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pubmed:abstractText |
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.
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pubmed:affiliation |
Iron Metabolism and Chelation Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia.
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