Complex structures, formation thermodynamics and substitution reaction kinetics in the copper(II) – glycylglycylglycine – L/D/DL-histidine system

Complex formation thermodynamics in the copper(II) – glycylglycylglycine (GGG·H) and copper(II) – glycylglycylglycine – L/D-histidine (HisH) systems (25.0 °C, 1.0 M KNO3) was investigated by pH-potentiometric titration and spectrophotometry methods in a wide pH range (2–13). Five hetero-ligand complexes were identified, three of which were characterized for the first time including one binuclear complex. Parameters of individual absorption spectra and ESR spectra of the heteroligand copper(II) complexes with glycylglycylglycine and histidine were obtained for the first time. Complex structures were optimized by DFT computations on the CAM-B3LYP/TZVPP and PBE/TZVPP levels with accounting solvent effect by the C-PCM model. For the complex Cu(GGG·H-2)(His)2− the rapid exchange between two isomers with axial coordination of the imidazole or carboxyl group of His− was first found. It was shown that the complex Cu2(GGG·H-2)(His)(HisH-1)2− presents as two isomers where deprotonated imidazole of the HisH-12− ligand connects two copper ions. The kinetics of glycylglycylglycine substitution by L/DL-histidine was investigated by stopped-flow technique with spectrophotometric detection and three-step scheme of the investigated process was proposed. An unusual stereoselective effect in the tripeptide substitution by anionic form of histidine was revealed and interpreted on the basis of the formation of heteroligand complexes as intermediates in overall processes, that was confirmed by DFT calculations. It is emphasized that only combination of several informative methods (pH-metry, UV–Vis-spectroscopy, ESR, stopped-flow, and DFT calculations) made it possible to reliably describe simultaneously the thermodynamics of formation, the kinetics of substitution reactions, and the structure of complexes in the complex ternary system under study

Bi-functional sterically hindered phenol lipid-based delivery systems as potential multi-target agents against Alzheimer's disease: Via an intranasal route

© The Royal Society of Chemistry. New lipid-based nanomaterials and multi-target directed ligands (MTDLs) based on sterically hindered phenol, containing a quaternary ammonium moiety (SHP-s-R, with s = 2,3) of varying hydrophobicity (R = CH2Ph and CnH2n+1, with n = 8, 10, 12, 16), have been prepared as potential drugs against Alzheimer's disease (AD). SHP-s-R are inhibitors of human cholinesterases with antioxidant properties. The inhibitory potency of SHP-s-R and selectivity ratio of cholinesterase inhibition were found to significantly depend on the length of the methylene spacer (s) and alkyl chain length. The compound SHP-2-16 showed the best IC50 for human AChE and the highest selectivity, being 30-fold more potent than for human BChE. Molecular modeling of SHP-2-16 binding to human AChE suggests that this compound is a dual binding site inhibitor that interacts with both the peripheral anionic site and catalytic active site. The relationship between self-assembly parameters (CMC, solubilization capacity, aggregation number), antioxidant activity and a toxicological parameter (hemolytic action on human red blood cells) was investigated. Two sterically hindered phenols (SHP-2-Bn and SHP-2-R) were loaded into L-a-phosphatidylcholine (PC) nanoparticles by varying the SHP alkyl chain length. For the brain AChE inhibition assay, PC/SHP-2-Bn/SHP-2-16 nanoparticles were administered to rats intranasally at a dose of 8 mg kg-1. The Morris water maze experiment showed that scopolamine-induced AD-like dementia in rats treated with PC/SHP-2-Bn/SHP-2-16 nanoparticles was significantly reduced. This is the first example of cationic SHP-phospholipid nanoparticles for inhibition of brain cholinesterases realized by the use of intranasal administration. This route has promising potential for the treatment of AD