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

Abstract

Peptidomimetics represent an attractive starting point for drug discovery programs; in particular, peptidomimetics that result from the incorporation of a heterocycle may take advantage of increased enzymatic stability and higher ability to reproduce the bioactive conformations of the parent peptides, resulting in enhanced therapeutic potential. Herein, we present mimetics of the α4β1 integrin antagonist BIO1211 (MPUPA-Leu-Asp-Val-Pro-OH), containing a aminomethyloxazolidine-2,4-dione scaffold (Amo). Interestingly, the retro-sequences PhCOAsp(OH)-Amo-APUMP including either (S)- or (R)-configured Amo displayed significant ability to inhibit the adhesion of α4β1 integrin expressing cells, and remarkable stability in mouse serum. Possibly, the conformational bias exerted by the Amo scaffold determined the affinity for the receptors. These peptidomimetics could be of interest for the development of small-molecule agents effective against inflammatory processes and correlated autoimmune diseases.

Controlling Cyclopeptide Backbone Conformation with β/α‐Hybrid Peptide–Heterocycle Scaffolds

“…Spectroscopic and computational conformational analysis carried out previously on Amo‐peptide models,, showed that homochiral scaffolds favour a bent disposition of the backbone. On the contrary, peptide models which include Amo and Phe in opposite configurations show fully extended backbone conformations, with the N ‐ and C ‐termini positioned on opposite sides of the Amo ring (Figure ) .…”

“…To date, the oxazolidine‐2,4‐dione heterocycle has found very little use in organic and medicinal chemistry, a couple of noteworthy exceptions being the recently proposed new procedure for the synthesis of the 5‐(aminomethyl)‐3‐oxazolidinone core of the antibiotic linezolid in enantiomerically pure form, and the enzymatically stable analogues of the α4β1 integrin antagonist BIO1211 …”

Selective detection of α4β1 integrin (VLA‐4)‐expressing cells using peptide‐functionalized nanostructured materials mimicking endothelial surfaces adjacent to inflammatory sites

“…The latter are known to express significant levels of β 1 integrins (in particular α 5 β 1 and α v β 1 ), but very low levels of α 4 integrins suggesting that the higher specificity of 3 @SAM for Jurkat cells might be correlated to the presence of the MPUPA unit at the N ‐terminus. Indeed, the diphenylurea moiety has demonstrated a strong efficacy to targeting the α4 subunit . It is worth to stress that the Jurkat cells undergo an efficient α 4 β 1 integrin‐mediated adhesion to 3 @SAM after a very rapid incubation compared to the lengthy times required for other systems (15 min vs ≥12 h) …”

DS‐70, a novel and potent α4 integrin antagonist, is an effective treatment for experimental allergic conjunctivitis in guinea pigs

“…In the present study, we report the synthesis of two novel hybrid α/β‐peptides and their pharmacological characterization as potent and selective α 4 integrin antagonists. Recently, we described a series of α 4 β 1 integrin antagonists based on a β‐amino acid central core, an α 4 integrin‐targeting diphenylurea moiety and a moiety carrying a β1‐targeting acidic functionality at the C terminus flanked by an aromatic substituent (Dattoli et al, ; De Marco et al, ). The β‐amino acids were chosen to increase peptide stability and for the conformational control exerted on the overall structure (De Marco et al, ).…”

“…In contrast, DS‐23 represented the partially retro analogue of DS‐70, since the β‐amino acid central core was connected to 1‐(4‐(aminomethyl)phenyl)‐3‐(O‐methyl)urea (AMPUMP) and to the diacid equivalent of glycine (Figure ). Indeed, retro‐peptide sequences showed higher efficacy against α 4 β 1 integrins compared to the corresponding normal sequences in our previous studies (Dattoli et al, ; De Marco et al, ).…”