Eleven γ-aminocyclopentane carboxylic acid (Acpca) platforms, including four dihydroxy representatives (19−22), three hydroxy analogues (34−36), and four deoxy derivatives (30−33), were prepared in a chiral nonracemic format. These simple units were then grafted onto an Arg-Gly-Asp (RGD) tripeptide framework by a mixed solid phase/solution protocol delivering an ensemble of 11 macrocyclic analogues of type cyclo-[-Arg-Gly-Asp-Acpca-], 1−11. The individual compounds were evaluated for their binding affinity toward the αVβ3 and αVβ5 integrin receptors. The analogue 10 exhibited a very interesting activity profile (IC50/αVβ3 = 1.5 nM; IC50/αVβ5 = 0.59 nM), comparable to that of reference compounds EMD121974 and ST1646. Closely related congeners 6, 8, and 9 also proved to be excellent dual binders with activity levels in the low nanomolar range. The three-dimensional (3D) NMR solution structures were determined, and docking studies to X-ray crystal structure of the extracellular segment of integrin αVβ3 in complex with the reference compound EMD121974 were performed on selected analogues to elucidate the interplay between structure and function in these systems and to evidence the subtle bases for receptorial recognition. The results prove that the principle of isosteric dipeptide replacement for peptidomimetics design and synthesis can be violated, without detriment to the development of highly effective integrin binders.

Grafting Aminocyclopentane Carboxylic Acids onto the RGD Tripeptide Sequence Generates Low Nanomolar alfaVbeta3/alfaVbeta5 Integrin Dual Binders / CASIRAGHI G.; RASSU G.; AUZZAS L.; BURREDDU P.; GAETANI E.; BATTISTINI L.; ZANARDI F.; CURTI C.; NICASTRO G.; BELVISI L.; MOTTO I.; CASTORINA M.; GIANNINI G.; PISANO C.. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 48(2005), pp. 7675-7687. [10.1021/jm050698x]

Grafting Aminocyclopentane Carboxylic Acids onto the RGD Tripeptide Sequence Generates Low Nanomolar alfaVbeta3/alfaVbeta5 Integrin Dual Binders

CASIRAGHI, Giovanni;GAETANI, Enrico;BATTISTINI, Lucia;ZANARDI, Franca;CURTI, Claudio;NICASTRO, Giuseppe;
2005

Abstract

Eleven γ-aminocyclopentane carboxylic acid (Acpca) platforms, including four dihydroxy representatives (19−22), three hydroxy analogues (34−36), and four deoxy derivatives (30−33), were prepared in a chiral nonracemic format. These simple units were then grafted onto an Arg-Gly-Asp (RGD) tripeptide framework by a mixed solid phase/solution protocol delivering an ensemble of 11 macrocyclic analogues of type cyclo-[-Arg-Gly-Asp-Acpca-], 1−11. The individual compounds were evaluated for their binding affinity toward the αVβ3 and αVβ5 integrin receptors. The analogue 10 exhibited a very interesting activity profile (IC50/αVβ3 = 1.5 nM; IC50/αVβ5 = 0.59 nM), comparable to that of reference compounds EMD121974 and ST1646. Closely related congeners 6, 8, and 9 also proved to be excellent dual binders with activity levels in the low nanomolar range. The three-dimensional (3D) NMR solution structures were determined, and docking studies to X-ray crystal structure of the extracellular segment of integrin αVβ3 in complex with the reference compound EMD121974 were performed on selected analogues to elucidate the interplay between structure and function in these systems and to evidence the subtle bases for receptorial recognition. The results prove that the principle of isosteric dipeptide replacement for peptidomimetics design and synthesis can be violated, without detriment to the development of highly effective integrin binders.
File in questo prodotto:
File Dimensione Formato  
2005_Battistini_JMedChem_abs.pdf

non disponibili

Tipologia: Abstract
Licenza: Creative commons
Dimensione 153.36 kB
Formato Adobe PDF
153.36 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
2005_Battistini_JMedChem_text.pdf

non disponibili

Tipologia: Documento in Post-print
Licenza: Creative commons
Dimensione 609.81 kB
Formato Adobe PDF
609.81 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
n38_2005_JMedChem_SI.pdf

non disponibili

Tipologia: Altro materiale allegato
Licenza: Creative commons
Dimensione 899.29 kB
Formato Adobe PDF
899.29 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11381/1444637
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 54
  • ???jsp.display-item.citation.isi??? 52
social impact