Targeting integrins αvβ3 and α5β1 with new β-lactam derivatives

• Published in: European journal of medicinal chemistry Vol. 83; pp. 284 - 293
• Main Authors: Galletti, Paola, Soldati, Roberto, Pori, Matteo, Durso, Margherita, Tolomelli, Alessandra, Gentilucci, Luca, Dattoli, Samantha Deianira, Baiula, Monica, Spampinato, Santi, Giacomini, Daria
• Format: Journal Article
• Language: English
• Published: France Elsevier Masson SAS 18.08.2014
• Subjects: Agonists; Azetidines - chemistry; Azetidinones; beta-Lactams - chemical synthesis; beta-Lactams - chemistry; beta-Lactams - pharmacology; Cell adhesion; Cell Line, Tumor; Drug Design; Humans; Integrin alpha5beta1 - agonists; Integrin alpha5beta1 - metabolism; Integrin alphaVbeta3 - agonists; Integrin alphaVbeta3 - metabolism; Integrins; Lactams; Ligands; Molecular Targeted Therapy; Peptidomimetics; Azetidinones; Lactams; Agonists; Peptidomimetics; Cell adhesion; Integrins
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2014.06.041

The αvβ3 and α5β1 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 (EC50 of 11 nM). [Display omitted] •Design and synthesis of new β-lactams targeting integrins αvβ3 and α5β1.•Synthesis of new peptidomimetics based on azetidinone core.•Azetidinones promoted enhancement in fibronectin-mediated cell adhesion.