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.
Keywords: Iron, chelator, cancer, thiosemicarbazones
Current Drug Delivery
Title: Iron Chelators: Development of Novel Compounds with High and Selective Anti-Tumour Activity
Volume: 7 Issue: 3
Author(s): Z. Kovacevic, D.S. Kalinowski, D.B. Lovejoy, P. Quach, J. Wong and D.R. Richardson
Affiliation:
Keywords: Iron, chelator, cancer, thiosemicarbazones
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.
Export Options
About this article
Cite this article as:
Kovacevic Z., Kalinowski D.S., Lovejoy D.B., Quach P., Wong J. and Richardson D.R., Iron Chelators: Development of Novel Compounds with High and Selective Anti-Tumour Activity, Current Drug Delivery 2010; 7 (3) . https://dx.doi.org/10.2174/156720110791560991
DOI https://dx.doi.org/10.2174/156720110791560991 |
Print ISSN 1567-2018 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-5704 |
Call for Papers in Thematic Issues
Advances of natural products, bio-actives and novel drug delivery system against emerging viral infections
Due to the increasing prevalence of viral infections and the ability of these human pathogens to develop resistance to current treatment strategies, there is a great need to find and develop new compounds to combat them. These molecules must have low toxicity, specific activity and high bioavailability. The most suitable ...read more
Electrospun Fibers as Drug Delivery Systems
In recent years, electrospun fibers have attracted considerable attention as potential platforms for drug delivery due to their distinctive properties and adaptability. These fibers feature a notable surface area-to-volume ratio and can be intentionally designed with high porosity, facilitating an increased capacity for drug loading and rendering them suitable for ...read more
Emerging Nanotherapeutics for Mitigation of Neurodegenerative Disorders
Conditions affecting the central nervous system (CNS) present a significant hurdle due to limited access of both treatments and diagnostic tools for the brain. The blood-brain barrier (BBB) acts as a barrier, restricting the passage of molecules from the bloodstream into the brain. The most formidable challenge facing scientists is ...read more
Nanotechnology Based Chemotherapy for the treatment of Head & Neck Cancer
The escalating recurrence rates observed in Head and Neck cancer, particularly within the chemo-therapeutically treated cohort (50-60%), can be attributed to the non-selective nature of current anticancer drug delivery modalities. In this context, nanotechnology-based drug delivery systems emerge as a promising avenue for achieving precise localization of therapeutic agents to ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
Related Articles
-
Role of PGE2 in Blood Pressure Regulation
Current Hypertension Reviews Pharmacotherapy in Type 2 Diabetes: A Functional Schema for Drug Classification
Current Diabetes Reviews The Role of Mammalian Target of Rapamycin (mTOR) Inhibitors in the Treatment of Solid Tumors
Current Cancer Therapy Reviews The Functions of Heparanase in Human Diseases
Mini-Reviews in Medicinal Chemistry EDITORIAL [Hot Topic-II: PPAR Ligands and Cardiovascular Disorders: Friend or Foe (Guest Editors: Pitchai Balakumar and Gowraganahalli Jagadeesh)]
Current Molecular Pharmacology Noteworthy Secondary Metabolites Naphthoquinones – their Occurrence, Pharmacological Properties and Analysis
Current Pharmaceutical Analysis Molecular Mechanisms, Proteinopathies and Therapeutic Strategies in Neurodegenerative Disorders
Current Genomics Etiopathogenesis, Classical Immunotherapy and Innovative Nanotherapeutics for Inflammatory Neurological Disorders
Current Nanoscience Heat Shock Proteins (HSPs) Based Anti-Cancer Vaccines
Current Molecular Medicine Near-infrared Light Responsive Upconversion Nanoparticles for Imaging, Drug Delivery and Therapy of Cancers
Current Nanoscience Hepatic Steatosis and Peroxisomal Fatty Acid Beta-oxidation
Current Drug Metabolism Small Players With Big Roles: MicroRNAs as Targets to Inhibit Breast Cancer Progression
Current Drug Targets Synthesis and Antitumor Evaluation of Thiophene Analogs of Kigelinone
Letters in Organic Chemistry Human Leukemia and Lymphoma Cell Lines as Models and Resources
Current Medicinal Chemistry Alpha-Helical Cationic Anticancer Peptides: A Promising Candidate for Novel Anticancer Drugs
Mini-Reviews in Medicinal Chemistry Multimodality Imaging of CXCR4 in Cancer: Current Status towards Clinical Translation
Current Molecular Medicine Multiple Functions of Generic Drugs: Future Perspectives of Aureolic Acid Group of Anti-Cancer Antibiotics and Non-Steroidal Anti-Inflammatory Drugs
Mini-Reviews in Medicinal Chemistry Garlic (<i>Allium sativum</i> L.): Its Chemistry, Nutritional Composition, Toxicity, and Anticancer Properties
Current Topics in Medicinal Chemistry Editorial [Hot Topic: SOD Enzymes and Their Mimics in Cancer: Pro- vs Anti-Oxidative Mode of Action-Part I (Guest Editor: Ines Batinic-Haberle)]
Anti-Cancer Agents in Medicinal Chemistry A Facile and Green Synthesis of Novel Imide and Amidic Acid Derivatives of Phenacetin as Potential Analgesic and Anti-Pyretic Agents
Letters in Organic Chemistry