Dimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part II: Structural and biological characterization

Daniele Lecis, Eloise Mastrangelo, Laura Belvisi, Martino Bolognesi, Monica Civera, Federica Cossu, Michelandrea De Cesare, Domenico Delia, Carmelo Drago, Giacomo Manenti, Leonardo Manzoni, Mario Milani, Elisabetta Moroni, Paola Perego, Donatella Potenza, Vincenzo Rizzo, Cinzia Scavullo, Carlo Scolastico, Federica Servida, Francesca VasilePierfausto Seneci

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Novel pro-apoptotic, homodimeric and heterodimeric Smac mimetics/IAPs inhibitors connected through head-head (8), tail-tail (9) or head-tail linkers (10), were biologically and structurally characterized. In vitro characterization (binding to BIR3 and linker-BIR2-BIR3 domains from XIAP and cIAP1, cytotoxicity assays) identified early leads from each dimer family. Computational models and structural studies (crystallography, NMR, gel filtration) partially rationalized the observed properties for each dimer class. Tail-tail dimer 9a was shown to be active in a breast and in an ovary tumor model, highlighting the potential of dimeric Smac mimetics/IAP inhibitors based on the N-AVPI-like 4-substituted 1-aza-2-oxobicyclo[5.3.0]decane scaffold as potential antineoplastic agents.

Original languageEnglish
Pages (from-to)6709-6723
Number of pages15
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number22
DOIs
Publication statusPublished - Nov 15 2012

Fingerprint

Dimers
Head
Crystallography
Structural Models
Cytotoxicity
Scaffolds
Antineoplastic Agents
Gel Chromatography
Tumors
Ovary
Assays
Breast
Gels
Nuclear magnetic resonance
Neoplasms
decane
In Vitro Techniques

Keywords

  • Apoptosis
  • IAP inhibitors
  • In vitro profiling
  • In vivo testing
  • Smac mimetics
  • Structural studies

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

Cite this

Dimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part II : Structural and biological characterization. / Lecis, Daniele; Mastrangelo, Eloise; Belvisi, Laura; Bolognesi, Martino; Civera, Monica; Cossu, Federica; De Cesare, Michelandrea; Delia, Domenico; Drago, Carmelo; Manenti, Giacomo; Manzoni, Leonardo; Milani, Mario; Moroni, Elisabetta; Perego, Paola; Potenza, Donatella; Rizzo, Vincenzo; Scavullo, Cinzia; Scolastico, Carlo; Servida, Federica; Vasile, Francesca; Seneci, Pierfausto.

In: Bioorganic and Medicinal Chemistry, Vol. 20, No. 22, 15.11.2012, p. 6709-6723.

Research output: Contribution to journalArticle

Lecis, D, Mastrangelo, E, Belvisi, L, Bolognesi, M, Civera, M, Cossu, F, De Cesare, M, Delia, D, Drago, C, Manenti, G, Manzoni, L, Milani, M, Moroni, E, Perego, P, Potenza, D, Rizzo, V, Scavullo, C, Scolastico, C, Servida, F, Vasile, F & Seneci, P 2012, 'Dimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part II: Structural and biological characterization', Bioorganic and Medicinal Chemistry, vol. 20, no. 22, pp. 6709-6723. https://doi.org/10.1016/j.bmc.2012.09.041
Lecis, Daniele ; Mastrangelo, Eloise ; Belvisi, Laura ; Bolognesi, Martino ; Civera, Monica ; Cossu, Federica ; De Cesare, Michelandrea ; Delia, Domenico ; Drago, Carmelo ; Manenti, Giacomo ; Manzoni, Leonardo ; Milani, Mario ; Moroni, Elisabetta ; Perego, Paola ; Potenza, Donatella ; Rizzo, Vincenzo ; Scavullo, Cinzia ; Scolastico, Carlo ; Servida, Federica ; Vasile, Francesca ; Seneci, Pierfausto. / Dimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part II : Structural and biological characterization. In: Bioorganic and Medicinal Chemistry. 2012 ; Vol. 20, No. 22. pp. 6709-6723.
@article{58e44bfd631e41df9ffbf0cdd274d27e,
title = "Dimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part II: Structural and biological characterization",
abstract = "Novel pro-apoptotic, homodimeric and heterodimeric Smac mimetics/IAPs inhibitors connected through head-head (8), tail-tail (9) or head-tail linkers (10), were biologically and structurally characterized. In vitro characterization (binding to BIR3 and linker-BIR2-BIR3 domains from XIAP and cIAP1, cytotoxicity assays) identified early leads from each dimer family. Computational models and structural studies (crystallography, NMR, gel filtration) partially rationalized the observed properties for each dimer class. Tail-tail dimer 9a was shown to be active in a breast and in an ovary tumor model, highlighting the potential of dimeric Smac mimetics/IAP inhibitors based on the N-AVPI-like 4-substituted 1-aza-2-oxobicyclo[5.3.0]decane scaffold as potential antineoplastic agents.",
keywords = "Apoptosis, IAP inhibitors, In vitro profiling, In vivo testing, Smac mimetics, Structural studies",
author = "Daniele Lecis and Eloise Mastrangelo and Laura Belvisi and Martino Bolognesi and Monica Civera and Federica Cossu and {De Cesare}, Michelandrea and Domenico Delia and Carmelo Drago and Giacomo Manenti and Leonardo Manzoni and Mario Milani and Elisabetta Moroni and Paola Perego and Donatella Potenza and Vincenzo Rizzo and Cinzia Scavullo and Carlo Scolastico and Federica Servida and Francesca Vasile and Pierfausto Seneci",
year = "2012",
month = "11",
day = "15",
doi = "10.1016/j.bmc.2012.09.041",
language = "English",
volume = "20",
pages = "6709--6723",
journal = "Bioorganic and Medicinal Chemistry",
issn = "0968-0896",
publisher = "Elsevier Limited",
number = "22",

