Evaluation of the therapeutic efficacy of small pyridine-containing molecules for treatment of neurodegenerative diseases

Abstract

Design of therapeutic molecules for treatment of neurodegenerative diseases must consider mechanisms of action that target misregulated reactive oxygen species (ROS), as extraneous ROS contribute to the development of disease. Antioxidant intervention of ROS includes quenching these species, as well as halting the generation of these species via redox cycling of mis-regulated transition metal ions. The study presented herein evaluates several antioxidant pathways of a new generation of Green Research Group molecules, including open-chain congeners and an indole derivative of established pyridinophane (PyN3) ligands. Open-chain congeners of PyN3 and OHPyN3, P-Py and P-OHPy respectively, failed to demonstrate radical scavenging reactivity due to an inability to quench 2,2-diphenyl-1-picrylhydrazyl. Conversely the indole derivative, IndPyN3, demonstrated a comparable reactivity to the parent hydroxyl pyridinophane, OHPyN3. The open-chain congeners also failed to reduce ROS generation via halting Cu(II/I) with ascorbic acid, while IndPyN3 was able to do so; the degree of inhibition ROS generation by IndPyN3 correlated with concentration and was comparable to OHPyN3. These results demonstrate that changing the macrocyclic structure of the pyridinophane to an open-chain structure disrupts therapeutic activity, while addition of the indole moiety to the pyridinophane scaffold does not do so. Finally, the complexation of pyridinophane ligands PyN3 and OHPyN3 with Cu2+, had varying effects on fatty acid peroxidation depending on incubation time. Both ligand-copper complexes increased fatty acid peroxidation with 2 hours of incubation at 37 °C. Conversely, both ligand-copper complexes reduced fatty acid peroxidation with 24 hours of incubation, demonstrating small amounts of antioxidant character.