In Vitro Anticancer Evaluation of Platinum(II/IV) Complexes with Diisoamyl Ester of (S,S)-ethylenediamine-N,N'-di-2-propanoic Acid

Anticancer Agents Med Chem. 2017;17(8):1136-1143. doi: 10.2174/1871520616666161207155634.

Abstract

Aims: Platinum(II) and platinum(IV) complexes [PtCln{(S,S)-(i-Am)2eddip}] (n = 2, 4: 1, 2, respectively; (S,S)-(i-Am)2eddip = O,O'-diisoamyl-(S,S)-ethylenediamine-N,N'-di-2-propanoate) were synthesized and characterized by elemental analysis, IR, 1H and 13C NMR spectroscopy and mass spectrometry.

Method: Quantum chemical calculations were used to predict formed isomers of 1 and 2. Furthermore, reduction of 2 with ascorbic acid was followed by time-dependant 13C NMR spectroscopy in order to enable assignation of the formed isomers for complex 1. In vitro cytotoxic activity was determined for 1 and 2 on a panel of five human tumor cell lines derived from cervix adenocarcinoma (HeLa), alveolar basal adenocarcinoma (A549), breast adenocarcinoma (MDA-453), colorectal cancer (LS 174), erythromyeloblastoid leukemia (K562), as well as one non-malignant human lung fibroblast cell line (MRC-5), using MTT assay.

Result: Both complexes exhibited high (2 against K562: IC50 = 5.4 μM), more active than cisplatin, to moderate activity (1). Both complexes caused considerable decrease of cell number in K562 cells in G1, S and G2 phases, concordantly increasing subpopulation in sub-G1 fraction. Morphological analysis of K562 cell death induced by platinum(II/IV) complexes indicate apoptosis.

Keywords: DFT calculations; Platinum complexes; R2eddip ligands; anticancer activity; apoptosis; cell cycle.

MeSH terms

  • Alanine / analogs & derivatives*
  • Alanine / chemistry
  • Alanine / pharmacology
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Death / drug effects
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Esters / chemistry
  • Esters / pharmacology*
  • Ethylenediamines / chemistry
  • Ethylenediamines / pharmacology*
  • Humans
  • Molecular Structure
  • Organoplatinum Compounds / chemical synthesis
  • Organoplatinum Compounds / chemistry
  • Organoplatinum Compounds / pharmacology*
  • Quantum Theory
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Esters
  • Ethylenediamines
  • Organoplatinum Compounds
  • ethylenediamine-N,N'-di-2-propanoic acid diisoamyl ester
  • Alanine