Targeting integrins αvβ3 and α5β1 with new β-lactam derivatives

  • Eur J Med Chem. 2014 Aug 18:83:284-93. doi: 10.1016/j.ejmech.2014.06.041.
Paola Galletti  1 ,  Roberto Soldati  2 ,  Matteo Pori  2 ,  Margherita Durso  2 ,  Alessandra Tolomelli  2 ,  Luca Gentilucci  2 ,  Samantha Deianira Dattoli  3 ,  Monica Baiula  3 ,  Santi Spampinato  4 ,  Daria Giacomini  5
Affiliations
  • 1. Department of Chemistry "G. Ciamician", University of Bologna, Via Selmi 2, 40126 Bologna, Italy. Electronic address: [email protected].
  • 2. Department of Chemistry "G. Ciamician", University of Bologna, Via Selmi 2, 40126 Bologna, Italy.
  • 3. Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy.
  • 4. Department of Pharmacy and Biotechnology, University of Bologna, Via Irnerio 48, 40126 Bologna, Italy. Electronic address: [email protected].
  • 5. Department of Chemistry "G. Ciamician", University of Bologna, Via Selmi 2, 40126 Bologna, Italy. Electronic address: [email protected].
PMID: 24973662 DOI: 10.1016/j.ejmech.2014.06.041
Abstract

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).

Keywords
Agonists; Azetidinones; Cell adhesion; Integrins; Lactams; Peptidomimetics.