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.
Novel Ametantrone-Amsacrine Related Hybrids as Topoisomerase IIβ Poisons and Cytotoxic Agents / Giuseppe Zagotto;Alessandra Gianoncelli;Claudia Sissi;Cristina Marzano;Valentina Gandin;Riccardo Pasquale;Giovanni Capranico;Giovanni Ribaudo;Manlio Palumbo. - In: ARCHIV DER PHARMAZIE. - ISSN 0365-6233. - STAMPA. - 347:(2014), pp. 728-737. [10.1002/ardp.201400111]
Novel Ametantrone-Amsacrine Related Hybrids as Topoisomerase IIβ Poisons and Cytotoxic Agents
CAPRANICO, GIOVANNI;
2014
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.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.