Alkyl substituted 2′-benzoylpyridine thiosemicarbazone chelators with potent and selective anti-neoplastic activity: novel ligands that limit methemoglobin formation

Stefani, Christian, Jansson, Patric J., Gutierrez, Elaine, Bernhardt, Paul V., Richardson, Des R. and Kalinowski, Danuta S. (2013) Alkyl substituted 2′-benzoylpyridine thiosemicarbazone chelators with potent and selective anti-neoplastic activity: novel ligands that limit methemoglobin formation. Journal of Medicinal Chemistry, 56 1: 357-370. doi:10.1021/jm301691s


Author Stefani, Christian
Jansson, Patric J.
Gutierrez, Elaine
Bernhardt, Paul V.
Richardson, Des R.
Kalinowski, Danuta S.
Title Alkyl substituted 2′-benzoylpyridine thiosemicarbazone chelators with potent and selective anti-neoplastic activity: novel ligands that limit methemoglobin formation
Journal name Journal of Medicinal Chemistry   Check publisher's open access policy
ISSN 0022-2623
1520-4804
Publication date 2013-01
Year available 2012
Sub-type Article (original research)
DOI 10.1021/jm301691s
Volume 56
Issue 1
Start page 357
End page 370
Total pages 14
Place of publication Washington, DC, United States
Publisher American Chemical Society
Collection year 2013
Language eng
Formatted abstract
Thiosemicarbazone chelators, including the 2′-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 FeIII/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 < 0.05-0.001) 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.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online: 31 December 2012.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2013 Collection
School of Chemistry and Molecular Biosciences
 
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Created: Fri, 08 Feb 2013, 13:23:02 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences