New self-assembled supramolecular hydrogels based on dehydropeptides

Abstract

Supramolecular hydrogels rely on small molecules that self-assemble in water as a result of the cooperative effect of several relatively weak intermolecular interactions. Peptide-based low molecular weight hydrogelators have attracted enormous interest owing to the simplicity of small molecules combined with the versatility and biocompatibility of peptides. In this work, naproxen, a well known non-steroidal anti-inflammatory drug, was N-conjugated with various dehydrodipeptides to give aromatic peptide amphiphiles that resist proteolysis. Molecular dynamic simulations were used to obtain insight into the underlying molecular mechanism of self-assembly and to rationalize the design of this type of hydrogelators. The results obtained were in excellent agreement with the experimental observations. Only dehydrodipeptides having at least one aromatic amino acid gave hydrogels. The characterization of the hydrogels was carried out using transmission electron microscopy (TEM), circular dichroism (CD), fluorescence spectroscopy and also rheological assays. Results and discussion SynthesisFive new dehydrodipeptides N-protected with naproxen (Npx) were prepared from the corresponding methyl esters of N-tertbutoxycarbonyl-β-hydroxydipeptides. The strategy deployed involved a dehydration reaction followed by cleavage of the tert-butoxycarbonyl group (Boc), reaction with (S)-(+)naproxen chloride and alkaline hydrolysis of the methyl esters (Scheme 1). The dehydroamino acids used were dehydrophenylalanine (∆Phe) and dehydroaminobutyric acid (∆Abu). This synthetic methodology was chosen to avoid racemization issues concerning the naproxen moiety. The N,Cdiprotected dipeptides having a β-hydroxyamino acid (Scheme 1, 1a-e) were dehydrated in good to high yields by treatment with tert-butyldicarbonate (Boc 2 O) and 4dimethylaminopyridine (DMAP) followed by N,N,N',N'tetramethylguanidine (TMG) 17 (Scheme 1, 2a-e). The Boc group was removed with trifluoroacetic acid (TFA) (Scheme 1, 3a-e) and the N-deprotected dehydrodipeptides were conjugated with (S)-(+)-naproxen (Scheme 1, 4a-e). Finally, the methyl esters were removed by treatment with a solution of NaOH (1 M) affording compounds 5a-e in good yields (Scheme 1).

Biological Evaluation of Naproxen–Dehydrodipeptide Conjugates with Self-Hydrogelation Capacity as Dual LOX/COX Inhibitors

“…In our laboratory, we have investigated peptides containing dehydroamino acids (dehydrophenylalanine-∆Phe, dehydroalanine-∆Ala, dehydroaminobutyric acid-∆Abu) as alternatives to D-amino acids, not only to provide proteolytic stability but also for the reduced conformational flexibility of the peptide backbone. We have recently reported that dehydrodipeptides capped on the N-terminus with naproxen self-assemble into nanostructured hydrogels [18,22]. These peptide conjugates were found to be resistant to proteolysis by chymotrypsin, whereas the corresponding canonical dipeptide-naproxen Pharmaceutics 2020, 12, 122 3 of 18 conjugates undergo proteolysis readily under the same conditions.…”

Synthesis and preliminary biological evaluation of new phenolic and catecholic dehydroamino acid derivatives

“…Recently, several low molecular weight dehydrodipeptide hydrogelators were prepared and studied as new drug delivery systems. 49,50 Thus, the combination of phenolic or catecholic moieties with dehydroamino acids can be a valuable approach to the development of new biologically active compounds.…”

Impact of the ΔPhe configuration on the Boc-Gly-ΔPhe-NHMe conformation: experiment and theory

“…Both isomers of the dehydroresidues occur in nature and they often exhibit different biological properties [7,9]. α,β-Dehydropeptides are more stable and resistant toward proteolytic degradation and thus could be used to design synthetic analogs of biologically active peptides [10][11][12]. According to the literature on α,βdehydropeptides, the (Z)-dehydrophenylalanine [13][14][15] is the most often studied residues.…”