title: Discovery of mono- and disubstituted 1H-pyrazolo[3,4]pyrimidines and 9H-purines as catalytic inhibitors of human DNA topoisomerase IIα.
abstract: 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 9H-purine compounds and a novel class of 1H-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.
authors.affiliation: National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana (Slovenia).
authors.forename: Barbara
authors.initials: B
authors.lastname: Pogorelčnik
authors.forename: Matjaž
authors.initials: M
authors.lastname: Brvar
authors.forename: Bojana
authors.initials: B
authors.lastname: Žegura
authors.forename: Metka
authors.initials: M
authors.lastname: Filipič
authors.forename: Tom
authors.initials: T
authors.lastname: Solmajer
authors.forename: Andrej
authors.initials: A
authors.lastname: Perdih
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D027081:DNA Gyrase / Q000737:chemistry / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011687:Purines / Q000737:chemistry* / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry* / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D020349:Surface Plasmon Resonance; D059005:Topoisomerase II Inhibitors / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D059005:Topoisomerase II Inhibitors; C014175:pyrazolo(3,4-d)pyrimidine; D027081:DNA Gyrase; D004250:DNA Topoisomerases, Type II; C030985:purine
keywords: MTT assay; anticancer agents; catalytic inhibitors; human DNA topoisomerase IIα; virtual screening