Enhancement of the Antioxidant Activity and Neurotherapeutic Features through Pyridol Addition to Tetraazamacrocyclic Molecules

Abstract

Alzheimer's and other neurodegenerative diseases are chronic conditions affecting millions of individuals worldwide. Oxidative stress is a consistent component described in the development of many neurodegenerative diseases. Therefore, innovative strategies to develop drug candidates that overcome oxidative stress in the brain are needed. To target these challenges, a new, water-soluble 12membered tetraaza macrocyclic pyridinophane L4 was designed and produced using a building-block approach. Potentiometric data show that the neutral species of L4 provides interesting zwitterionic behavior at physiological pH, akin to amino acids, and a nearly ideal isoelectric point of 7.3. The copper(II) complex of L4 was evaluated by X-ray diffraction and cyclic voltammetry to show the potential modes of antioxidant activity derived, which was also demonstrated by 2,2-diphenyl-1-picrylhydrazyl and coumarin carboxylic acid antioxidant assays. L4 was shown to have dramatically enhanced antioxidant activity and increased biological compatibility compared to parent molecules reported previously. L4 attenuated hydrogen peroxide (H 2 O 2 )-induced cell viability loss more efficiently than precursor molecules in the mouse hippocampal HT-22 cell model. L4 also showed potent (fM) level protection against H 2 O 2 cell death in a BV2 microglial cell culture. Western blot studies indicated that L4 enhanced the cellular antioxidant defense capacity via Nrf2 signaling activation as well. Moreover, a low-cost analysis and high metabolic stability in phase I and II models were observed. These encouraging results show how the rational design of lead compounds is a suitable strategy for the development of treatments for neurodegenerative diseases where oxidative stress plays a substantial role.

Amentoflavone: A Bifunctional Metal Chelator that Controls the Formation of Neurotoxic Soluble Aβ42 Oligomers

“…Given the mounting evidence supporting the role of transition metal ions in the pathophysiology of AD, use of metal-chelating chemical agents is emerging as a promising treatment strategy. ,,− Bifunctional metal chelators can interact with the Aβ species, and the metal ions are proposed to potentially be more effective therapeutics for AD. − These chelators should be able to cross the blood-brain barrier (BBB) and have to be minimally neurotoxic to be a valid method to control the onset of AD . However, we have previously shown that, for the Aβ 42 peptide, in contrast to the Aβ 40 peptide, the previously employed strategy of inhibiting Aβ aggregation and promoting amyloid fibril disaggregation may not be optimal for the development of potential AD therapeutics, due to formation of neurotoxic soluble Aβ 42 oligomers .…”

Recent progress in the chemistry of 12-membered pyridine-containing tetraazamacrocycles: from synthesis to catalysis

“…In line with their previous studies with OH-substituted pyclen derivatives (see Scheme 2), [10][11][12][13] Green's group also reported the synthesis of di-hydroxyl macrocyclic pyridinophane L40. 55 The ligand L40 was prepared by dimerization of 4-benzyloxy-2,6-bis-(chloromethyl)pyridine (2a) with tosyl amide 74 (Scheme 17). The removal of all protecting groups was performed in one step with lithium naphthalenide and acidic work-up.…”

A macrocyclic molecule with multiple antioxidative activities protects the lens from oxidative damage

“…As a result of the current challenges for diseases that involve oxidative stress, we designed the OH Py 2 N 2 multimodal small molecule ( Figure 1 ) with direct targeting reactivity against ROS ( Johnston et al, 2019 ). Several benchtop assays validated our initial hypothesis that the water soluble molecule could function as a direct antioxidant molecule.…”

“…Several benchtop assays validated our initial hypothesis that the water soluble molecule could function as a direct antioxidant molecule. Integration of a hydroxyl substituted pyridine group within a tetra-aza macrocyclic ring generates the OH Py 2 N 2 small molecule that can readily scavenge free radicals as well as bind mis-regulated transition metal ions, halting toxic metal redox processes ( Green et al, 2019 ; Johnston et al, 2019 ). Interestingly and not part of our initial design, which focused on direct reactivity with ROS, OH Py 2 N 2 showed the potential to activate cellular antioxidant defense capacity via activation of the Nrf2 (Nuclear factor erythroid 2-related factor 2) signaling pathway in neuronal cell culture along with low toxicity, high metabolic stability, and proving to be highly water soluble ( Johnston et al, 2019 ).…”

“…The recently established understanding of the direct antioxidant activity of OH Py 2 N 2 through radical and transition metal scavenging, along with preliminary results suggesting catalytic protection via the Nrf2 pathway prompted the present studies focused on the therapeutic potential and activation of defensive antioxidant mechanisms induced by OH Py 2 N 2 to protect against oxidative stress in the eye ( Johnston et al, 2019 ). To explore this potential, human lens epithelial cells were exposed to conditions that model oxidative stress and showed excellent cell viability when treated with OH Py 2 N 2 .…”