Synthesis, characterization, and cytotoxicity of a series of estrogen-tethered platinum(IV) complexes

Katie R. Barnes, Alexander Kutikov, Stephen J. Lippard

Research output: Contribution to journalArticlepeer-review

263 Scopus citations

Abstract

Several estrogen-tethered platinum(IV) complexes were prepared and characterized by ESI-MS and 1H NMR spectroscopy. Their design was inspired by the observation that estrogen receptor-positive cells exposed to the hormone are sensitized to cisplatin. Intracellular reduction of bis-estrogen-cis-diamminedichloroplatinum(IV), BEPn (where n = 1-5 methylene groups between Pt and estrogen), occurs to afford cisplatin and two equivalents of the linker-modified estrogen. The ability of BEPn to induce overexpression of HMGB1 was established by immunofluorescence microscopy. The cytotoxicity of the compounds was evaluated in ER(+) MCF-7 and ER(-) HCC-1937 human breast cancer cell lines. BEP3 selectively induces overexpression of HMGB1 in MCF-7 cells, compared to HCC-1937 cells, and enhances their sensitivity (IC50 = 2.1 ± 0.4 μM versus 3.7 ± 0.9 μM, respectively) to the compound. The difference in compound activities and the potential of compounds of this class for treating breast and ovarian cancer are discussed.

Original languageEnglish
Pages (from-to)557-564
Number of pages8
JournalChemistry and Biology
Volume11
Issue number4
DOIs
StatePublished - Apr 2004

Keywords

  • Breast Neoplasms/drug therapy
  • Cell Line, Tumor
  • Cell Survival/drug effects
  • Dose-Response Relationship, Drug
  • Drug Design
  • Drug Screening Assays, Antitumor
  • Estradiol/pharmacology
  • Estrogens/chemistry
  • Gene Expression/drug effects
  • HMGB1 Protein/drug effects
  • Humans
  • Organoplatinum Compounds/chemical synthesis
  • Receptors, Estrogen/drug effects
  • Structure-Activity Relationship

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