Structure-activity relationships, biological evaluation and structural studies of novel pyrrolonaphthoxazepines as antitumor agents

Margherita Brindisi, Cristina Ulivieri, Gloria Alfano, Sandra Gemma, Francisco de Asís Balaguer, Tuhina Khan, Alessandro Grillo, Giulia Chemi, Grégory Menchon, Andrea E. Prota, Natacha Olieric, Daniel Lucena-Agell, Isabel Barasoain, J. Fernando Diaz, Angela Nebbioso, Mariarosaria Conte, Ludovica Lopresti, Stefania Magnano, Rebecca Amet, Paula KinsellaDaniela M. Zisterer, Ola Ibrahim, Jeff O'Sullivan, Lucia Morbidelli, Roberta Spaccapelo, Cosima Baldari, Stefania Butini, Ettore Novellino, Giuseppe Campiani, Lucia Altucci, Michel O. Steinmetz, Simone Brogi

Research output: Contribution to journalArticlepeer-review


Microtubule-targeting agents (MTAs) are a class of clinically successful anti-cancer drugs. The emergence of multidrug resistance to MTAs imposes the need for developing new MTAs endowed with diverse mechanistic properties. Benzoxazepines were recently identified as a novel class of MTAs. These anticancer agents were thoroughly characterized for their antitumor activity, although, their exact mechanism of action remained elusive. Combining chemical, biochemical, cellular, bioinformatics and structural efforts we developed improved pyrrolonaphthoxazepines antitumor agents and their mode of action at the molecular level was elucidated. Compound 6j, one of the most potent analogues, was confirmed by X-ray as a colchicine-site MTA. A comprehensive structural investigation was performed for a complete elucidation of the structure-activity relationships. Selected pyrrolonaphthoxazepines were evaluated for their effects on cell cycle, apoptosis and differentiation in a variety of cancer cells, including multidrug resistant cell lines. Our results define compound 6j as a potentially useful optimized hit for the development of effective compounds for treating drug-resistant tumors.

Original languageEnglish
Pages (from-to)290-320
Number of pages31
JournalEuropean Journal of Medicinal Chemistry
Publication statusE-pub ahead of print - Nov 3 2018


  • Antitumor agents
  • Apoptosis
  • Microtubule-targeting agent
  • Molecular modeling
  • Tubulin
  • X-ray crystallography

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


Dive into the research topics of 'Structure-activity relationships, biological evaluation and structural studies of novel pyrrolonaphthoxazepines as antitumor agents'. Together they form a unique fingerprint.

Cite this