Bioisosteric peptidomimetics: investigation on both conformation and biological activity

I peptidomimetici sono composti sviluppati come nuovi agenti terapeutici, progettati per aggirare alcuni dei problemi associati all’utilizzo dei peptidi naturali e aventi le caratteristiche responsabili dell’attività biologica. In quest’ottica, abbiamo sintetizzato isosteri conformazionalmente costretti della (S)-α-metilomoserina, da impiegare come nuovi agenti terapeutici a base peptidica in seguito alla loro introduzione in peptidi bioattivi. Sempre allo scopo di studiare la conformazione di nuovi peptidomimetici, abbiamo preparato eteroligomeri contenenti acido antranilico, impiegato per la sua capacità di formare un legame idrogeno intramolecolare a 6 termini tra l’NH e il CO di uno stesso residuo, e un β amminoacido [acido 3,4-trans-3-amminopirrolidin-2-one-4-carbossilico (AOPPC, acronimo IUPAC)] a configurazione definita. Inoltre il problema della crescente resistenza agli antibiotici ha dato luogo a un’urgente richiesta di nuove tipologie di antimicrobici. Gli AMPs (AntiMicrobial Peptides), anche se sono stati considerati una promettente alternativa agli antibiotici ora in uso, presentano numerosi inconvenienti che possono essere superati con la sintesi di nuovi foldameri misti α-β. Abbiamo quindi, impiegato come building blocks l’α- e la β-lisina insieme con AOPPC e il suo derivato alchilato al C4 (AMOPPC), per ottenere peptidi cationici e anfifilici che potessero interagire con la superficie cellulare polianionica dei batteri. Infine molti studi sono rivolti alle integrine, in particolare all’integrina αvβ1 che svolge un ruolo chiave nell’attivazione del fattore di crescita TGF-β e nell’indurre la fibrosi tissutale nel polmone e nel fegato. Per meglio comprendere la relazione esistente tra integrina-TGF-β-fibrosi e partendo dal c8, un potente inibitore dell’αvβ1 avente una struttura che mima l’RGD, sono stati sviluppati e testati analoghi di agenti antifibrotici basati su modifiche strutturali del c8, un potente inibitore ottenuto per sintesi.Peptidomimetics are compounds developed as new therapeutics, designed to circumvent some of the problems associated with natural peptides and provided with the features responsible for biological activity. According to this approach, we synthesized isosteres such as conformationally restricted analogues of (S)-α-methylhomoserine, suitable for novel peptide-based therapeutics after introduction in bioactive peptides. With the aim to prepare new peptidomimetics, we synthesized hetero-oligomers containing a β-amino acid [enantiopure 3,4-trans-3-aminopyrrolidin-2-one-4-carboxylic acid (AOPPC, IUPAC acronym) and anthranilic acid, owing to its ability to give an intramolecular 6-membered hydrogen-bonded ring between NH and CO within the same residue. Moreover, the growing problem of resistance to conventional antibiotics has created an urgent need for the development of novel classes of antimicrobials. Although AMPs (AntiMicrobial Peptides) have been heralded as a promising alternative to today’s antibiotics, they show many drawbacks that could be bypassed by novel mixed α-β foldamers containing α-lysine and β-lysine as building blocks, together with AOPPC and its derivative methylated at C-4 (AMOPPC), leading to cationic amphiphilic peptides suitable for interaction with polyanionic microbial cell surface. Eventually, many medicinal chemistry efforts are direct towards integrins, in particular αvβ1 integrin, which plays a critical role in activating the growth factor TGF-β and in driving tissue fibrosis in the lung and liver. To better understand the integrin-TGF-β-fibrosis relationship and starting from c8, a potent αvβ1 inhibitor with a RGD mimetic scaffold, a number of analogs of antifibrotic agents based upon its modification was developed

Highly stable atropisomers by electrophilic amination of a chiral γ-lactam within the synthesis of an elusive conformationally restricted analogue of α-methylhomoserine

Starting from chiral-protected 4-hydroxymethyl pyrrolidin-2-ones, the otherwise elusive 3,4-trans-3,3,4-trisubstituted isosteres of alpha-methyl homoserine, tethered on a gamma-lactam ring, were prepared exploiting stereoselective electrophilic aminations. These reactions led to the isolation and characterization of a novel type of atropisomers, exceedingly stable at room temperature, that were directly converted to the desired products by a novel non-reductive N-N bond cleavage reaction

Exploring NArylsulfonyllproline Scaffold as a Platform for Potent and Selective v1 Integrin Inhibitors

[Image: see text] One small molecule inhibitor of αvβ1 integrin, c8, shows antifibrotic effects in multiple in vivo mouse models. Here we synthesized c8 analogues and systematically investigate their structure–activity relationships (SAR) in αvβ1 integrin inhibition. N-Phenylsulfonyl-l-homoproline analogues of c8 maintained excellent potency against αvβ1 integrin while retaining good selectivity over other RGD integrins. In addition, 2-aminopyridine or cyclic guanidine analogues were shown to be equally potent to c8. A rigid phenyl linker increased the potency compared to c8, but the selectivity over other RGD integrins diminished. These results can provide further insights on design of αvβ1 integrin inhibitors as antifibrotics

Exploring N-Arylsulfonyl-l-proline Scaffold as a Platform for Potent and Selective αvβ1 Integrin Inhibitors.

One small molecule inhibitor of αvβ1 integrin, c8, shows antifibrotic effects in multiple in vivo mouse models. Here we synthesized c8 analogues and systematically investigate their structure-activity relationships (SAR) in αvβ1 integrin inhibition. N-Phenylsulfonyl-l-homoproline analogues of c8 maintained excellent potency against αvβ1 integrin while retaining good selectivity over other RGD integrins. In addition, 2-aminopyridine or cyclic guanidine analogues were shown to be equally potent to c8. A rigid phenyl linker increased the potency compared to c8, but the selectivity over other RGD integrins diminished. These results can provide further insights on design of αvβ1 integrin inhibitors as antifibrotics

Exploring <i>N</i>‑Arylsulfonyl‑l‑proline Scaffold as a Platform for Potent and Selective αvβ1 Integrin Inhibitors

One small molecule inhibitor of αvβ1 integrin, <b>c8</b>, shows antifibrotic effects in multiple in vivo mouse models. Here we synthesized <b>c8</b> analogues and systematically investigate their structure–activity relationships (SAR) in αvβ1 integrin inhibition. <i>N</i>-Phenylsulfonyl-l-homoproline analogues of <b>c8</b> maintained excellent potency against αvβ1 integrin while retaining good selectivity over other RGD integrins. In addition, 2-aminopyridine or cyclic guanidine analogues were shown to be equally potent to <b>c8</b>. A rigid phenyl linker increased the potency compared to <b>c8</b>, but the selectivity over other RGD integrins diminished. These results can provide further insights on design of αvβ1 integrin inhibitors as antifibrotics

Highly stable atropisomers by electrophilic amination of a chiral γ-lactam within the synthesis of an elusive conformationally restricted analogue of α-methylhomoserine

Starting from chiral-protected 4-hydroxymethyl pyrrolidin-2-ones, the otherwise elusive 3,4-trans-3,3,4-trisubstituted isosteres of α-methyl homoserine, tethered on a γ-lactam ring, were prepared exploiting stereoselective electrophilic aminations. These reactions led to the isolation and characterization of a novel type of atropisomers, exceedingly stable at room temperature, that were directly converted to the desired products by a novel non-reductive N–N bond cleavage reaction