Synthesis, cytotoxic evaluation and molecular docking study of novel quinazoline derivatives as PARP-1 inhibitors

Acta Pol Pharm. 2013 Sep-Oct;70(5):833-49.

Abstract

Novel series of spiro[(2H,3H)-quinazoline-2,1'-cyclohexane] derivatives (I-XVI) were synthesized and biologically evaluated as cytotoxic agents against human breast carcinoma cell lines (MCF-7) using doxorubicin as a reference drug. Most of the tested compounds displayed promising cytotoxic activity, especially derivatives V, VIb and XIb. The most active compounds were docked into the PARP-1 enzyme binding site to predict the ligand-protein binding modes. Lipinski rule of five and ADME profile suggested strongly that compounds V and VIb are promising agents as breast cancer inhibitors with drug likeness approach that have PARP-1 inhibitory activity. The structures of all newly synthesized compounds were confirmed by microanalysis and IR, 1H-NMR and mass spectral data.

MeSH terms

  • Antibiotics, Antineoplastic
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology*
  • Binding Sites / drug effects
  • Breast Neoplasms / drug therapy
  • Cell Line, Tumor / drug effects
  • Doxorubicin / pharmacology
  • Female
  • Humans
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerase Inhibitors*
  • Poly(ADP-ribose) Polymerases / metabolism
  • Quinazolines / chemical synthesis*
  • Quinazolines / pharmacology*
  • Spectrophotometry, Infrared

Substances

  • Antibiotics, Antineoplastic
  • Antineoplastic Agents
  • Poly(ADP-ribose) Polymerase Inhibitors
  • Quinazolines
  • Doxorubicin
  • PARP1 protein, human
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases