An unsymmetric cisplatin-based Pt(iv) derivative containing 2-(2-propynyl)octanoate: a very efficient multi-action antitumor prodrug candidate

Dalton Trans. 2017 Oct 24;46(41):14174-14185. doi: 10.1039/c7dt02928d.


The design, synthesis, characterization and biological properties of a Pt(iv) complex containing the very active inhibitor of histone deacetylase (2-propynyl)octanoic acid, POA, as an axial ligand are reported here. The title complex, namely (OC-6-44)-acetatodiamminedichlorido(2-(2-propynyl)octanoato)platinum(iv), 1, containing POA in racemic or in enantiomeric forms, was one/two orders of magnitude more active than cisplatin, depending on the chemo-sensitivity of the cancer cell lines. Moreover, 1 exhibited similar or even better antiproliferative activity than (OC-6-33)-diamminedichloridobis(2-propylpentanoato)platinum(iv), 2, containing two molecules of the well-known histone deacetylase inhibitor 2-propylpentanoic (valproic) acid. The high potency of 1 is likely due to its high cellular accumulation and to the synergism between the DNA-damaging cisplatin and the histone deacetylase inhibitor POA, both released upon the intracellular reduction of 1. Prodrug 1, after oral administration, caused an impressive reduction of the tumor mass (94%) in a model of solid tumor (murine Lewis lung carcinoma), compared to that of the control, whereas (intraperitoneal) cisplatin induced a tumor regression of 75% only. A good accumulation of 1 was observed in the tumor mass. The time course of the body weight attested that cisplatin induced elevated anorexia, whereas treatment with 1 did not induce significant body weight loss throughout the therapeutic experiment.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Antineoplastic Agents / therapeutic use
  • Caprylates / chemistry
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cisplatin / chemistry*
  • Coordination Complexes / chemistry*
  • Coordination Complexes / metabolism
  • Coordination Complexes / pharmacology
  • Drug Screening Assays, Antitumor
  • Histone Deacetylase Inhibitors / chemistry
  • Histone Deacetylase Inhibitors / metabolism
  • Histone Deacetylase Inhibitors / pharmacology
  • Humans
  • Isomerism
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / pathology
  • Mice
  • Mice, Inbred C57BL
  • Platinum / chemistry*
  • Prodrugs / chemistry*
  • Prodrugs / pharmacology
  • Prodrugs / therapeutic use
  • Tissue Distribution
  • Transplantation, Homologous


  • Antineoplastic Agents
  • Caprylates
  • Coordination Complexes
  • Histone Deacetylase Inhibitors
  • Prodrugs
  • Platinum
  • Caspases
  • octanoic acid
  • Cisplatin