Dehydro-?-proline Containing ?4?1 Integrin Antagonists: Stereochemical Recognition in Ligand-Receptor Interplay.

ABSTRACT: A novel class of dehydro-?-proline-containing peptidomimetics, designed to be effective as ?4?1 integrin ligands, has been developed on the basis of the fundamental requirements for the interactions of these transmembrane receptors with bioactive ligands. Dehydro-?-proline ring has been synthesized through an original pathway, involving ring closing metathesis of a diallylamino derivative. The synthesized products showed to be effective and selective as ?4?1 integrin antagonists and displayed IC50 values in the nanomolar range in cell adhesion inhibition assays and in VCAM-1-induced phosphorylation of extracellular-signal-regulated kinases. Significant activity was observed also toward the homologous integrin ?4?7, while they did not display any activity toward selected members of ?1, ?2, and ?3 families. A strong dependence on the stereochemistry of the heterocyclic central core could be observed. The great importance of ?4?1 integrin in chronic inflammatory and autoimmune diseases suggests a possible exploitation of these ligands as lead compounds for therapeutic tools development.

SUBMITTER: Tolomelli A 

PROVIDER: S-EPMC4468404 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature