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

Antineoplastic Agents / chemistry Apoptosis / drug effects Cell Cycle / drug effects Cell Differentiation / drug effects Cell Line, Tumor Drug Resistance, Multiple / drug effects Drug Screening Assays, Antitumor Humans Microtubules / drug effects Molecular Structure Oxazepines / chemistry Structure-Activity Relationship
Antitumor agents Apoptosis Microtubule-targeting agent Molecular modeling Tubulin X-ray crystallography

Journal

European journal of medicinal chemistry
ISSN: 1768-3254
Titre abrégé: Eur J Med Chem
Pays: France
ID NLM: 0420510

Informations de publication

Date de publication:
15 Jan 2019
Historique:
received: 16 07 2018
revised: 11 10 2018
accepted: 02 11 2018
pubmed: 19 11 2018
medline: 8 2 2019
entrez: 19 11 2018
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.ejmech.2018.11.004 PMID: 30448418
pubmed: 30448418
pii: S0223-5234(18)30952-8
doi: 10.1016/j.ejmech.2018.11.004
pii:
doi:

Substances chimiques

Antineoplastic Agents 0
Oxazepines 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

290-320

Informations de copyright

Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Auteurs

Margherita Brindisi (M)

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.

Cristina Ulivieri (C)

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.

Gloria Alfano (G)

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.

Sandra Gemma (S)

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.

Francisco de Asís Balaguer (F)

Department of Physical and Chemical Biology, Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Cientificas, Ramiro de Maeztu 9, 28040, Madrid, Spain.

Tuhina Khan (T)

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.

Alessandro Grillo (A)

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.

Giulia Chemi (G)

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.

Grégory Menchon (G)

Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, 5232, Villigen, Switzerland; University of Basel, Biozentrum, 4056 Basel, Switzerland.

Andrea E Prota (AE)

Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, 5232, Villigen, Switzerland; University of Basel, Biozentrum, 4056 Basel, Switzerland.

Natacha Olieric (N)

Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, 5232, Villigen, Switzerland; University of Basel, Biozentrum, 4056 Basel, Switzerland.

Daniel Lucena-Agell (D)

Department of Physical and Chemical Biology, Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Cientificas, Ramiro de Maeztu 9, 28040, Madrid, Spain.

Isabel Barasoain (I)

Department of Physical and Chemical Biology, Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Cientificas, Ramiro de Maeztu 9, 28040, Madrid, Spain.

J Fernando Diaz (JF)

Department of Physical and Chemical Biology, Centro de Investigaciones Biologicas, Consejo Superior de Investigaciones Cientificas, Ramiro de Maeztu 9, 28040, Madrid, Spain.

Angela Nebbioso (A)

Department of Precision Medicine, University of Campania Luigi Vanvitelli, Vico L. de Crecchio 7, 80138, Naples, Italy.

Mariarosaria Conte (M)

IRCCS, SDN, Via E. Gianturco 113, 80143, Naples, Italy.

Ludovica Lopresti (L)

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.

Stefania Magnano (S)

School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160, Pearse Street, Dublin 2, Ireland.

Rebecca Amet (R)

School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160, Pearse Street, Dublin 2, Ireland.

Paula Kinsella (P)

School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160, Pearse Street, Dublin 2, Ireland.

Daniela M Zisterer (DM)

School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160, Pearse Street, Dublin 2, Ireland.

Ola Ibrahim (O)

School of Dental Science, Trinity College Dublin, Lincoln Place, Dublin 2, Ireland.

Jeff O'Sullivan (J)

School of Dental Science, Trinity College Dublin, Lincoln Place, Dublin 2, Ireland.

Lucia Morbidelli (L)

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.

Roberta Spaccapelo (R)

Department of Experimental Medicine, University of Perugia, P.le Gambuli, I-06132, Perugia, Italy.

Cosima Baldari (C)

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.

Stefania Butini (S)

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.

Ettore Novellino (E)

Department of Pharmacy, University of Napoli Federico II, DoE Department of Excellence 2018-2022, Via D. Montesano 49, 80131, Napoli, Italy.

Giuseppe Campiani (G)

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.

Lucia Altucci (L)

Department of Precision Medicine, University of Campania Luigi Vanvitelli, Vico L. de Crecchio 7, 80138, Naples, Italy.

Michel O Steinmetz (MO)

Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institut, 5232, Villigen, Switzerland; University of Basel, Biozentrum, 4056 Basel, Switzerland.

Simone Brogi (S)

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.

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Classifications MeSH

questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Utilisations thérapeutiques › Antinéoplasiques › Structure-activity relationships, biological...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Mort cellulaire › Mort cellulaire régulée › Apoptose › Structure-activity relationships, biological...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Cycle cellulaire › Structure-activity relationships, biological...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Différenciation cellulaire › Structure-activity relationships, biological...
questionsmedicales.fr › Cellules › Cellules cultivées › Cellules cancéreuses en culture › Lignée cellulaire tumorale › Structure-activity relationships, biological...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Multirésistance aux médicaments › Structure-activity relationships, biological...
questionsmedicales.fr › Techniques d'investigation › Évaluation préclinique de médicament › Tests de criblage d'agents antitumoraux › Structure-activity relationships, biological...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Structure-activity relationships, biological...
questionsmedicales.fr › Cellules › Structures cellulaires › Espace intracellulaire › Cytoplasme › Structures cytoplasmiques › Cytosquelette › Microtubules › Structure-activity relationships, biological...
questionsmedicales.fr › Phénomènes chimiques › Structure moléculaire › Structure-activity relationships, biological...
questionsmedicales.fr › Composés hétérocycliques › Composés hétéromonocycliques › Azépines › Oxazépines › Structure-activity relationships, biological...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Relation structure-activité › Structure-activity relationships, biological...