Department of Pathology, University of Sydney, Sydney, New South Wales, Australia.
J Med Chem. 2009 Mar 12;52(5):1459-70. doi: 10.1021/jm801585u.
Through systematic structure-activity studies of the 2-benzoylpyridine thiosemicarbazone (HBpT), 2-(3-nitrobenzoyl)pyridine thiosemicarbazone (HNBpT) and dipyridylketone thiosemicarbazone (HDpT) series of iron (Fe) chelators, we identified structural features necessary to form Fe complexes with potent anticancer activity (J. Med. Chem. 2007, 50, 3716-3729). In this investigation, we generated the related 2-acetylpyridine thiosemicarbazone (HApT) analogues to examine the influence of the methyl group at the imine carbon. Four of the six HApT chelators had potent antitumor activity (IC(50): 0.001-0.002 microM) and Fe chelation efficacy that was similar to the most effective HBpT and HDpT ligands. The HApT Fe complexes had the lowest Fe(III/II) redox potentials of any thiosemicarbazone series we have generated. This property, in combination with their ability to effectively chelate cellular Fe, make the HApT series one of the most potent antiproliferative agents developed by our group.
通过对 2-苯甲酰基吡啶缩氨硫脲（HBpT）、2-(3-硝基苯甲酰基)吡啶缩氨硫脲（HNBpT）和二吡啶酮缩氨硫脲（HDpT）系列铁（Fe）螯合剂的系统结构活性研究，我们确定了形成具有强大抗癌活性的 Fe 配合物所需的结构特征（J. Med. Chem. 2007, 50, 3716-3729）。在这项研究中，我们生成了相关的 2-乙酰基吡啶缩氨硫脲（HApT）类似物，以研究亚胺碳原子上甲基的影响。六个 HApT 螯合剂中的四个具有很强的抗肿瘤活性（IC50：0.001-0.002 μM）和与最有效的 HBpT 和 HDpT 配体相似的 Fe 螯合效力。HApT Fe 配合物具有我们所生成的任何硫代缩氨脲系列中最低的 Fe(III/II)氧化还原电位。这种特性，加上它们有效螯合细胞内 Fe 的能力，使 HApT 系列成为我们小组开发的最有效的抗增殖剂之一。