}

TY - JOUR

T1 - Dimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part II

T2 - Structural and biological characterization

AU - Lecis, Daniele

AU - Mastrangelo, Eloise

AU - Belvisi, Laura

AU - Bolognesi, Martino

AU - Civera, Monica

AU - Cossu, Federica

AU - De Cesare, Michelandrea

AU - Delia, Domenico

AU - Drago, Carmelo

AU - Manenti, Giacomo

AU - Manzoni, Leonardo

AU - Milani, Mario

AU - Moroni, Elisabetta

AU - Perego, Paola

AU - Potenza, Donatella

AU - Rizzo, Vincenzo

AU - Scavullo, Cinzia

AU - Scolastico, Carlo

AU - Servida, Federica

AU - Vasile, Francesca

AU - Seneci, Pierfausto

PY - 2012/11/15

Y1 - 2012/11/15

N2 - Novel pro-apoptotic, homodimeric and heterodimeric Smac mimetics/IAPs inhibitors connected through head-head (8), tail-tail (9) or head-tail linkers (10), were biologically and structurally characterized. In vitro characterization (binding to BIR3 and linker-BIR2-BIR3 domains from XIAP and cIAP1, cytotoxicity assays) identified early leads from each dimer family. Computational models and structural studies (crystallography, NMR, gel filtration) partially rationalized the observed properties for each dimer class. Tail-tail dimer 9a was shown to be active in a breast and in an ovary tumor model, highlighting the potential of dimeric Smac mimetics/IAP inhibitors based on the N-AVPI-like 4-substituted 1-aza-2-oxobicyclo[5.3.0]decane scaffold as potential antineoplastic agents.

AB - Novel pro-apoptotic, homodimeric and heterodimeric Smac mimetics/IAPs inhibitors connected through head-head (8), tail-tail (9) or head-tail linkers (10), were biologically and structurally characterized. In vitro characterization (binding to BIR3 and linker-BIR2-BIR3 domains from XIAP and cIAP1, cytotoxicity assays) identified early leads from each dimer family. Computational models and structural studies (crystallography, NMR, gel filtration) partially rationalized the observed properties for each dimer class. Tail-tail dimer 9a was shown to be active in a breast and in an ovary tumor model, highlighting the potential of dimeric Smac mimetics/IAP inhibitors based on the N-AVPI-like 4-substituted 1-aza-2-oxobicyclo[5.3.0]decane scaffold as potential antineoplastic agents.

KW - Apoptosis

KW - IAP inhibitors

KW - In vitro profiling

KW - In vivo testing

KW - Smac mimetics

KW - Structural studies

UR - http://www.scopus.com/inward/record.url?scp=84867863403&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84867863403&partnerID=8YFLogxK

U2 - 10.1016/j.bmc.2012.09.041

DO - 10.1016/j.bmc.2012.09.041

M3 - Article

C2 - 23062821

AN - SCOPUS:84867863403

VL - 20

SP - 6709

EP - 6723

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

SN - 0968-0896

IS - 22

ER -