Innovative N-Acridine Thiosemicarbazones and Their Zn(II) Complexes Transmetallate with Cu(II): Redox Activity and Suppression of Detrimental Oxy-Myoglobin Oxidation.

Busra Kaya, Henry Smith, Yanbing Chen, Mahan Gholam Azad, Tiffany M Russell, Vera Richardson, Mahendiran Dharmasivam, Des R Richardson

Inorganic chemistry 2024 Oct 28

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The coordination chemistry and electrochemistry of novel N-acridine thiosemicarbazones (NATs) were investigated along with their redox activity, antiproliferative efficacy, transmetalation, and dissociation properties. The ability of NAT Fe(III) complexes to inhibit detrimental oxy-myoglobin (oxy-Mb) oxidation was also examined. The NATs act as tridentate ligands with a 2:1 L/Zn(II) complex crystal structure, revealing a distorted octahedral geometry, where both ligands bind Zn(II) in a meridional conformation. The NAT Fe(III) complexes exhibited fully reversible one-electron FeIII/II couples with more positive potentials than the Fe(III) complexes of a related clinically trialed thiosemicarbazone (e.g., [Fe(DpC)2]+) due to the electron-donating capacity of acridine. Surprisingly, the NAT-Zn(II) complexes showed generally greater or similar antiproliferative activity than their ligands, Cu(II), or Fe(III) complexes. This may be explained by (1) formation of a highly lipophilic Zn(II) complex that acts as a chaperone to promote cellular uptake and (2) the capacity of the Zn(II) complex to dissociate or undergo transmetalation to the redox-active Cu(II) complex. Of the NAT-Fe(III) complexes, [Fe(AOBP)2]+ demonstrated a significant (p < 0.0001) improvement in preventing oxy-Mb oxidation than the Fe(III) complex of the clinically trialed thiosemicarbazone, DpC. This article advances our understanding of NAT coordination chemistry, electrochemistry, and the intriguing biological activity of their complexes.

Citation

Busra Kaya, Henry Smith, Yanbing Chen, Mahan Gholam Azad, Tiffany M Russell, Vera Richardson, Mahendiran Dharmasivam, Des R Richardson. Innovative N-Acridine Thiosemicarbazones and Their Zn(II) Complexes Transmetallate with Cu(II): Redox Activity and Suppression of Detrimental Oxy-Myoglobin Oxidation. Inorganic chemistry. 2024 Oct 28;63(43):20840-20858