Dipyridyl thiosemicarbazone chelators with potent and selective antitumor activity form iron complexes with redox activity

Des R. Richardson*, Philip C. Sharpe, David B. Lovejoy, Dakshita Senaratne, Danuta S. Kalinowski, Mohammad Islam, Paul V. Bernhardt

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

300 Citations (Scopus)

Abstract

There has been much interest in the development of iron (Fe) chelators for the treatment of cancer. We developed a series of di-2-pyridyl ketone thiosemicarbazone (HDpT) ligands which show marked and selective antitumor activity in vitro and in vivo. In this study, we assessed chemical and biological properties of these ligands and their Fe complexes in order to understand their marked activity. This included examination of their solution chemistry, electrochemistry, ability to mediate redox reactions, and antiproliferative activity against tumor cells. The higher antiproliferative efficacy of the HDpT series of chelators relative to the related di-2-pyridyl ketone isonicotinoyl hydrazone (HPKIH) analogues can be ascribed, in part, to the redox potentials of their Fe complexes which lead to the generation of reactive oxygen species. The most effective HDpT ligands as antiproliferative agents possess considerable lipophilicity and were shown to be charge neutral at physiological pH, allowing access to intracellular Fe pools.

Original languageEnglish
Pages (from-to)6510-6521
Number of pages12
JournalJournal of Medicinal Chemistry
Volume49
Issue number22
DOIs
Publication statusPublished - 2 Nov 2006
Externally publishedYes

Keywords

  • PYRIDOXAL ISONICOTINOYL HYDRAZONE
  • RIBONUCLEOTIDE REDUCTASE INHIBITOR
  • EFFECTIVE ANTIPROLIFERATIVE AGENTS
  • SALICYLALDEHYDE BENZOYL HYDRAZONE
  • RETICULOCYTES IN-VITRO
  • DI-2-PYRIDYL KETONE
  • PHASE-I
  • PARTITION-COEFFICIENTS
  • OVERLOAD DISEASE
  • 3-AMINOPYRIDINE-2-CARBOXALDEHYDE THIOSEMICARBAZONE

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