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

Chem Biol. 2004 Apr;11(4):557-64. doi: 10.1016/j.chembiol.2004.03.024.


Several estrogen-tethered platinum(IV) complexes were prepared and characterized by ESI-MS and (1)H 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), BEP(n) (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 BEP(n) 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 (IC(50) = 2.1 +/- 0.4 microM versus 3.7 +/- 0.9 microM, 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.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Breast Neoplasms / drug therapy*
  • Breast Neoplasms / metabolism
  • 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
  • HMGB1 Protein / genetics
  • HMGB1 Protein / metabolism
  • Humans
  • Organoplatinum Compounds* / chemical synthesis
  • Organoplatinum Compounds* / chemistry
  • Organoplatinum Compounds* / pharmacology
  • Receptors, Estrogen / drug effects
  • Receptors, Estrogen / metabolism
  • Structure-Activity Relationship


  • Estrogens
  • HMGB1 Protein
  • Organoplatinum Compounds
  • Receptors, Estrogen
  • Estradiol