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Discovery of Mono‐ and Disubstituted 1 H ‐Pyrazolo[3,4]pyrimidines and 9 H ‐Purines as Catalytic Inhibitors of Human DNA Topoisomerase IIα
Author(s) -
Pogorelčnik Barbara,
Brvar Matjaž,
Žegura Bojana,
Filipič Metka,
Solmajer Tom,
Perdih Andrej
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402459
Subject(s) - topoisomerase , pharmacophore , virtual screening , chemistry , stereochemistry , docking (animal) , drug discovery , dna , surface plasmon resonance , purine metabolism , combinatorial chemistry , biochemistry , computational biology , enzyme , biology , nanotechnology , medicine , materials science , nursing , nanoparticle
Human DNA topoisomerase IIα (htIIα) is a validated target for the development of anticancer agents. Based on structural data regarding the binding mode of AMP‐PNP (5′‐adenylyl‐β,γ‐imidodiphosphate) to htIIα, we designed a two‐stage virtual screening campaign that combines structure‐based pharmacophores and molecular docking. In the first stage, we identified several monosubstituted 9 H ‐purine compounds and a novel class of 1 H ‐pyrazolo[3,4]pyrimidines as inhibitors of htIIα. In the second stage, disubstituted analogues with improved cellular activities were discovered. Compounds from both classes were shown to inhibit htIIα‐mediated DNA decatenation, and surface plasmon resonance (SPR) experiments confirmed binding of these two compounds on the htIIα ATPase domain. Proposed complexes and interaction patterns between both compounds and htIIα were further analyzed in molecular dynamics simulations. Two compounds identified in the second stage showed promising anticancer activities in hepatocellular carcinoma (HepG2) and breast cancer (MCF‐7) cell lines. The discovered compounds are suitable starting points for further hit‐to‐lead development in anticancer drug discovery.