A library of 11 bifunctional 2,5-diketopiperazine (DKP) scaffolds, derived from L- or D-Ser and either L- or D-Asp or D-Glu, was designed and synthesized. All the DKP scaffolds feature a carboxylic acid functionality and an amino group, either protected as Boc or masked as azide, which can be locked in a cis- or trans-relationship as a consequence of the absolute configurations of the two α-amino acids. Moreover, the DKP scaffolds differ from each other for the substitution at the intracyclic nitrogens (N-1, N-4), as they are either mono- or bis-benzylated. The DKP scaffolds, while being derived from α-amino acids, can be seen as constrained dipeptides formed by two β-amino acids or one β- and one γ-amino acid. Two different synthetic strategies were devised to prepare the mono benzylated scaffolds, depending on the nitrogen substitution (N-1 or N-4). In particular, the synthesis of DKP scaffolds bearing a benzyl group at the serine-derived nitrogen N-4 was accomplished making use of a serine ligation strategy, via the isopeptide. On the other hand, the synthesis of DKP scaffolds bearing a benzyl group at the aspartic acid-derived nitrogen N-1 occurred through the formation of a dipeptide intermediate. Bis N-benzyl substituted scaffolds were easily accessed benzylating mono-substituted advanced intermediates. An efficient synthesis in solution of eight cyclic peptidomimetics containing a DKP scaffold and the Arg-Gly-Asp (RGD) motif has been developed and optimized. The ligands were tested for their ability to inhibit biotinylated vitronectin binding to integrin αvβ3 and αvβ5 receptors. All the ligands, except for the one containing a cis-scaffold, displayed low nanomolar inhibitory activity for both αVβ3 and αVβ5 integrin receptors, with a slight selectivity in favour of the former receptor. In order to rationalize, on a molecular basis, the affinity of these cyclic RGD peptidomimetics for the αvβ3 receptor, conformational and docking studies were performed by NMR spectroscopy and computational methods. Two cyclic peptidomimetics containing a DKP scaffold and the isoAsp-Gly-Arg (isoDGR) motif were prepared, combining a solid phase and a solution phase synthetic approach. Very promising results (low nanomolar inhibitory activity) were obtained for their ability to inhibit biotinylated vitronectin binding to the αvβ3 and αvβ5 integrin receptors. Based on the good results recently obtained by the group of Prof. Oliver Reiser (Univ. Regensburg) in the design of helices, alternating two α- and two β-amino acids, a linear pseudodecapeptide was prepared alternating a cis-DKP, which serves as a ββ-constrained dipeptide, and Ala-Ala as the αα-subunit. The folding properties of the αα,ββ-pseudodecapeptide were studied by NMR spectroscopy, CD spectroscopy and computational methods. The results obtained, though not exhaustive, are indicative of a turn-inducing ability of the cis-DKP.  M. Marchini, M. Mingozzi, R. Colombo, C. Gennari, M. Durini, U. Piarulli, Tetrahedron 2010, 66, 9528-9531.  A. S. M. da Ressurreição, A. Vidu, M. Civera, L. Belvisi, D. Potenza, L. Manzoni, S. Ongeri, C. Gennari, U. Piarulli, Chem. Eur. J. 2009, 15, 12184-12188.  L. Berlicki, L. Pilsl, E. Wéber, I. M. Mándity, C. Cabrele, T. A. Martinek, F. Fülöp, O. Reiser, Angew. Chem. Int. Ed., in press.  a) A. S. M. Ressurreição, A. Bordessa, M. Civera, L. Belvisi, C. Gennari, U. Piarulli, J. Org. Chem. 2008, 73, 652-660; b) R. Delatouche, M. Durini, M. Civera, L. Belvisi, U. Piarulli, Tetrahedron Lett. 2010, 51, 4278-4280.
PEPTIDOMIMETICS CONTAINING NEW BIFUNCTIONAL 2,5-DIKETOPIPERAZINE SCAFFOLDS: SYNTHESIS, CONFORMATIONAL ANALYSIS AND USE AS POTENT INTEGRIN LIGANDS / M. Marchini ; tutor: C. Gennari ; co-tutor: U. Piarulli ; co-ordinator: S. Ardizzone. - Milano : Università degli studi di Milano. Universita' degli Studi di Milano, 2012 Jan 11. ((24. ciclo, Anno Accademico 2011.
|Titolo:||PEPTIDOMIMETICS CONTAINING NEW BIFUNCTIONAL 2,5-DIKETOPIPERAZINE SCAFFOLDS: SYNTHESIS, CONFORMATIONAL ANALYSIS AND USE AS POTENT INTEGRIN LIGANDS|
|Supervisori e coordinatori interni:||ARDIZZONE, SILVIA|
|Data di pubblicazione:||11-gen-2012|
|Parole Chiave:||2,5-diketopiperazine ; integrins ; RGD ; isoDGR ; foldamers|
|Settore Scientifico Disciplinare:||Settore CHIM/06 - Chimica Organica|
|Citazione:||PEPTIDOMIMETICS CONTAINING NEW BIFUNCTIONAL 2,5-DIKETOPIPERAZINE SCAFFOLDS: SYNTHESIS, CONFORMATIONAL ANALYSIS AND USE AS POTENT INTEGRIN LIGANDS / M. Marchini ; tutor: C. Gennari ; co-tutor: U. Piarulli ; co-ordinator: S. Ardizzone. - Milano : Università degli studi di Milano. Universita' degli Studi di Milano, 2012 Jan 11. ((24. ciclo, Anno Accademico 2011.|
|Digital Object Identifier (DOI):||http://dx.doi.org/10.13130/marchini-mattia_phd2012-01-11|
|Appare nelle tipologie:||Tesi di dottorato|