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

被引：35

作者：

Brindisi, Margherita ^{[1
,2
]}

Ulivieri, Cristina ^{[2
,3
]}

Alfano, Gloria ^{[1
,2
]}

Gemma, Sandra ^{[1
,2
]}

de Asis Balaguer, Francisco ^{[4
]}

Khan, Tuhina ^{[1
]}

Grillo, Alessandro ^{[1
,2
]}

Chemi, Giulia ^{[1
,2
]}

Menchon, Gregory ^{[5
,6
]}

Prota, Andrea E. ^{[5
,6
]}

Olieric, Natacha ^{[5
,6
]}

Lucena-Agell, Daniel ^{[4
]}

Barasoain, Isabel ^{[4
]}

Fernando Diaz, J. ^{[4
]}

Nebbioso, Angela ^{[7
]}

Conte, Mariarosaria ^{[8
]}

Lopresti, Ludovica ^{[2
,3
]}

Magnano, Stefania ^{[9
]}

Amet, Rebecca ^{[9
]}

Kinsella, Paula ^{[9
]}

Zisterer, Daniela M. ^{[9
]}

Ibrahim, Ola ^{[10
]}

O'Sullivan, Jeff ^{[10
]}

Morbidelli, Lucia ^{[2
,3
]}

Spaccapelo, Roberta ^{[11
]}

Baldari, Cosima ^{[2
,3
]}

Butini, Stefania ^{[1
,2
]}

Novellino, Ettore ^{[12
]}

Campiani, Giuseppe ^{[1
,2
]}

Altucci, Lucia ^{[7
]}

Steinmetz, Michel O. ^{[5
,6
]}

Brogi, Simone ^{[1
,2
,12
]}

机构：

[1] Univ Siena, Dept Biotechnol Chem & Pharm, DoE 2018 2022, European Res Ctr Drug Discovery & Dev NatSynDrugs, Via Aldo Moro 2, I-53100 Siena, Italy

[2] Univ Siena, Ist Toscano Tumori, Via Aldo Moro 2, I-53100 Siena, Italy

[3] Dept Life Sci, Via Aldo Moro 2, I-53100 Siena, Italy

[4] CSIC, Ctr Invest Biol, Dept Phys & Chem Biol, Ramiro de Maeztu 9, Madrid 28040, Spain

[5] Paul Scherrer Inst, Lab Biomol Res, Div Biol & Chem, CH-5232 Villigen, Switzerland

[6] Univ Basel, Biozentrum, CH-4056 Basel, Switzerland

[7] Univ Campania Luigi Vanvitelli, Dept Precis Med, Vico L de Crecchio 7, I-80138 Naples, Italy

[8] IRCCS, SDN, Via E Gianturco 113, I-80143 Naples, Italy

[9] Trinity Coll Dublin, Trinity Biomed Sci Inst, Sch Biochem & Immunol, 152-160 Pearse St, Dublin 2, Ireland

[10] Trinity Coll Dublin, Sch Dent Sci, Lincoln Pl, Dublin 2, Ireland

[11] Univ Perugia, Dept Expt Med, Ple Gambuli, I-06132 Perugia, Italy

[12] Univ Napoli Federico 11, DoE 2018 2022, Dept Pharm, Via D Montesano 49, I-80131 Naples, Italy

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 162卷

基金：

瑞士国家科学基金会;

关键词：

Apoptosis; Antitumor agents; Microtubule-targeting agent; Tubulin; X-ray crystallography; Molecular modeling; CANCER CELLS; FORCE-FIELD; TUBULIN; AUTOPHAGY; MICROTUBULES; APOPTOSIS; COLCHICINE; BINDING; INHIBITORS; DYNAMICS;

D O I：

10.1016/j.ejmech.2018.11.004

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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. (C) 2018 Elsevier Masson SAS. All rights reserved.

引用

页码：290 / 320

页数：31

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