Kinetico-mechanistic studies on methemoglobin generation by biologically active thiosemicarbazone iron(III) complexes

The oxidation of human oxyhemoglobin (HbO₂) to methemoglobin (metHb) is an undesirable side effect identified in some promising thiosemicarbazone anti-cancer drugs. This is attributable to oxidation reactions driven by Fe^III complexes of these drugs formed in vivo. In this work the Fe^III complexes of selected 2-benzoylpyridine thiosemicarbazones (HBpT), 2-acetylpyridine thiosemicarbazones (HApT), and the clinically trialled thiosemicarbazone, Triapine® (3-amino-2-pyridinecarboxaldehyde thiosemicarbazone, H3-AP), have been studied. This was achieved by time-resolved UV-Visible absorption spectroscopy and the sequential oxidation of the α- and β-chains of HbO₂ at distinctly different rates has been identified. A key structural element, namely a terminal -NH₂ group on the thiosemicarbazone moiety, was found to be an important common feature of the most active HbO₂ oxidising complexes that were investigated. Therefore, these studies indicate that an unsubstituted -NH₂ moiety at the terminus of the thiosemicarbazone group should be avoided in the design of future compounds from this class.