Alkyl Substituted 2鈥?Benzoylpyridine Thiosemicarbazone Chelators with Potent and Selective Anti-Neoplastic Activity: Novel Ligands that Limit Methemoglobin Formation

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• 作者：Christian Stefani ; Patric J. Jansson ; Elaine Gutierrez ; Paul V. Bernhardt ; Des R. Richardson ; Danuta S. Kalinowski
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：January 10, 2013
• 年：2013
• 卷：56
• 期：1
• 页码：357-370
• 全文大小：673K
• 年卷期：v.56,no.1(January 10, 2013)
• ISSN：1520-4804

文摘

Thiosemicarbazone chelators, including the 2鈥?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鈥?.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.