title: Novel ametantrone-amsacrine related hybrids as topoisomerase IIβ poisons and cytotoxic agents.
abstract: The precise definition of the structural requirements for effective topoisomerase II poisoning by drug molecules is still an elusive issue. In the attempt to better define a pharmacophoric pattern, we prepared several conjugates combining the chemical features of two well-known topoisomerase II poisons, amsacrine and ametantrone. Indeed, an appropriate fusion geometry, which entails the anthracenedione moiety of ametantrone appropriately connected to the methanesulfonamidoaniline side chain of amsacrine, elicits DNA-intercalating properties, the capacity to inhibit the human topoisomerase IIβ isoform, and cytotoxic activity resembling that of the parent compounds. In addition, the properties of the lateral groups linked to the anthracenedione group play an important role in modulating DNA binding and cell cytotoxicity. Among the compounds tested, 10, 11, and 19 appear to be promising for further development.
authors.affiliation: Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Zagotto
authors.forename: Alessandra
authors.initials: A
authors.lastname: Gianoncelli
authors.forename: Claudia
authors.initials: C
authors.lastname: Sissi
authors.forename: Cristina
authors.initials: C
authors.lastname: Marzano
authors.forename: Valentina
authors.initials: V
authors.lastname: Gandin
authors.forename: Riccardo
authors.initials: R
authors.lastname: Pasquale
authors.forename: Giovanni
authors.initials: G
authors.lastname: Capranico
authors.forename: Giovanni
authors.initials: G
authors.lastname: Ribaudo
authors.forename: Manlio
authors.initials: M
authors.lastname: Palumbo
mesh_terms: D000677:Amsacrine / Q000138:chemical synthesis / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D061986:MCF-7 Cells; D008942:Mitoxantrone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D015394:Molecular Structure; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D013329:Structure-Activity Relationship; D059005:Topoisomerase II Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*
chemical_list: D004268:DNA-Binding Proteins; D059005:Topoisomerase II Inhibitors; D000677:Amsacrine; D004247:DNA; D008942:Mitoxantrone; D004250:DNA Topoisomerases, Type II; C020182:ametantrone
keywords: Ametantrone; Amsacrine; DNA; Intercalation; Topoisomerase II