Design, synthesis, and characterization of new iron chelators with anti-proliferative activity: structure-activity relationships of novel thiohydrazone analogues.
Di-2-pyridylketone isonicotinoyl hydrazone Fe chelators utilize the N,N,O-donor set and have moderate anti-proliferative effects. Their closely related N,N,S-thiosemicarbazone analogues, namely, the di-2-pyridylketone thiosemicarbazones, exhibit markedly increased anti-proliferative and redox activity, and this was thought to be due to the inclusion of a sulfur donor atom (Richardson, D. R. et al. J. Med. Chem. 2006, 49, 6510-6521). To further examine the effect of donor atom identity on anti-proliferative activity, we synthesized thiohydrazone analogues of extensively examined aroylhydrazone chelators. The O,N,S-thiohydrazones exhibited decreased anti-proliferative effects compared to their parent aroylhydrazones and reduced redox activity. In contrast, the N,N,S-thiohydrazones showed vastly increased anti-proliferative activity compared to their hydrazone analogues, being comparable to potent thiosemicarbazones. Additionally, N,N,S-thiohydrazone complexes had reversible FeIII/II couples and exhibited increased redox activity. These observations demonstrate that the N,N,S-donor set is critical for potent anti-proliferative efficacy.
Kalinowski
Danuta S
DS
Iron Metabolism and Chelation Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia.
Sharpe
Philip C
PC
Bernhardt
Paul V
PV
Richardson
Des R
DR
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001205:Ascorbic Acid / Q000378:metabolism; D001565:Benzoates / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D004563:Electrochemistry; D005296:Ferrous Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006835:Hydrazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006900:Hydroxylation; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D015394:Molecular Structure; D010084:Oxidation-Reduction; D013329:Structure-Activity Relationship; D013871:Thiones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014168:Transferrin / Q000378:metabolism
D000970:Antineoplastic Agents; D001565:Benzoates; D005296:Ferrous Compounds; D006835:Hydrazones; D007502:Iron Chelating Agents; D008024:Ligands; D013871:Thiones; D014168:Transferrin; D007501:Iron; D001205:Ascorbic Acid