Kinetic studies on the oxidation of oxyhemoglobin by biologically active iron thiosemicarbazone complexes: relevance to iron-chelator-induced methemoglobinemia

Abstract

The oxidation of oxyhemoglobin to methemoglobin has been found to be facilitated by low molecular weight iron(III) thiosemicarbazone complexes. This deleterious reaction, which produces hemoglobin protein units unable to bind dioxygen and occurs during the administration of iron chelators such as the well-known 3-aminopyridine-2-pyridinecarbaldehyde thiosemicarbazone (3-AP; Triapine), has been observed in the reaction with Fe(III) complexes of some members of the 3-AP structurally-related thiosemicarbazone ligands derived from di-2-pyridyl ketone (HDpxxT series). We have studied the kinetics of this oxidation reaction in vitro using human hemoglobin and found that the reaction proceeds with two distinct time-resolved steps. These have been associated with sequential oxidation of the two different oxyheme cofactors in the α and β protein chains. Unexpected steric and hydrogen-bonding effects on the Fe(III) complexes appear to be the responsible for the observed differences in the reaction rate across the series of HDpxxT ligand complexes used in this study.

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

“…It also has been shown that [Fe III (Dp44mT) 2 ] + and [Fe III (Bp4eT) 2 ] + induce HbO 2 oxidation on intact human erythrocytes, erythrocyte lysates and purified oxyhemoglobin [4]. In an initial investigation [17], we revealed some interesting structural features that led to some members of the Fe III -HDpT complex family being more active than others toward HbO 2 oxidation. Against this background, herein we report a kinetico-mechanistic study on the ability of the Fe III complexes of the HBpT and…”

“…Given our previous knowledge on the oxidation reactions of HbO 2 by the HDpT series of Fe III complexes [4,17] and that the HDpT series may be altered by choice of a different parent ketone, tuning the reactivity toward HbO 2 can be easily achieved (Chart 1). Using 2-benzoylpyridine (instead of di-2-pyridyl ketone) a phenyl ring may be introduced at the imine carbon (instead of a noncoordinating pyridyl ring), generating the 2-benzoylpyridine thiosemicarbazone series (HBpT) [30].…”

“…HBp4mT and HBp44mT), HApT series (HApT, HAp4mT and HAp44mT), and Triapine ® (H3-AP) (Chart 1) have been examined under the same conditions as the HDpT series [17]. Analysis of the time-resolved spectral changes revealed a two-step process on different time-scales; no more than two steps were identified.…”

“…Outer sphere electron transfer reactions between synthetic complexes and HbO 2 , and its related monomeric protein myoglobin, have been extensively investigated [3,[10][11][12][13][14][15][16][17]. Given the environment of the heme prosthetic group, only an outer sphere mechanism is plausible and indeed this has been established [13,14].…”

Phase I Trial of Triapine–Cisplatin–Paclitaxel Chemotherapy for Advanced Stage or Metastatic Solid Tumor Cancers

“…In this trial, there was an elevated rate of grade 3 or 4 anemia (77%) after triapine–cisplatin–paclitaxel, possibly as a result of potent iron chelation by triapine (27) without interference in total iron binding capacity (22). This rate of anemia was not observed in contemporary cisplatin–paclitaxel trials [18–25% (5, 28)].…”