Discovery of Mono- and Disubstituted 1H-Pyrazolo[3,4]pyrimidines and 9H-Purines as Catalytic Inhibitors of Human DNA TopoisomeraseII[alpha]

• Published in: ChemMedChem 2015-02, Vol.10 (2), p.345
• Main Authors: Pogorelcnik, Barbara, Brvar, Matjaz, egura, Bojana, Filipic, Metka, Solmajer, Tom, Perdih, Andrej
• Format: Article
• Language: English
• Subjects: Cancer; Deoxyribonucleic acid; DNA; Medical research
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201402459

Human DNA topoisomeraseII[alpha] (htII[alpha]) is a validated target for the development of anticancer agents. Based on structural data regarding the binding mode of AMP-PNP (5'-adenylyl-[beta],[gamma]-imidodiphosphate) to htII[alpha], we designed a two-stage virtual screening campaign that combines structure-based pharmacophores and molecular docking. In the first stage, we identified several monosubstituted 9H-purine compounds and a novel class of 1H-pyrazolo[3,4]pyrimidines as inhibitors of htII[alpha]. In the second stage, disubstituted analogues with improved cellular activities were discovered. Compounds from both classes were shown to inhibit htII[alpha]-mediated DNA decatenation, and surface plasmon resonance (SPR) experiments confirmed binding of these two compounds on the htII[alpha] ATPase domain. Proposed complexes and interaction patterns between both compounds and htII[alpha] 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.