Development of Isoxazoline‐Containing Peptidomimetics as Dual α_vβ₃ and α₅β₁ Integrin Ligands

Abstract

Isoxazoline-containing peptidomimetics, designed to be effective α(v)β(3) and α(5)β(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.

5‐aminomethyloxazolidine‐2,4‐dione hybrid α/β‐dipeptide scaffolds as inductors of constrained conformations: Applications to the synthesis of integrin antagonists

“…Moving from our previous experience in the field of highly stable and biologically active peptides containing β‐amino acids, including integrin ligands, we envisaged the opportunity to design new peptidomimetic α4β1 integrin antagonists containing the Amo α/β‐dipeptide scaffold. In this sense, we observed that the large majority of the peptidomimetic α4β1 ligands share common structural features: a α4‐targeting diphenylurea moiety at the N ‐terminus, a suitable spacer, and a C ‐terminal Asp or a mimetic containing a carboxylic acid.…”

Synthesis and Evaluation of the Aldolase Antibody-Derived Chemical-Antibodies Targeting α5β1 Integrin

“…There are numerous potent anti-α5β1 integrin inhibitors 27,28,29,30 that could be modified with a linker and conjugated to Ab 38C2 giving anti-α5β1 chem-Abs. Initially, we focused on compound 1 27 (Figure 1), and synthesized an analogous compound 2 that possessed an alkyne function for introducing a linker enroute the Ab-PAs, 4 ’s, and chem-Abs 38C2- 4 ’s.…”

Side chain effect in the modulation of αvβ3/α5β1 integrin activity via clickable isoxazoline-RGD-mimetics: development of molecular delivery systems

“…Cell adhesion assay. In our previous experience, isoxazoline-based integrin ligands showed a strong potency towards α v β 3 and α 5 β 1 integrins, not affected by changing the alkyl group linked to position 3 18 . In designing this novel small library of peptidomimetics, alkyl chains were substituted by polyfunctionalized linkers including the triazole ring and amide, carbamate or ester moieties, that may create further interactions with the binding pocket.…”