Innovative <i>N</i>‑Acridine Thiosemicarbazones\nand Their Zn(II) Complexes Transmetallate with Cu(II): Redox Activity\nand Suppression of Detrimental Oxy-Myoglobin Oxidation

The\ncoordination chemistry and electrochemistry of novel <i>N</i>-acridine thiosemicarbazones (NATs) were investigated along\nwith their redox activity, antiproliferative efficacy, transmetalation,\nand dissociation properties. The ability of NAT Fe(III) complexes\nto inhibit detrimental oxy-myoglobin (oxy-Mb) oxidation was also examined.\nThe NATs act as tridentate ligands with a 2:1 L/Zn(II) complex crystal\nstructure, revealing a distorted octahedral geometry, where both ligands\nbind Zn(II) in a meridional conformation. The NAT Fe(III) complexes\nexhibited fully reversible one-electron Fe<sup>III/II</sup> couples\nwith more positive potentials than the Fe(III) complexes of a related\nclinically trialed thiosemicarbazone (e.g., [Fe(DpC)<sub>2</sub>]<sup>+</sup>) due to the electron-donating capacity of acridine. Surprisingly,\nthe NAT-Zn(II) complexes showed generally greater or similar antiproliferative\nactivity than their ligands, Cu(II), or Fe(III) complexes. This may\nbe explained by (<b>1</b>) formation of a highly lipophilic\nZn(II) complex that acts as a chaperone to promote cellular uptake\nand (<b>2</b>) the capacity of the Zn(II) complex to dissociate\nor undergo transmetalation to the redox-active Cu(II) complex. Of\nthe NAT-Fe(III) complexes, [Fe(AOBP)<sub>2</sub>]<sup>+</sup> demonstrated\na significant (<i>p</i> < 0.0001) improvement in preventing\noxy-Mb oxidation than the Fe(III) complex of the clinically trialed\nthiosemicarbazone, DpC. This article advances our understanding of\nNAT coordination chemistry, electrochemistry, and the intriguing biological\nactivity of their complexes.