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Eur J Med Chem. 2014 Aug 18;83:284-93. doi: 10.1016/j.ejmech.2014.06.041. Epub 2014 Jun 19.

Targeting integrins αvβ3 and α5β1 with new β-lactam derivatives.

Author information

1
Department of Chemistry "G. Ciamician", University of Bologna, Via Selmi 2, 40126 Bologna, Italy. Electronic address: paola.galletti@unibo.it.
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: santi.spampinato@unibo.it.
5
Department of Chemistry "G. Ciamician", University of Bologna, Via Selmi 2, 40126 Bologna, Italy. Electronic address: daria.giacomini@unibo.it.

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

PMID:
24973662
DOI:
10.1016/j.ejmech.2014.06.041
[Indexed for MEDLINE]
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