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Iron Chelators: Development of Novel Compounds with High and Selective Anti-Tumour Activity
Z Kovacevic, D S Kalinowski, D B Lovejoy
1Iron 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.
Abstract:
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.
Insights
Novel iron chelators, like di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT), show potent anti-cancer activity by generating radicals and inhibiting tumor growth. These compounds are effective at low doses and may be orally administered.
Area of Science:
- Medicinal Chemistry
- Cancer Therapeutics
- Molecular Biology
Background:
- Targeting essential nutrients for DNA synthesis is a proven cancer treatment strategy (e.g., methotrexate).
- Systematic exploration of iron's role in DNA synthesis for cancer therapy has been limited.
- Our laboratory has focused on developing novel iron chelators for anti-cancer applications.
Purpose of the Study:
- To develop novel iron chelators with anti-cancer efficacy through structure-activity studies.
- To investigate the anti-cancer potential of dipyridyl thiosemicarbazone chelators.
- To evaluate the efficacy and safety of di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT).
Main Methods:
- Structure-activity relationship studies of dipyridyl thiosemicarbazone derivatives.
- In vivo efficacy studies of Dp44mT in inhibiting tumor growth.
- Assessment of Dp44mT's mechanism of action involving redox-active iron complexes and radical generation.
Main Results:
- Developed dipyridyl thiosemicarbazone chelators with potent and selective anti-cancer activity, overcoming resistance to other agents.
- Dp44mT significantly inhibits tumor growth at low doses (0.4 mg/kg) without causing overt iron depletion.
- Dp44mT demonstrates superior activity and lower toxicity compared to the clinical chelator Triapine®.
Conclusions:
- Dipyridyl thiosemicarbazone chelators, exemplified by Dp44mT, represent a promising new class of anti-cancer agents.
- The anti-cancer mechanism involves the formation of redox-active iron complexes that generate radicals.
- Dp44mT's properties suggest potential for oral administration in addition to intravenous use.
