Targeting integrins alpha(v)beta(3) and alpha(5)beta(1) with new beta-lactam derivatives

The alpha(v)beta(3) and alpha(5)beta(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 beta-lactam derivatives spe...

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Published inEuropean 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
LanguageEnglish
Published ISSY-LES-MOULINEAUX Elsevier 18.08.2014
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
ANTIBODIES
ACTIVATION
HOMEOSTASIS
Lactams
CELL-ADHESION
CD11B/CD18
SMALL-MOLECULE AGONIST
Peptidomimetics
AMINO ACIDS
Cell adhesion
Azetidinones
Agonists
ANTAGONISTS
MODULATION
Integrins
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Summary:The alpha(v)beta(3) and alpha(5)beta(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 beta-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 alpha(5)beta(1) integrin (EC50 of 12 nM) and 2 was more selective for integrin alpha(v)beta(3) (EC50 of 11 nM). (C) 2014 Elsevier Masson SAS. All rights reserved.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2014.06.041