Journal
CHEMMEDCHEM
Volume 6, Issue 12, Pages 2264-2272Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cmdc.201100372
Keywords
cancer; cell adhesion; drug discovery; heterocycles; peptidomimetics
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Funding
- Italian Minister for Foreign Affairs (MAE) (General Direction for the Cultural Promotion and Cooperation)
- Consorzio Interuniversitario Nazionale Metodologie e Processi Innovativi di Sintesi (CINMPIS)
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Isoxazoline-containing peptidomimetics, designed to be effective alpha(v)beta(3) and alpha(5)beta(1) integrin ligands, were synthesized through an original procedure involving N,O-bis(trimethylsilyl)hydroxyamine conjugate addition to alkylidene acetoacetates, followed by intramolecular hemiketalization. To mimic the RGD recognition sequence, basic and acidic terminal appendages were introduced, and the final products were tested in cell adhesion inhibition assays. All the synthesized compounds proved to be excellent ligands for both integrin receptors, and a strong influence on intracellular signaling and phosphorylation pathways was demonstrated by evaluation of fibronectin-induced phosphorylation of ERK. The molecular basis of the observed inhibitory activity was suggested on the results of docking experiments.
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