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Issue 33, 2019
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Dialing in on pharmacological features for a therapeutic antioxidant small molecule

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Abstract

The pyridinophane molecule L2 (3,6,9,15-tetraazabicyclo[9.3.1]penta-deca-1(15),11,13-trien-13-ol) has shown promise as a therapuetic for neurodegenerative diseases involving oxidative stress and metal ion misregulation. Protonation and metal binding stability constants with Mg2+, Ca2+, Cu2+, and Zn2+ ions were determined to further explore the therapeutic and pharmacological potential of this water soluble small molecule. These studies show that incorporation of an –OH group in position 4 of the pyridine ring decreases the pI values compared to cyclen and L1 (3,6,9,15-tetraazabicyclo[9.3.1]penta-deca-1(15),11,13-triene). Furthermore, this approach tunes the basicity of the tetra-aza macrocyclic ligand through the enhanced resonance stabilization of the –OH in position 4 and rigidity of the pyridine ring such that L2 has increased basicity compared to previously reported tetra-aza macrocycles. A metal binding preference for Cu2+, a redox cycling agent known to produce oxidative stress, indicates that this would be the in vivo metal target of L2. However, the binding constant of L2 with Cu2+ is moderated compared to cyclen due to the rigidity of the ligand and shows how ligand design can be used to tune metal selectivity. An IC50 = 298.0 μM in HT-22 neuronal cells was observed. Low metabolic liability was determined in both Phase I and II in vitro models. Throughout these studies other metal binding systems were used for comparison and as appropriate controls. The reactivity reported to date and pharmacological features described herein warrant further studies in vivo and the pursuit of L2 congeners using the knowledge that pyridine substitution in a pyridinophane can be used to tune the structure of the ligand and retain the positive therapeutic outcomes.

Graphical abstract: Dialing in on pharmacological features for a therapeutic antioxidant small molecule

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Publication details

The article was received on 29 Apr 2019, accepted on 16 Jul 2019 and first published on 25 Jul 2019


Article type: Paper
DOI: 10.1039/C9DT01800J
Dalton Trans., 2019,48, 12430-12439

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    Dialing in on pharmacological features for a therapeutic antioxidant small molecule

    K. N. Green, K. Pota, G. Tircsó, R. A. Gogolák, O. Kinsinger, C. Davda, K. Blain, S. M. Brewer, P. Gonzalez, H. M. Johnston and G. Akkaraju, Dalton Trans., 2019, 48, 12430
    DOI: 10.1039/C9DT01800J

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