Grafting Aminocyclopentane Carboxylic Acids onto the RGD Tripeptide Sequence Generates Low Nanomolar aVb3/aVb5 Integrin Dual Binders. (Articolo in rivista)

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  • Grafting Aminocyclopentane Carboxylic Acids onto the RGD Tripeptide Sequence Generates Low Nanomolar aVb3/aVb5 Integrin Dual Binders. (Articolo in rivista) (literal)
Anno
  • 2005-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1021/jm050698x (literal)
Alternative label
  • 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. (2005)
    Grafting Aminocyclopentane Carboxylic Acids onto the RGD Tripeptide Sequence Generates Low Nanomolar aVb3/aVb5 Integrin Dual Binders.
    in Journal of medicinal chemistry
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • 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. (literal)
Pagina inizio
  • 7675 (literal)
Pagina fine
  • 7687 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#url
  • http://pubs.acs.org/doi/pdf/10.1021/jm050698x (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
  • 48 (literal)
Rivista
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#pagineTotali
  • 13 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroFascicolo
  • 24 (literal)
Note
  • Scopu (literal)
  • ISI Web of Science (WOS) (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • Dipartimento Farmaceutico, Universita` di Parma, Parco Area delle Scienze 27A, I-43100 Parma, Italy, Istituto di Chimica Biomolecolare del CNR, Traversa La Crucca 3, I-07040 Li Punti, Sassari, Italy, Centro Interfacolta` Misure \"G. Casnati\", Universita` di Parma, Parco Area delle Scienze 23A, I-43100 Parma, Italy, Dipartimento di Chimica Organica e Industriale, Universita` di Milano, Via Venezian 21, I-20133 Milano, Italy, and Sigma-Tau, Research & Development, Via Pontina Km 30.400, 00040 Pomezia, Roma, Italy (literal)
Titolo
  • Grafting Aminocyclopentane Carboxylic Acids onto the RGD Tripeptide Sequence Generates Low Nanomolar aVb3/aVb5 Integrin Dual Binders. (literal)
Abstract
  • Eleven gamma-aminocyclopentane carboxylic acid (Acpca) platforms, including four dihydroxy representatives (19-22), three hydroxy analogues (34-36), and four deoxy derivatives (3033), 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 alfaVbeta3 and alfaVbeta5 integrin receptors. The analogue 10 exhibited a very interesting activity profile (IC50/alfaVbeta3 = 1.5 nM; IC50/alfaVbeta = 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 alfaVbeta3 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. (literal)
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