Structure-activity relationships of novel substituted naphthalene diimides as anticancer agents

Andrea Milelli, Vincenzo Tumiatti, Marialuisa Micco, Michela Rosini, Guendalina Zuccari, Lizzia Raffaghello, Giovanna Bianchi, Vito Pistoia, J. Fernando Díaz, Benet Pera, Chiara Trigili, Isabel Barasoain, Caterina Musetti, Marianna Toniolo, Claudia Sissi, Stefano Alcaro, Federica Moraca, Maddalena Zini, Claudio Stefanelli, Anna Minarini

Research output: Contribution to journalArticle

Abstract

Novel 1,4,5,8-naphthalenetetracarboxylic diimide (NDI) derivatives were synthesized and evaluated for their antiproliferative activity on a wide number of different tumor cell lines. The prototypes of the present series were derivatives 1 and 2 characterized by interesting biological profiles as anticancer agents. The present investigation expands on the study of structure-activity relationships of prototypes 1 and 2, namely, the influence of the different substituents of the phenyl rings on the biological activity. Derivatives 3-22, characterized by a different substituent on the aromatic rings and/or a different chain length varying from two to three carbon units, were synthesized and evaluated for their cytostatic and cytotoxic activities. The most interesting compound was 20, characterized by a linker of three methylene units and a 2,3,4-trimethoxy substituent on the two aromatic rings. It displayed antiproliferative activity in the submicromolar range, especially against some different cell lines, the ability to inhibit Taq polymerase and telomerase, to trigger caspase activation by a possible oxidative mechanism, to downregulate ERK 2 protein and to inhibit ERKs phosphorylation, without acting directly on microtubules and tubuline. Its theoretical recognition against duplex and quadruplex DNA structures have been compared to experimental thermodynamic measurements and by molecular modeling investigation leading to putative binding modes. Taken together these findings contribute to define this compound as potential Multitarget-Directed Ligands interacting simultaneously with different biological targets.

Original languageEnglish
Pages (from-to)417-428
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume57
DOIs
Publication statusPublished - Nov 2012

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Keywords

  • Anticancer
  • Cytotoxicity
  • Multitarget-directed ligands
  • Naphthalene diimides

ASJC Scopus subject areas

  • Drug Discovery
  • Organic Chemistry
  • Pharmacology

Cite this

Milelli, A., Tumiatti, V., Micco, M., Rosini, M., Zuccari, G., Raffaghello, L., Bianchi, G., Pistoia, V., Fernando Díaz, J., Pera, B., Trigili, C., Barasoain, I., Musetti, C., Toniolo, M., Sissi, C., Alcaro, S., Moraca, F., Zini, M., Stefanelli, C., & Minarini, A. (2012). Structure-activity relationships of novel substituted naphthalene diimides as anticancer agents. European Journal of Medicinal Chemistry, 57, 417-428. https://doi.org/10.1016/j.ejmech.2012.06.045