Kalinowski Danuta S, Sharpe Philip C, Bernhardt Paul V, Richardson Des R
Iron Metabolism and Chelation Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia.
J Med Chem. 2007 Nov 29;50(24):6212-25. doi: 10.1021/jm070839q. Epub 2007 Oct 27.
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.
二 - 2 - 吡啶酮异烟酰腙铁螯合剂利用N，N，O供体组，具有中等的抗增殖作用。它们密切相关的N，N，S - 硫代半卡巴腙类似物，即二 - 2 - 吡啶酮硫代半卡巴腙，表现出显著增强的抗增殖和氧化还原活性，这被认为是由于包含了一个硫供体原子（理查森，D.R.等人，《药物化学杂志》，2006年，49卷，6510 - 6521页）。为了进一步研究供体原子特性对抗增殖活性的影响，我们合成了经过广泛研究的芳酰腙螯合剂的硫腙类似物。与它们的母体芳酰腙相比，O，N，S - 硫腙表现出降低的抗增殖作用和降低的氧化还原活性。相反，与它们的腙类似物相比，N，N，S - 硫腙显示出极大增强的抗增殖活性，与有效的硫代半卡巴腙相当。此外，N，N，S - 硫腙配合物具有可逆的FeIII/II电对，并表现出增强的氧化还原活性。这些观察结果表明，N，N，S供体组对于有效的抗增殖功效至关重要。
