Synthesis, characterization, and cytotoxicity studies of Cu(II), Zn(II), and Fe(III) complexes of N-derivatized 3-hydroxy-4-pyridiones

• 3-Hydroxy-4-pyridinone derivatives form complexes with Zn(II) and Fe(III) ions.
• Zn(II) complex is a bis multinuclear species in the solid state.
• Fe(III) tris complexes include hydrogen-bonded water networks in the solid state.
• Ligands are more cytotoxic than reference compound cisplatin.
• Toxicity of ligands and selected complexes was examined in a neuronal cell line.

The deleterious role of metal ions in Alzheimer's disease has inspired the study of various metal chelators. We previously showed the synthesis and in vitro activity of several bidentate hydroxypyridinone compounds, including 3-hydroxy-2-methyl-1-phenyl-4(1H)-pyridinone (1), 1-(4-aminophenyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (2), and 1-(2-benzothiazolyl)-3-hydroxy-2-methyl-4(1H)-pyridinone (3). While the focus has been on the Cu(II) ion, the other biorelevant metals, Zn(II) and Fe(III) have been largely neglected. Herein, we report the synthesis of Zn(II) and Fe(III) complexes of ligands 1, 2, and 3, and their characterization by infrared (IR) spectroscopy, high resolution mass spectrometry (HR-MS), elemental analysis, and NMR, where applicable. Solid state structures of Zn(1)2, Fe(1)3, and Cu(3)2 are analyzed with X-ray crystallography. The cytotoxicity of pro-ligands 1, 2, and 3, and the three metal complexes of 2 are examined in a neuronal cell line to determine the effect of metal chelation on toxicity of the compounds.

3-Hydroxy-4-pyridinone derivatives bind bioactive Zn(II) and Fe(III) metal ions. X-ray crystallography reveals that Zn(II) complex is a bis multinuclear species, while Fe(III) complexes include extended hydrogen bonded water networks. The cytotoxicity of Cu(II), Zn(II), and Fe(III) complexes of one ligand was determined in a neuronal cell line.Figure optionsDownload as PowerPoint slide