title: Monocyclic 4-amino-6-(phenylamino)-1,3,5-triazines as inhibitors of human DNA topoisomerase IIα.
abstract: Human DNA topoisomerase IIα (htIIα) is a validated target for the development of anticancer agents. Starting from the available information about the binding of the purine-based htIIα inhibitors in the ATP binding site we designed a virtual screening campaign combining structure-based and ligand-based pharmacophores with a molecular docking calculation searching for compounds that would contain a monocycle mimetic of the purine moiety. We discovered novel 4-amino-6-(phenylamino)-1,3,5-triazines 6, 7 and 11 as monocyclic htIIα inhibitors targeting the ATP binding site. Compound 6 from the 1,3,5-triazine series also displayed cytotoxicity properties in hepatocellular carcinoma (HepG2) cell lines and selectivity against human umbilical vein endothelial (HUVEC) cell lines.
authors.affiliation: National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pogorelčnik
authors.affiliation: National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia.
authors.forename: Matjaž
authors.initials: M
authors.lastname: Brvar
authors.affiliation: National Institute of Biology, Department of Genetic Toxicology and Cancer Biology, Večna pot 111, 1000 Ljubljana, Slovenia.
authors.forename: Irena
authors.initials: I
authors.lastname: Zajc
authors.affiliation: National Institute of Biology, Department of Genetic Toxicology and Cancer Biology, Večna pot 111, 1000 Ljubljana, Slovenia.
authors.forename: Metka
authors.initials: M
authors.lastname: Filipič
authors.affiliation: National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia.
authors.forename: Tom
authors.initials: T
authors.lastname: Solmajer
authors.affiliation: National Institute of Chemistry, Hajdrihova 19, 1001 Ljubljana, Slovenia. Electronic address: andrej.perdih@ki.si.
authors.forename: Andrej
authors.initials: A
authors.lastname: Perdih
mesh_terms: D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015195:Drug Design; D056945:Hep G2 Cells; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011687:Purines / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013859:Thiocarbamates / Q000138:chemical synthesis / Q000737:chemistry* / Q000633:toxicity; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014227:Triazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity
chemical_list: D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D011687:Purines; D013859:Thiocarbamates; D059005:Topoisomerase II Inhibitors; D014227:Triazines; D000255:Adenosine Triphosphate; D004250:DNA Topoisomerases, Type II; C030985:purine
keywords: Anticancer agents; Catalytic inhibitors; Drug design; Human DNA topoisomerase IIα; Virtual screening