European Journal of Medicinal Chemistry p. 290 - 320 (2019)
Update date:2022-08-16
Topics:
Brindisi, Margherita
Ulivieri, Cristina
Alfano, Gloria
Gemma, Sandra
de Asís Balaguer, Francisco
Khan, Tuhina
Grillo, Alessandro
Chemi, Giulia
Menchon, Grégory
Prota, Andrea E.
Olieric, Natacha
Lucena-Agell, Daniel
Barasoain, Isabel
Diaz, J. Fernando
Nebbioso, Angela
Conte, Mariarosaria
Lopresti, Ludovica
Magnano, Stefania
Amet, Rebecca
Kinsella, Paula
Zisterer, Daniela M.
Ibrahim, Ola
O'Sullivan, Jeff
Morbidelli, Lucia
Spaccapelo, Roberta
Baldari, Cosima
Butini, Stefania
Novellino, Ettore
Campiani, Giuseppe
Altucci, Lucia
Steinmetz, Michel O.
Brogi, Simone
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.
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