4-Aminoproline-based arginine-glycine-aspartate integrin binders with exposed ligation points: practical in-solution synthesis, conjugation and binding affinity evaluation

Abstract

An expedient and practical in-solution synthesis of three new 4-aminoproline-based arginine-glycine-aspartate integrin binders – compounds 15, 17 and 19– is presented. Two candidates carrying exposed azide and amine functional points were further advanced to trimeric platform 21 as well as fluorescein- and DOTA-conjugates 23 and 25. The new compounds were assayed for their binding affinity towards human α_Vβ₃ and α_Vβ₅ integrin receptors. Both monomeric candidates and covalent conjugates revealed potent ligand competence for the α_Vβ₃ receptor in the one-digit nanomolar range (IC₅₀α_Vβ₃ = 0.2–8.0 nM; IC₅₀α_Vβ₅ = 5.0–1621 nM), thus demonstrating that conjugation does not impair the exquisite binding profile of this new generation of integrin ligands.