Understanding the self-assembly of Fmoc–phenylalanine to hydrogel formation

Abstract

Hydrogels of low molecular weight molecules are important in biomedical applications. Multiple factors are responsible for hydrogel formation, but their role in governing self-assembly to hydrogel formation is poorly understood. Herein, we report the hydrogel formation of fluorenylmethyloxycarbonyl phenylalanine (FmocF) molecule. We used physical and thermal stimuli for solubilizing FmocF above the critical concentration to induce gel formation. The key role of Fmoc, Fmoc and phenylalanine covalent linkage, flexibility of phe side chain, pH, and buffer ions in self-assembly of FmocF to gel formation is described. We found that the collective action of different non-covalent interactions play a role in making FmocF hydrogel. Using powder diffraction and infrared spectroscopy, we also report a new polymorphic form of FmocF after transitioning to hydrogel. In addition, we are proposing a model for drug release from FmocF hydrogel.

Weak bond-based injectable and stimuli responsive hydrogels for biomedical applications

“…136 For example, 3,4-dihydroxy-phenyl on the DOPA side chain is more hydrophilic than the phenyl group on F. This leads to Fmoc-DOPA gelling at pH 2 but Fmoc-F-OH at pH 7.4 (Table 1). 138, 143 A similar trend was also observed in the gelation of pentapeptidic derivatives. 136 …”

“…140–142 Recently, an aromatic moiety containing short peptides and N-terminal Fmoc-amino acids have been reported for robust self-assembly into supramolecular architectures for biomedical applications. 136–138, 143, 144 Table 1 summarizes the categories of these gelators and their gelation conditions.…”

“…In addition to the π-π stacking interaction on N-terminal Fmoc groups, the final fibrous gel formation is also dependent on other intermolecular interactions such as the hydrogen bond, ionic interaction and additional π-π stacking between the side chains on the amino acids. 137, 138, 143, 144 For example, F, Y and W molecules bear an aromatic ring on their side chains. This makes Fmoc-F-OH, Fmoc-Y-OH and Fmoc-W-OH self-assemble into hydrogels at a lower critical concentration than Fmoc-G-OH and Fmoc-I-OH without an aromatic group on the side chains (Table 1).…”

“…136–138, 143, 144 This is because they all have free carboxylic acid groups on the C-termini and some species, such as VTEEI derivatives, have carboxylic acid on the E side chain as well. The hydrophilicity and hydrophobicity of these molecules are balanced by the degree of deprotonation of the carboxylic acid group, their hydrophobic side groups and the aromatic moieties on N-termini.…”

Self‐Assembling of Fmoc‐GC Peptide Nucleic Acid Dimers into Highly Fluorescent Aggregates

“…This enlargement of NMR lines supports the formation of aggregates for the modified PNA chain. The observed intensity and chemical shift changes resemble those observed in self‐assembly of Fmoc‐Phenylalanine into hydrogel and points to π–π stacking interactions mediated by Fmoc …”