N-fused imidazoles as novel anticancer agents that inhibit catalytic activity of topoisomerase IIα and induce apoptosis in G1/S phase

Ashish T Baviskar; Chetna Madaan; Ranjan Preet; Purusottam Mohapatra; Vaibhav Jain; Amit Agarwal; Sankar K Guchhait; Chanakya N Kundu; Uttam C Banerjee; Prasad V Bharatam

doi:10.1021/jm200235u

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.

Authors

Ashish T Baviskar¹, Chetna Madaan, Ranjan Preet, Purusottam Mohapatra, Vaibhav Jain, Amit Agarwal, Sankar K Guchhait, Chanakya N Kundu, Uttam C Banerjee, Prasad V Bharatam

Affiliation

¹ National Institute of Pharmaceutical Education and Research (NIPER), Sector 67, SAS Nagar (Mohali), Punjab-160062, India.

PMID: 21644529
DOI: 10.1021/jm200235u

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