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.

Dimeric Smac mimetics/IAP inhibitors as in vivo-active pro-apoptotic agents. Part II : Structural and biological characterization / D. Lecis, E. Mastrangelo, L. Belvisi, M. Bolognesi, M. Civera, F. Cossu, M. De Cesare, D. Delia, C. Drago, G. Manenti, L. Manzoni, M. Milani, E. Moroni, P. Perego, D. Potenza, V. Rizzo, C. Scavullo, C. Scolastico, F. Servida, F. Vasile, P. Seneci. - In: BIOORGANIC & MEDICINAL CHEMISTRY. - ISSN 0968-0896. - 20:22(2012), pp. 6709-6723. [10.1016/j.bmc.2012.09.041]

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

E. Mastrangelo
Secondo
;
L. Belvisi;M. Bolognesi;M. Civera;F. Cossu;E. Moroni;D. Potenza;F. Vasile
Penultimo
;
P. Seneci
Ultimo
2012

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.
apoptosis; IAP inhibitors; in vitro profiling; in vivo testing; Smac mimetics; structural studies
Settore CHIM/06 - Chimica Organica
2012
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/211034
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