authors.lastname: Keri
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal. Electronic address: silvia.chaves@tecnico.ulisboa.pt.
authors.forename: Sílvia
authors.initials: S
authors.lastname: Chaves
authors.affiliation: Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais 1, 1049-001 Lisboa, Portugal.
authors.forename: M Amélia
authors.initials: MA
authors.lastname: Santos
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy; D016229:Amyloid beta-Peptides / Q000737:chemistry; D002614:Chelating Agents / Q000737:chemistry; D002800:Cholinesterase Inhibitors / Q000737:chemistry; D056831:Coordination Complexes / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D003545:Cysteine / Q000737:chemistry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D015394:Molecular Structure; D021241:Spectrometry, Mass, Electrospray Ionization; D013619:Tacrine / Q000737:chemistry*
chemical_list: D016229:Amyloid beta-Peptides; D002614:Chelating Agents; D002800:Cholinesterase Inhibitors; D056831:Coordination Complexes; D013619:Tacrine; D003300:Copper; D003545:Cysteine
keywords: Anti-neurodegeneratives; Copper chelation; S-allylcysteine; S-propargylcysteine; Tacrine