Cyclic RGD and isoDGR Integrin Ligands Containing cis-2-amino-1-cyclopentanecarboxylic (cis-β-ACPC) Scaffolds

Panzeri S, Arosio D, Gazzola S, Belvisi L, Civera M, Potenza D, Vasile F, Kemker I, Ertl T, Sewald N, Reiser O, et al. (2020)
Molecules 25(24): 5966.

Zeitschriftenaufsatz | Veröffentlicht | Englisch
 
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Panzeri, Silvia; Arosio, Daniela; Gazzola, Silvia; Belvisi, Laura; Civera, Monica; Potenza, Donatella; Vasile, Francesca; Kemker, IsabellUniBi; Ertl, Thomas; Sewald, NorbertUniBi ; Reiser, Oliver; Piarulli, Umberto
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Abstract / Bemerkung
Integrin ligands containing the tripeptide sequences Arg-Gly-Asp (RGD) and iso-Asp-Gly- Arg (isoDGR) were actively investigated as inhibitors of tumor angiogenesis and directing unit in tumor-targeting drug conjugates. Reported herein is the synthesis, of two RGD and one isoDGR cyclic peptidomimetics containing (1S,2R) and (1R,2S) cis-2-amino-1-cyclopentanecarboxylic acid (cis-β-ACPC), using a mixed solid phase/solution phase synthetic protocol. The three ligands were examined in vitro in competitive binding assays to the purified αvβ3 and α5β1 receptors using biotinylated vitronectin (αvβ3) and fibronectin (α5β1) as natural displaced ligands. The IC50 values of the ligands ranged from nanomolar (the two RGD ligands) to micromolar (the isoDGR ligand) with a pronounced selectivity for αvβ3 over α5β1. In vitro cell adhesion assays were also performed using the human skin melanoma cell line WM115 (rich in integrin αvβ3). The two RGD ligands showed IC50 values in the same micromolar range as the reference compound (cyclo[RGDfV]), while for the isoDGR derivative an IC50 value could not be measured for the cell adhesion assay. A conformational analysis of the free RGD and isoDGR ligands by NMR (VT-NMR and NOESY experiments) and computational studies (MC/EM and MD), followed by docking simulations performed in the αVβ3 integrin active site, provided a rationale for the behavior of these ligands toward the receptor.
Stichworte
peptidomimetics; integrin ligands; beta-amino acids; NMR conformational analysis
Erscheinungsjahr
2020
Zeitschriftentitel
Molecules
Band
25
Ausgabe
24
Art.-Nr.
5966
eISSN
1420-3049
Page URI
https://pub.uni-bielefeld.de/record/2949877

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Panzeri S, Arosio D, Gazzola S, et al. Cyclic RGD and isoDGR Integrin Ligands Containing cis-2-amino-1-cyclopentanecarboxylic (cis-β-ACPC) Scaffolds. Molecules. 2020;25(24): 5966.
Panzeri, S., Arosio, D., Gazzola, S., Belvisi, L., Civera, M., Potenza, D., Vasile, F., et al. (2020). Cyclic RGD and isoDGR Integrin Ligands Containing cis-2-amino-1-cyclopentanecarboxylic (cis-β-ACPC) Scaffolds. Molecules, 25(24), 5966. https://doi.org/10.3390/molecules25245966
Panzeri, S., Arosio, D., Gazzola, S., Belvisi, L., Civera, M., Potenza, D., Vasile, F., Kemker, I., Ertl, T., Sewald, N., et al. (2020). Cyclic RGD and isoDGR Integrin Ligands Containing cis-2-amino-1-cyclopentanecarboxylic (cis-β-ACPC) Scaffolds. Molecules 25:5966.
Panzeri, S., et al., 2020. Cyclic RGD and isoDGR Integrin Ligands Containing cis-2-amino-1-cyclopentanecarboxylic (cis-β-ACPC) Scaffolds. Molecules, 25(24): 5966.
S. Panzeri, et al., “Cyclic RGD and isoDGR Integrin Ligands Containing cis-2-amino-1-cyclopentanecarboxylic (cis-β-ACPC) Scaffolds”, Molecules, vol. 25, 2020, : 5966.
Panzeri, S., Arosio, D., Gazzola, S., Belvisi, L., Civera, M., Potenza, D., Vasile, F., Kemker, I., Ertl, T., Sewald, N., Reiser, O., Piarulli, U.: Cyclic RGD and isoDGR Integrin Ligands Containing cis-2-amino-1-cyclopentanecarboxylic (cis-β-ACPC) Scaffolds. Molecules. 25, : 5966 (2020).
Panzeri, Silvia, Arosio, Daniela, Gazzola, Silvia, Belvisi, Laura, Civera, Monica, Potenza, Donatella, Vasile, Francesca, Kemker, Isabell, Ertl, Thomas, Sewald, Norbert, Reiser, Oliver, and Piarulli, Umberto. “Cyclic RGD and isoDGR Integrin Ligands Containing cis-2-amino-1-cyclopentanecarboxylic (cis-β-ACPC) Scaffolds”. Molecules 25.24 (2020): 5966.
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