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: Giuseppe Zagotto, Alessandra Gianoncelli, Claudia Sissi, Cristina Marzano, Valentina Gandin, Riccardo Pasquale, Giovanni Capranico, Giovanni Ribaudo, Manlio Palumbo
• Journal: Archiv der Pharmazie (Arch Pharm (Weinheim)) Vol. 347 Issue 10 Pg. 728-37 (Oct 2014) ISSN: 1521-4184 [Electronic] Germany
• PMID: 25042690 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Chemical References

• DNA-Binding Proteins
• Topoisomerase II Inhibitors
• Amsacrine
• DNA
• Mitoxantrone
• DNA Topoisomerases, Type II
• ametantrone

Topics

• Amsacrine (chemical synthesis, pharmacology)
• Cell Proliferation (drug effects)
• Cell Survival (drug effects)
• DNA (metabolism)
• DNA Topoisomerases, Type II (metabolism)
• DNA-Binding Proteins (antagonists & inhibitors, metabolism)
• Dose-Response Relationship, Drug
• Drug Design
• HL-60 Cells
• Humans
• Inhibitory Concentration 50
• MCF-7 Cells
• Mitoxantrone (analogs & derivatives, chemical synthesis, pharmacology)
• Molecular Structure
• Neoplasms (enzymology, genetics, pathology)
• Structure-Activity Relationship
• Topoisomerase II Inhibitors (chemical synthesis, pharmacology)