Development of novel cyclic peptides as pro-apoptotic agents

被引：21

作者：

Brindisi, Margherita ^{[1
,2
]}

Maramai, Samuele ^{[1
,2
]}

Brogi, Simone ^{[1
,2
]}

Fanigliulo, Emanuela ^{[3
]}

Butini, Stefania ^{[1
,2
]}

Guarino, Egeria ^{[1
,2
]}

Casagni, Alice ^{[1
,2
]}

Lamponi, Stefania ^{[1
,2
]}

Bonechi, Claudia ^{[1
,2
]}

Nathwani, Seema M. ^{[4
]}

Finetti, Federica ^{[2
,3
]}

Ragonese, Francesco ^{[5
]}

Arcidiacono, Paola ^{[5
]}

Campiglia, Pietro ^{[6
]}

Valenti, Salvatore ^{[1
,2
]}

Novellino, Ettore ^{[1
,7
]}

Spaccapelo, Roberta ^{[5
]}

Morbidelli, Lucia ^{[2
,3
]}

Zisterer, Daniela M. ^{[4
]}

Williams, Clive D. ^{[4
]}

Donati, Alessandro ^{[1
,2
]}

Baldari, Cosima ^{[3
]}

Campiani, Giuseppe ^{[1
,2
]}

Ulivieri, Cristina ^{[3
]}

Gemma, Sandra ^{[1
,2
]}

机构：

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

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

[6] Univ Salerno, Dipartimento DIFARMA, I-84084 Salerno, Italy

[7] Univ Naples Federico II, Dipartimento Farm, Via A Montesano 49, I-80131 Naples, Italy

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 117卷

关键词：

Pro-apoptotic agents; Anticancer agents; Cyclic peptides; Peptidomimetics; Nur77; Tubulin; Bcl-2; NMR studies; Molecular modeling; Confocal microscopy; FACS analysis; STRUCTURE PREDICTION; GENETIC ALGORITHM; ANTICANCER DRUGS; NATURAL-PRODUCTS; FORCE-FIELD; SIDE-CHAIN; PROTEINS; DOCKING; INHIBITORS; TUBULIN;

D O I：

10.1016/j.ejmech.2016.04.001

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Our recent finding that paclitaxel behaves as a peptidomimetic of the endogenous protein Nur77 inspired the design of two peptides (PEP1 and PEP2) reproducing the effects of paclitaxel on Bcl-2 and tubulin, proving the peptidomimetic nature of paclitaxel. Starting from these peptide-hits, we herein describe the synthesis and the biological investigation of linear and cyclic peptides structurally related to PEP2. While linear peptides (2a,b, 3a,b, 4, 6a-f) were found inactive in cell-based assays, biological analysis revealed a pro-apoptotic effect for most of the cyclic peptides (5a-g). Cellular permeability of 5a (and also of 2a,b) on HL60 cells was assessed through confocal microscopy analysis. Further cellular studies on a panel of leukemic cell lines (HL60, Jurkat, MEC, EBVB) and solid tumor cell lines (breast cancer MCF-7 cells, human melanoma A375 and 501Mel cells, and murine melanoma B16F1 cells) confirmed the proapoptotic effect of the cyclic peptides. Cell cycle analysis revealed that treatment with 5a, 5c, 5d or 5f resulted in an increase in the number of cells in the sub-G(0)/G(1) peak. Direct interaction with tubulin (turbidimetric assay) and with microtubules (immunostaining experiments) was assessed in vitro for the most promising compounds. (C) 2016 Elsevier Masson SAS. All rights reserved.

引用

页码：301 / 320

页数：20

共 56 条

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