An in vivo active 1,2,5-oxadiazole Pt(II) complex: A promising anticancer agent endowed with STAT3 inhibitory properties

Eur J Med Chem. 2017 May 5:131:196-206. doi: 10.1016/j.ejmech.2017.03.017. Epub 2017 Mar 15.

Abstract

New Pt(II) complexes (Pt-1-3) bearing 1,2,5-oxadiazole ligands (1-3) were synthesized, characterized and evaluated for their ability to disrupt STAT3 dimerization. Ligand 3·HCl showed cytotoxic effects on HCT-116 cells (IC50 = 95.2 μM) and a selective ability to interact with STAT3 (IC50 = 8.2 μM) versus STAT1 (IC50 > 30 μM). Its corresponding platinum complex Pt-3 exhibited an increased cytotoxicity (IC50 = 18.4 μM) and a stronger interaction with STAT3 (IC50 = 1.4 μM), leading to inhibition of its signaling pathway. Pt-3 was also evaluated in cell-based assays for its action on p53 expression and on STAT3 phosphorylation. In syngeneic murine Lewis lung carcinoma (LLC) implanted in C57BL/6 mice, Pt-3 showed a higher antitumor activity with fewer side effects than cisplatin.

Keywords: Antitumor agents; Cytotoxic activity; DNA-interaction; Platinum diamine complex; Protein–protein interactions.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Molecular Structure
  • Organoplatinum Compounds / chemical synthesis
  • Organoplatinum Compounds / chemistry
  • Organoplatinum Compounds / pharmacology*
  • Oxadiazoles / chemistry
  • Oxadiazoles / pharmacology*
  • Platinum / chemistry
  • Platinum / pharmacology*
  • STAT3 Transcription Factor / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents
  • Organoplatinum Compounds
  • Oxadiazoles
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • Platinum