Iron Chelators: Development of Novel Compounds with High and Selective Anti-Tumour Activity.
Targeting essential nutrients (eg., those required for DNA synthesis) to inhibit cancer cell growth is a well established therapeutic strategy. A good example is the highly successful folate antagonist, methotrexate. However, up until recently, strategies to target iron which is also crucial for DNA synthesis have not been systematically explored to develop agents for the treatment of cancer. Over the last 15 years, our laboratory has embarked upon structure-activity studies designed to develop novel Fe chelators with anti-cancer efficacy. These studies have led to the development of the dipyridyl thiosemicarbazone chelators that show potent and selective anti-cancer activity and which overcome resistance to other cytotoxic agents. This class of compounds include the chelator, di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), which at optimal doses markedly inhibits tumour growth and is well tolerated. Moreover, this ligand does not induce overt Fe-depletion in vivo, probably because very low doses (0.4 mg/kg) are effective at inhibiting tumour growth. Importantly, our compounds are far more active and less toxic than the chelator, Triapine®, that is being assessed in a wide variety of international clinical trials. A vital part of the mechanism of action of these compounds is their ability to form a redox-active Fe complex that generates radicals to inhibit tumour growth. Due to their relatively high lipophilicity and low molecular weight of this class of compounds, oral activity may be expected in addition to their well known efficacy via the intravenous route.
Kovacevic
Z
Z
Kalinowski
D S
DS
Lovejoy
D B
DB
Quach
P
P
Wong
J
J
Richardson
D R
DR
Iron Metabolism and Chelation Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales, 2006 Australia. d.richardson@med.usyd.edu.au.
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D001692:Biological Transport; D015195:Drug Design; D006801:Humans; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D011725:Pyridines / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D013882:Thiosemicarbazones / Q000009:adverse effects / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D007502:Iron Chelating Agents; D011725:Pyridines; D013882:Thiosemicarbazones; C078157:3-aminopyridine-2-carboxaldehyde thiosemicarbazone; D007501:Iron