On the stability of PtIV pro-drugs with haloacetato ligands in the axial positions

Ezequiel Wexselblatt, Raji Raveendran, Sawsan Salameh, Aviva Friedman-Ezra, Eylon Yavin, Dan Gibson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

47 Scopus citations

Abstract

The design of PtIV pro-drugs as anticancer agents is predicated on the assumption that they will not undergo substitution reactions before entering the cancer cell. Attempts to improve the cytotoxic properties of PtIV pro-drugs included the use of haloacetato axial ligands. Herein, we demonstrate that PtIV complexes with trifluoroacetato (TFA) or dichloroacetato (DCA) ligands can be unstable under biologically relevant conditions and readily undergo hydrolysis, which results in the loss of the axial TFA or DCA ligands. The half-lives for PtIV complexes with two TFA or DCA ligands at pH 7 and 37°C range from 6 to 800 min, which is short relative to the duration of cytotoxicity experiments that last 24-96 h. However, complexes with two monochloroacetato (MCA) or acetato axial ligands are stable under biologically relevant conditions. The loss of the axial ligands depends primarily on the electron-withdrawing strength of the axial ligands, but also upon the nature of the equatorial ligands. We were unable to find obvious correlations between the structures of the PtIV complexes and the rates of decay of the parent compounds. The X-ray crystal structures of the bis-DCA and bis-MCA PtIV derivatives of oxaliplatin did not reveal any significant structural differences that could explain the observed differences in stability.

Original languageAmerican English
Pages (from-to)3108-3114
Number of pages7
JournalChemistry - A European Journal
Volume21
Issue number7
DOIs
StatePublished - 9 Feb 2015

Bibliographical note

Publisher Copyright:
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA.

Keywords

  • Haloacetato ligands
  • Hydrolysis
  • Ligand effect
  • Platinum(IV)
  • Pro-drugs

Fingerprint

Dive into the research topics of 'On the stability of PtIV pro-drugs with haloacetato ligands in the axial positions'. Together they form a unique fingerprint.

Cite this