Metal-ion misregulation and oxidative stress have been linked to the progressive neurological decline associated with multiple neurodegenerative disorders. Transition metal-mediated oxidation of biomolecules via Fenton chemical reactions plays a role in disease progression. Herein we report the synthesis, characterization and antioxidant activity of 2; a pyclen derivative with enhanced antioxidant character.

Alzheimer's disease is a neurodegenerative disorder characterized by the development of intracellular neurofibrillary tangles, deposition of extracellular amyloid beta (Aβ) plaques, along with a disruption of transition metal ion homeostasis in conjunction with oxidative stress. Spectroscopic, transmission electron microscopy, and scanning electron microscopy imaging studies show that 1 (pyclen) is capable of both preventing and disrupting Cu 2+ induced AB 1−40 aggregation. The pyridine backbone of 1 engenders antioxidant capacity, as shown by cellular DCFH-DA (dichlorodihydrofluorescein diacetate) assay in comparison to other N-heterocyclic amines lacking this aromatic feature. Finally, 1 prevents cell death induced by oxidative stress as shown by the Calcein AM assay. The results are supported using density functional theory studies which show that the pyridine backbone is responsible for the antioxidant capacity observed.

The structural, electronic, and electrochemical properties of a series of novel 12-membered pyridine- and pyridol-based tetra-aza transition-metal (Ni, Cu, Zn) complexes {[M(II)(L1)Cl](ClO4), [M(II)(L2)Cl](ClO4), and [M(II)(L3)Cl](ClO4)} are described (L1 (Pyclen) = 1,4,7,10-tetra-aza-2,6-pyridinophane; L2 = 3,6,9,15-tetraazabicyclo[9.3.1]penta-deca-1(15),11,13-trien-13-ol; L3 = 3,6,9,15-tetra-azabicyclo[9.3.1]penta-deca- 1(15),11,13-trien-12-ol). The subtle variations in the chemical properties of these complexes were investigated using X-ray crystallography, UV-vis and NMR spectroscopy, and cyclic voltammetry. In the solid-state, the Ni(II) complexes adopt a unique bimetallic and cis-octahedral (μ-Cl)2 coordination sphere, and the electronic studies provide further evidence for the existence of a six-coordinate Ni(II) species in solution. The pyridol-based Cu(II) and Zn(II) complexes contain five-coordinate (N4Cl) geometries in the solid-state, in which the four N-donor atoms are not coplanar. Hydroxylation of the pyridine ring was found to increase the amount of π electronic charge density residing throughout the aromatic system of the ligand backbone, increase the strength of the M-Cl and M-N (pyridine) basal x- and y-plane interactions, and decrease the axial M-N bonding interaction. The electrochemical studies demonstrate that (i) the Lewis-acidity of the metal center systematically decreases across the series {[Cu(II)(L3)Cl](ClO4) > [Cu(II)(L1)Cl](ClO4) > [Cu(II)(L2)Cl](ClO4)}, and (ii) the aromatic backbones allow access to both Cu(I) and Cu(III) species in solution. Overall, the experimental findings are consistent with the idea that p-hydroxylation enhances the Lewis-basicity of pyridine-based macrocycle and decreases the Lewis-acidity of the metal-ion, while m-hydroxylation decreases the electron-donating ability of the backbone and increases the metal-ion Lewis-acidity.

The reaction of copper(II) perchlorate with the hydrochloride salt of 3, 6,9,15-tetraazabicyclo[9.3.1]penta-deca-1,11,13-triene (L1) in acetonitrile forms two macrocyclic complexes that can be characterized; [L1Cu II Cl][ClO 4 ] (1) and [L1Cu II Cl] 2 [CuCl 4 ] (2). The structural, electronic and redox properties of these complexes were studied using spectroscopy (EPR and UV-visible), and electrochemistry. In addition the solid state structure of 1 was obtained using X-ray diffraction. The copper(II) is five-coordinate; ligated by four N-atoms of the macrocycle and a chloride atom. EPR studies of 1 both DMF and aqueous solution indicate the presence of a single copper(II) species. In contrast, EPR studies of 2 performed in frozen DMF and in the solid-state reveal the presence of two spectroscopically distinct copper(II) complexes assigned as [L1Cu II Cl] + and [Cu II Cl 4 ] 2-. Lastly, electrochemical studies demonstrate that both [L1Cu II Cl] + and [Cu II Cl 4 ] 2-are redox active. Specifically, the [L1Cu II Cl] + undergoes a quasi-reversible Cu(II)/(I) redox reaction in the absence of excess chloride.In the presence of chloride, however, the chemical irreversibility of this couple becomes evident at concentrations of chloride that exceed 50 mM. As a result, the presence of chloride from the chemical equilibrium of this latter species impedes the reversibility of the reduction of [L1Cu II Cl] + to [L1Cu I Cl] 0 .