Design, synthesis, and characterization of novel iron chelators: structure-activity relationships of the 2-benzoylpyridine thiosemicarbazone series and their 3-nitrobenzoyl analogues as potent antitumor agents.
Previously, we demonstrated that the potent antiproliferative activity of the di-2-pyridylketone thiosemicarbazone (DpT) series of Fe chelators was due to their ability to induce Fe depletion and form redox-active Fe complexes (Richardson, D. R.; et al. J. Med. Chem. 2006, 49, 6510-6521). We now examine the role of aromatic substituents on the antiproliferative and redox activity of novel DpT analogues, namely, the 2-benzoylpyridine thiosemicarbazone (BpT) and 2-(3-nitrobenzoyl)pyridine thiosemicarbazone (NBpT) series. Both series exhibited selective antiproliferative effects, with the majority having greater antineoplastic activity than their DpT homologues. This makes the BpT chelators the most active anticancer agents developed within our laboratory. The BpT series Fe complexes exhibit lower redox potentials than their corresponding DpT and NBpT complexes, highlighting their enhanced redox activity. The increased ability of BpT-Fe complexes to catalyze ascorbate oxidation and benzoate hydroxylation, relative to their DpT and NBpT analogues, suggested that redox cycling plays an important role in their antiproliferative activity.
Kalinowski
Danuta S
DS
Iron Metabolism and Chelation Program, Department of Pathology, University of Sydney, Sydney, New South Wales 2006, Australia.
Yu
Yu
Y
Sharpe
Philip C
PC
Islam
Mohammad
M
Liao
Yi-Tyng
YT
Lovejoy
David B
DB
Kumar
Naresh
N
Bernhardt
Paul V
PV
Richardson
Des R
DR
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001205:Ascorbic Acid / Q000737:chemistry; D002460:Cell Line; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005290:Ferric Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D005296:Ferrous Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007501:Iron / Q000378:metabolism; D007502:Iron Chelating Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D015394:Molecular Structure; D009579:Nitrobenzoates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010084:Oxidation-Reduction; D011485:Protein Binding; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014168:Transferrin / Q000378:metabolism
D000970:Antineoplastic Agents; D005290:Ferric Compounds; D005296:Ferrous Compounds; D007502:Iron Chelating Agents; D008024:Ligands; D009579:Nitrobenzoates; D011725:Pyridines; D013882:Thiosemicarbazones; D014168:Transferrin; D007501:Iron; D001205:Ascorbic Acid