The medicinal chemistry of novel iron chelators for the treatment of cancer

Zaklina Kovacevic, Danuta S. Kalinowski, David B. Lovejoy, Yu Yu, Yohan Suryo Rahmanto, Phillip C. Sharpe, Paul V. Bernhardt, Des R. Richardson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

60 Citations (Scopus)

Abstract

Cancer is one of the leading causes of death worldwide and there is an increasing need for novel anti-tumor therapeutics with greater selectivity and potency. A new strategy in the treatment of cancer has focused on targeting an essential cell metabolite, iron (Fe). Iron is vital for cell growth and metabolism, forming a crucial component of the active site of ribonucleotide reductase (RR), the rate-limiting enzyme in DNA synthesis. Cancer cells in particular require large amounts of Fe to proliferate, making them more susceptible to the Fe deficiency caused by Fe chelators. Beginning with primordial siderophores, Fe chelators have since evolved to a new generation of potent and efficient anti-cancer agents. Recently, investigations have led to the generation of novel di-2-pyridylketone thiosemicarbazone (DpT) and 2-benzoylpyridine thiosemicarbazone (BpT) ligands that demonstrate marked and selective anti-tumor activity both in vitro and in vivo against a wide spectrum of tumors. The mechanism of action of these novel ligands includes alterations in the expression of key regulatory molecules as well as the generation of redox active Fe complexes. Interestingly, non-synthetic Fe chelators including silybin and curcumin, both of which are derived from plants, also have a high potential in the treatment of cancer. This review explores the development of novel Fe chelators for the treatment of cancer and their mechanisms of action.

Original languageEnglish
Pages (from-to)483-499
Number of pages17
JournalCurrent Topics in Medicinal Chemistry
Volume11
Issue number5
Publication statusPublished - Mar 2011
Externally publishedYes

Keywords

  • Iron
  • chelators
  • cancer
  • complexes
  • thiosemicarbazones
  • PYRIDOXAL ISONICOTINOYL HYDRAZONE
  • EFFECTIVE ANTIPROLIFERATIVE AGENTS
  • METASTASIS SUPPRESSOR GENE
  • HYPOXIA-INDUCIBLE FACTOR-1
  • CELL-CYCLE PROGRESSION
  • RIBONUCLEOTIDE REDUCTASE-ACTIVITY
  • KINASE INHIBITOR P21(CIP1/WAF1)
  • DIVALENT METAL TRANSPORTER-1
  • SELECTIVE ANTITUMOR-ACTIVITY
  • MESSENGER-RNA EXPRESSION

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