Frank Lewis

Northumbria University United Kingdom
{{numberWithCommas(33)}} Publications

Novel 1-hydroxypyridin-2-one metal chelators prevent and rescue ubiquitin proteasomal-related neuronal injury in an in vitro model of Parkinson’s disease


Ubiquitin proteasome system (UPS) impairment, excessive cellular oxidative stress, and iron dyshomeostasis are key to substantia nigra dopaminergic neuronal degeneration in Parkinson's disease (PD); however, a link between these features remains unconfirmed. Using the proteasome inhibitor lactacystin we confirm that nigral injury via UPS impairment disrupts iron homeostasis, in turn increasing oxidative stress and promoting protein aggregation. We demonstrate the neuroprotective potential of two novel 1-hydroxy-2(1H)-pyridinone (1,2-HOPO) iron chelators, compounds C6 and C9, against lactacystin-induced cell death. We demonstrate that this cellular preservation relates to the compounds’ iron chelating capabilities and subsequent reduced capacity of iron to form reactive oxygen species (ROS), where we also show that the ligands act as antioxidant agents. Our results also demonstrate the ability of C6 and C9 to reduce intracellular lactacystin-induced α-synuclein burden. Stability constant measurements confirmed a high affinity of C6 and C9 for Fe3+ and display a 3:1 HOPO:Fe3+ complex formation at physiological pH. Reducing iron reactivity could prevent the demise of nigral dopaminergic neurons. We provide evidence that the lactacystin model presents with several neuropathological hallmarks of PD related to iron dyshomeostasis and that the novel chelating compounds C6 and C9 can protect against lactacystin-related neurotoxicity.

Exploring the Subtle Effect of Aliphatic Ring Size on Minor Actinide Extraction Properties and Metal Ion Speciation in Bis‐1,2,4‐Triazine Ligands

The synthesis and evaluation of three novel bis‐1,2,4‐triazine ligands containing 5‐membered aliphatic rings are reported. Compared to the more hydrophobic ligands 1–3 containing 6‐membered aliphatic rings, the distribution ratios for relevant f‐block metal ions were approx. one order of magnitude lower in each case. Ligand 10 showed an efficient, selective and rapid separation of Am(III) and Cm(III) from nitric acid. The speciation of the ligands with trivalent f‐block metal ions was probed using NMR titrations and competition experiments, time‐resolved laser fluorescence spectroscopy and X‐ray crystallography. While the tetradentate ligands 8 and 10 formed Ln(III) complexes of the same stoichiometry as their more hydrophobic analogues 2 and 3, significant differences in speciation were observed between the two classes of ligand, with a lower percentage of the extracted 1:2 complexes being formed for ligands 8 and 10. The structures of the solid state 1:1 and 1:2 complexes formed by 8 and 10 with Y(III), Lu(III) and Pr(III) are very similar to those formed by 2 and 3 with Ln(III). Ligand 10 forms Cm(III) and Eu(III) 1:2 complexes that are thermodynamically less stable than those formed by ligand 3, suggesting that less hydrophobic ligands form less stable An(III) complexes. Thus we show for the first time how tuning the cyclic aliphatic part of these ligands leads to subtle changes in their metal ion speciation, complex stability and metal extraction affinity.Chemistry – A European Journal, Volume 0, Issue ja, -Not available-.

Plutonium coordination and redox chemistry with the CyMe4-BTPhen polydentate N-donor extractant ligand

Complexation of Pu(iv) with the actinide extractant CyMe4-BTPhen (2,9-bis(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-1,2,4-benzotriazin-3-yl)-1,10-phenanthroline) was studied experimentally and by computational analysis.

Hydrophilic sulfonated bis-1,2,4-triazine ligands are highly effective reagents for separating actinides(iii) from lanthanides(iii) via selective formation of aqueous actinide complexes

Tetrasulfonated bis-1,2,4-triazine ligands can selectively complex and separate actinides from lanthanides in aqueous nitric acid with very high selectivities.

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