Pt(II) versus Pt(IV) in Carbene Glycoconjugate Antitumor Agents: Minimal Structural Variations and Great Performance Changes

Inorg Chem. 2020 Mar 16;59(6):4002-4014. doi: 10.1021/acs.inorgchem.9b03683. Epub 2020 Mar 4.

Abstract

Octahedral Pt(IV) complexes (2Pt-R) containing a glycoconjugate carbene ligand were prepared and fully characterized. These complexes are structural analogues to the trigonal bipyramidal Pt(II) species (1Pt-R) recently described. Thus, an unprecedented direct comparison between the biological properties of Pt compounds with different oxidation states and almost indistinguishable structural features was performed. The stability profile of the novel Pt(IV) compounds in reference solvents was determined and compared to that of the analogous Pt(II) complexes. The uptake and antiproliferative activities of 2Pt-R and 1Pt-R were evaluated on the same panel of cell lines. DNA and protein binding properties were assessed using human serum albumin, the model protein hen egg white lysozyme, and double stranded DNA model systems by a variety of experimental techniques, including UV-vis absorption spectroscopy, fluorescence, circular dichroism, and electrospray ionization mass spectrometry. Although the compounds present similar structures, their in-solution stability, cellular uptake, and DNA binding properties are diverse. These differences may represent the basis of their different cytotoxicity and biological activity.

MeSH terms

  • Animals
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / metabolism
  • Antineoplastic Agents / pharmacology*
  • Cattle
  • Cell Line, Tumor
  • Chickens
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / metabolism
  • Coordination Complexes / pharmacology*
  • DNA / metabolism
  • Drug Screening Assays, Antitumor
  • Glycoconjugates / chemical synthesis
  • Glycoconjugates / metabolism
  • Glycoconjugates / pharmacology*
  • Humans
  • Ligands
  • Mice
  • Molecular Structure
  • Muramidase / metabolism
  • Platinum / chemistry
  • Protein Binding
  • Serum Albumin, Human / metabolism

Substances

  • Antineoplastic Agents
  • Coordination Complexes
  • Glycoconjugates
  • Ligands
  • Platinum
  • DNA
  • calf thymus DNA
  • hen egg lysozyme
  • Muramidase
  • Serum Albumin, Human