The αvβ3 and α5β 1 integrins are widely expressed in different cancer types and recognize the tripeptide Arg-Gly-Asp (RGD) motif present in several extracellular matrix proteins. We report here the design, synthesis and biological activity of some new β-lactam derivatives specifically designed to target integrins. The new molecules contain the azetidinone as the only cyclic framework armed with carboxylic acid and amine terminals spaced from 9 to 14 atoms to switch on recognition by integrins. All tested molecules showed a concentration-dependent enhancement in fibronectin-mediated adhesion of K562 and SK-MEL-24 cells; in particular 1, expressed a higher affinity towards α5β1 integrin (EC50 of 12 nM) and 2 was more selective for integrin αvβ3 (EC 50 of 11 nM). © 2014 Elsevier Masson SAS. All rights reserved.
Paola Galletti, Roberto Soldati, Matteo Pori, Margherita Durso, Alessandra Tolomelli, Luca Gentilucci, et al. (2014). Targeting integrins αvβ3 and α5β1 with new β-lactam derivatives. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 83, 284-293 [10.1016/j.ejmech.2014.06.041].
Targeting integrins αvβ3 and α5β1 with new β-lactam derivatives
GALLETTI, PAOLA;SOLDATI, ROBERTO;PORI, MATTEO;DURSO, MARGHERITA;TOLOMELLI, ALESSANDRA;GENTILUCCI, LUCA;DATTOLI, SAMANTHA DEIANIRA;BAIULA, MONICA;SPAMPINATO, SANTI MARIO;GIACOMINI, DARIA
2014
Abstract
The αvβ3 and α5β 1 integrins are widely expressed in different cancer types and recognize the tripeptide Arg-Gly-Asp (RGD) motif present in several extracellular matrix proteins. We report here the design, synthesis and biological activity of some new β-lactam derivatives specifically designed to target integrins. The new molecules contain the azetidinone as the only cyclic framework armed with carboxylic acid and amine terminals spaced from 9 to 14 atoms to switch on recognition by integrins. All tested molecules showed a concentration-dependent enhancement in fibronectin-mediated adhesion of K562 and SK-MEL-24 cells; in particular 1, expressed a higher affinity towards α5β1 integrin (EC50 of 12 nM) and 2 was more selective for integrin αvβ3 (EC 50 of 11 nM). © 2014 Elsevier Masson SAS. All rights reserved.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
