title: Kinetico-mechanistic studies on methemoglobin generation by biologically active thiosemicarbazone iron(III) complexes.
abstract: 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 FeIIIcomplexes of these drugs formed in vivo. In this work the FeIIIcomplexes 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 HbO2at distinctly different rates has been identified. A key structural element, namely a terminal -NH2group on the thiosemicarbazone moiety, was found to be an important common feature of the most active HbO2oxidising complexes that were investigated. Therefore, these studies indicate that an unsubstituted -NH2moiety at the terminus of the thiosemicarbazone group should be avoided in the design of future compounds from this class.
authors.affiliation: School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane 4072, Australia.
authors.forename: Maram T
authors.initials: MT
authors.lastname: Basha
authors.affiliation: School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane 4072, Australia.
authors.forename: Jeane
authors.initials: J
authors.lastname: Bordini
authors.affiliation: Molecular Pharmacology and Pathology Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney 2006, Australia.
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
authors.affiliation: Departament de Química Inorgànica, Universitat de Barcelona, Martí i Franquès 1-11, E-08028 Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Martinez
authors.affiliation: School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane 4072, Australia. Electronic address: p.bernhardt@uq.edu.au.
authors.forename: Paul V
authors.initials: PV
authors.lastname: Bernhardt
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D056831:Coordination Complexes / Q000737:chemistry*; D006801:Humans; D007501:Iron / Q000737:chemistry; D007502:Iron Chelating Agents / Q000737:chemistry*; D007700:Kinetics; D008706:Methemoglobin / Q000737:chemistry*; D008958:Models, Molecular; D010084:Oxidation-Reduction; D010108:Oxyhemoglobins / Q000737:chemistry*; D017433:Protein Structure, Secondary; D011725:Pyridines / Q000737:chemistry*; D012996:Solutions; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000737:chemistry*
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D007502:Iron Chelating Agents; D010108:Oxyhemoglobins; D011725:Pyridines; D012996:Solutions; D013882:Thiosemicarbazones; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; C033836:2-acetylpyridine thiosemicarbazone; D008706:Methemoglobin; D007501:Iron
keywords: Haemoglobin; Iron; Methemoglobin; Thiosemicarbazone