New β-Lactam Derivatives Modulate Cell Adhesion and Signaling Mediated by RGD-Binding and Leukocyte Integrins

A novel series of β-lactam derivatives that was designed and synthesized to target RGD-binding and leukocyte integrins is reported. The compound library was evaluated by investigating the effects on integrin-mediated cell adhesion and cell signaling in cell lines expressing α_vβ₃, α_vβ₅, α_vβ₆, α₅β₁, α_IIbβ₃, α₄β₁, and α_Lβ₂ integrins. SAR analysis of the new series of azetidinones enabled the recognition of structural elements associated with integrin selectivity. We obtained selective and potent agonists that could induce cell adhesion and promote cell signaling mediated by α_vβ₃, α_vβ₅, α₅β₁, or α₄β₁ integrin, and antagonists for the integrins α_vβ₃ and α₅β_1, as well as α₄β₁ and α_Lβ₂, preventing the effects elicited by the respective endogenous agonists.