title: Alkyl substituted 2'-benzoylpyridine thiosemicarbazone chelators with potent and selective anti-neoplastic activity: novel ligands that limit methemoglobin formation.
abstract: Thiosemicarbazone chelators, including the 2'-benzoylpyridine thiosemicarbazones (BpT) class, show marked potential as anticancer agents. Importantly, 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) has been investigated in >20 phase I and II clinical trials. However, side effects associated with 3-AP administration include methemoglobinemia. Considering this problem, novel BpT analogues were designed bearing hydrophobic, electron-donating substituents at the para position of the phenyl group (RBpT). Their Fe(III/II) redox potentials were all within the range accessible to cellular oxidants and reductants, suggesting they can redox cycle. These RBpT ligands exhibited potent and selective antiproliferative activity, which was comparable or exceeded their BpT counterparts. Major findings include that methemoglobin formation mediated by the lipophilic t-BuBpT series was significantly (p < 0.05-0.001) decreased in comparison to 3-AP in intact red blood cells and were generally comparable to the control. These data indicate the t-BuBpT ligands may minimize methemoglobinemia, which is a marked advantage over 3-AP and other potent thiosemicarbazones.
authors.affiliation: Iron Metabolism and Chelation Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Christian
authors.initials: C
authors.lastname: Stefani
authors.forename: Patric J
authors.initials: PJ
authors.lastname: Jansson
authors.forename: Elaine
authors.initials: E
authors.lastname: Gutierrez
authors.forename: Paul V
authors.initials: PV
authors.lastname: Bernhardt
authors.forename: Des R
authors.initials: DR
authors.lastname: Richardson
authors.forename: Danuta S
authors.initials: DS
authors.lastname: Kalinowski
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001205:Ascorbic Acid / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004354:Drug Screening Assays, Antitumor; D005290:Ferric Compounds / Q000138:chemical synthesis / Q000737:chemistry; D005296:Ferrous Compounds / Q000138:chemical synthesis / Q000737:chemistry; D006801:Humans; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008706:Methemoglobin / Q000096:biosynthesis*; D015394:Molecular Structure; D010084:Oxidation-Reduction; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014168:Transferrin / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D005290:Ferric Compounds; D005296:Ferrous Compounds; D007502:Iron Chelating Agents; D008024:Ligands; D011725:Pyridines; D013882:Thiosemicarbazones; D014168:Transferrin; D008706:Methemoglobin; D001205:Ascorbic Acid