2. Academic Validation
  3. Structure-activity relationships, biological evaluation and structural studies of novel pyrrolonaphthoxazepines as antitumor agents

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

  • Eur J Med Chem. 2019 Jan 15:162:290-320. doi: 10.1016/j.ejmech.2018.11.004.
Margherita Brindisi 1,  Cristina Ulivieri 2,  Gloria Alfano 1,  Sandra Gemma 1,  Francisco de Asís Balaguer 3,  Tuhina Khan 4,  Alessandro Grillo 1,  Giulia Chemi 1,  Grégory Menchon 5,  Andrea E Prota 5,  Natacha Olieric 5,  Daniel Lucena-Agell 3,  Isabel Barasoain 3,  J Fernando Diaz 3,  Angela Nebbioso 6,  Mariarosaria Conte 7,  Ludovica Lopresti 2,  Stefania Magnano 8,  Rebecca Amet 8,  Paula Kinsella 8,  Daniela M Zisterer 8,  Ola Ibrahim 9,  Jeff O'Sullivan 9,  Lucia Morbidelli 2,  Roberta Spaccapelo 10,  Cosima Baldari 2,  Stefania Butini 11,  Ettore Novellino 12,  Giuseppe Campiani 13,  Lucia Altucci 6,  Michel O Steinmetz 5,  Simone Brogi 14
Affiliations

Affiliations

  • 1 European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, via Aldo Moro 2, I-53100, Siena, Italy; Istituto Toscano Tumori, University of Siena, via Aldo Moro 2, I-53100, Siena, Italy.
  • 2 Istituto Toscano Tumori, University of Siena, via Aldo Moro 2, I-53100, Siena, Italy; Department of Life Sciences, via Aldo Moro 2, I-53100, Siena, Italy.
  • 3 Department of Physical and Chemical Biology, Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Cientificas, Ramiro de Maeztu 9, 28040, Madrid, Spain.
  • 4 European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, via Aldo Moro 2, I-53100, Siena, Italy.
  • 5 Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, 5232, Villigen, Switzerland; University of Basel, Biozentrum, 4056 Basel, Switzerland.
  • 6 Department of Precision Medicine, University of Campania Luigi Vanvitelli, Vico L. de Crecchio 7, 80138, Naples, Italy.
  • 7 IRCCS, SDN, Via E. Gianturco 113, 80143, Naples, Italy.
  • 8 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160, Pearse Street, Dublin 2, Ireland.
  • 9 School of Dental Science, Trinity College Dublin, Lincoln Place, Dublin 2, Ireland.
  • 10 Department of Experimental Medicine, University of Perugia, P.le Gambuli, I-06132, Perugia, Italy.
  • 11 European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, via Aldo Moro 2, I-53100, Siena, Italy; Istituto Toscano Tumori, University of Siena, via Aldo Moro 2, I-53100, Siena, Italy. Electronic address: butini3@unisi.it.
  • 12 Department of Pharmacy, University of Napoli Federico II, DoE Department of Excellence 2018-2022, Via D. Montesano 49, 80131, Napoli, Italy.
  • 13 European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, via Aldo Moro 2, I-53100, Siena, Italy; Istituto Toscano Tumori, University of Siena, via Aldo Moro 2, I-53100, Siena, Italy. Electronic address: campiani@unisi.it.
  • 14 European Research Centre for Drug Discovery and Development (NatSynDrugs), University of Siena, Department of Biotechnology, Chemistry and Pharmacy, DoE Department of Excellence 2018-2022, via Aldo Moro 2, I-53100, Siena, Italy; Istituto Toscano Tumori, University of Siena, via Aldo Moro 2, I-53100, Siena, Italy; Department of Pharmacy, University of Napoli Federico II, DoE Department of Excellence 2018-2022, Via D. Montesano 49, 80131, Napoli, Italy.
PMID: 30448418 DOI: 10.1016/j.ejmech.2018.11.004
Abstract

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.

Keywords

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

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