Monocyclic 4-amino-6-(phenylamino)-1,3,5-triazines as inhibitors of human DNA topoisomerase IIα

Bioorg Med Chem Lett. 2014 Dec 15;24(24):5762-5768. doi: 10.1016/j.bmcl.2014.10.042. Epub 2014 Oct 22.

Abstract

Human DNA topoisomerase IIα (htIIα) is a validated target for the development of anticancer agents. Starting from the available information about the binding of the purine-based htIIα inhibitors in the ATP binding site we designed a virtual screening campaign combining structure-based and ligand-based pharmacophores with a molecular docking calculation searching for compounds that would contain a monocycle mimetic of the purine moiety. We discovered novel 4-amino-6-(phenylamino)-1,3,5-triazines 6, 7 and 11 as monocyclic htIIα inhibitors targeting the ATP binding site. Compound 6 from the 1,3,5-triazine series also displayed cytotoxicity properties in hepatocellular carcinoma (HepG2) cell lines and selectivity against human umbilical vein endothelial (HUVEC) cell lines.

Keywords: Anticancer agents; Catalytic inhibitors; Drug design; Human DNA topoisomerase IIα; Virtual screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism
  • Antigens, Neoplasm / metabolism
  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology
  • Binding Sites
  • Cell Survival / drug effects
  • DNA Topoisomerases, Type II / metabolism
  • DNA-Binding Proteins / antagonists & inhibitors*
  • DNA-Binding Proteins / metabolism
  • Drug Design
  • Hep G2 Cells
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Molecular Docking Simulation
  • Protein Binding
  • Protein Structure, Tertiary
  • Purines / chemistry*
  • Structure-Activity Relationship
  • Thiocarbamates / chemical synthesis
  • Thiocarbamates / chemistry*
  • Thiocarbamates / toxicity
  • Topoisomerase II Inhibitors / chemical synthesis
  • Topoisomerase II Inhibitors / chemistry*
  • Topoisomerase II Inhibitors / pharmacology
  • Triazines / chemical synthesis
  • Triazines / chemistry*
  • Triazines / pharmacology
  • Triazines / toxicity

Substances

  • Antigens, Neoplasm
  • Antineoplastic Agents
  • DNA-Binding Proteins
  • Purines
  • Thiocarbamates
  • Topoisomerase II Inhibitors
  • Triazines
  • Adenosine Triphosphate
  • DNA Topoisomerases, Type II
  • purine