Probing the Interactions of Cytotoxic [Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenanthroline)] and Its PtIV Derivatives with Human Serum

ChemMedChem. 2017 Apr 6;12(7):510-519. doi: 10.1002/cmdc.201700092. Epub 2017 Mar 21.

Abstract

The discrepancy between the in vitro cytotoxic results and the in vivo performance of Pt56MeSS prompted us to look into its interactions and those of its PtIV derivatives with human serum (HS), human serum albumin (HSA), lipoproteins, and serum-supplemented cell culture media. The PtII complex, Pt56MeSS, binds noncovalently and reversibly to slow-tumbling proteins in HS and in cell culture media and interacts through the phenanthroline group with HSA, with a Kd value of ∼1.5×10-6 m. All PtIV complexes were found to be stable toward reduction in HS, but those with axial carboxylate ligands, cct-[Pt(1S,2S-DACH)(5,6-dimethyl-1,10-phenantroline)(acetato)2 ](TFA)2 (Pt56MeSS(OAc)2 ) and cct-[Pt(1S,2S-DACH)(5,6-dimehtyl-1,10-phenantroline)(phenylbutyrato)2 ](TFA)2 (Pt56MeSS(PhB)2 ), were spontaneously reduced at pH 7 or higher in phosphate buffer, but not in Tris buffer (pH 8). HS also decreased the rate of reduction by ascorbate of the PtIV complexes relative to the reduction rates in phosphate buffer, suggesting that for this compound class, phosphate buffer is not a good model for HS.

Keywords: DNA; human serum; platinum drugs; reduction; stability.

MeSH terms

  • Ascorbic Acid / chemistry
  • Coordination Complexes / blood
  • Coordination Complexes / chemical synthesis
  • Coordination Complexes / chemistry*
  • Cyclohexylamines / chemistry
  • Drug Stability
  • Electrochemical Techniques
  • Humans
  • Magnetic Resonance Spectroscopy
  • Oxidation-Reduction
  • Phenanthrolines / chemistry
  • Platinum / chemistry*
  • Prohibitins

Substances

  • Coordination Complexes
  • Cyclohexylamines
  • PHB protein, human
  • PHB2 protein, human
  • Phenanthrolines
  • Prohibitins
  • Platinum
  • 1,2-cyclohexanediamine
  • Ascorbic Acid
  • 1,10-phenanthroline