N-fused Imidazoles as Novel Anticancer Agents That Inhibit Catalytic Activity of Topoisomerase IIα and Induce Apoptosis in G1/S Phase

J Med Chem. 2011 Jul 28;54(14):5013-30. doi: 10.1021/jm200235u. Epub 2011 Jun 23.

Abstract

On the basis of structures of known topoisomerase II catalytic inhibitors and initial molecular docking studies, bicyclic N-fused aminoimidazoles were predicted as potential topoisomerase II inhibitors. They were synthesized by multicomponent reactions and evaluated against human topoisomerase IIα (hTopoIIα) in decatenation, relaxation, cleavage complex, and DNA intercalation in vitro assays. Among 31 compounds of eight different bicyclic scaffolds, it was found that imidazopyridine, imidazopyrazole, and imidazopyrazine with suitable substituents exhibited potent inhibition of catalytic activity of hTopoIIα while not showing DNA intercalation. Molecular docking studies and molecular dynamics (MD) simulation analysis, ATPase-kinetics and ATP-dependent plasmid relaxation assay revealed the catalytic mode of inhibition of the title compounds plausibly by blocking the ATP-binding site. N-Fused aminoimidazoles showed potent anticancer activities in kidney and breast cancer cell lines, low toxicity to normal cells, relatively higher potency compared to etoposide and 5-fluorouracil in kidney cancer cell lines, and potent inhibition in cell migration. These compounds were found to exert apoptotic effect in G1/S phase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / chemistry
  • Adenosine Triphosphate / chemistry
  • Animals
  • Antigens, Neoplasm
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Binding Sites
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Survival / drug effects
  • Chlorocebus aethiops
  • DNA Topoisomerases, Type II
  • DNA-Binding Proteins / antagonists & inhibitors*
  • Drug Screening Assays, Antitumor
  • Etoposide / pharmacology
  • Fluorouracil / pharmacology
  • G1 Phase*
  • HEK293 Cells
  • Heterocyclic Compounds, 2-Ring / chemical synthesis*
  • Heterocyclic Compounds, 2-Ring / chemistry
  • Heterocyclic Compounds, 2-Ring / pharmacology
  • Humans
  • Imidazoles / chemical synthesis*
  • Imidazoles / chemistry
  • Imidazoles / pharmacology
  • Intercalating Agents / chemical synthesis
  • Intercalating Agents / chemistry
  • Intercalating Agents / pharmacology
  • Models, Molecular*
  • Molecular Dynamics Simulation
  • S Phase*
  • Structure-Activity Relationship
  • Topoisomerase II Inhibitors / chemical synthesis*
  • Topoisomerase II Inhibitors / chemistry
  • Topoisomerase II Inhibitors / pharmacology
  • Vero Cells

Substances

  • Antigens, Neoplasm
  • Antineoplastic Agents
  • DNA-Binding Proteins
  • Heterocyclic Compounds, 2-Ring
  • Imidazoles
  • Intercalating Agents
  • Topoisomerase II Inhibitors
  • Etoposide
  • Adenosine Triphosphate
  • Adenosine Triphosphatases
  • DNA Topoisomerases, Type II
  • Fluorouracil