Synthesis of <i>S</i>- and <i>N</i>,<i>S</i>-Heterocycle–Dipeptide Conjugates for Supramolecular Hydrogel Formation
Small peptides with aromatic nuclei at the <i>N</i>-terminus have been shown to form bioactive, biocompatible, and biodegradable supramolecular peptide hydrogels. Novel heterocycle–dipeptide conjugates with potential biological activity or application as drug carriers were synthesized by...
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2025-02-01
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| author | Ana-Morgana G. P. Silva Maria F. Martins Carlos B. P. Oliveira José A. Martins Paula M. T. Ferreira Maria-João R. P. Queiroz |
| author_facet | Ana-Morgana G. P. Silva Maria F. Martins Carlos B. P. Oliveira José A. Martins Paula M. T. Ferreira Maria-João R. P. Queiroz |
| author_sort | Ana-Morgana G. P. Silva |
| collection | DOAJ |
| description | Small peptides with aromatic nuclei at the <i>N</i>-terminus have been shown to form bioactive, biocompatible, and biodegradable supramolecular peptide hydrogels. Novel heterocycle–dipeptide conjugates with potential biological activity or application as drug carriers were synthesized by using <i>S-</i>(benzo[<i>b</i>]thiophene) and <i>N</i>,<i>S-</i>(thieno [2,3-<i>b</i>]pyridine and thieno[2,3-<i>b</i>]quinoline) heterocycles as <i>N</i>-protective groups for dipeptides <span style="font-variant: small-caps;">l</span>-Phe-<span style="font-variant: small-caps;">l</span>-Phe and <span style="font-variant: small-caps;">l</span>-Phe-<span style="font-variant: small-caps;">l</span>-Leu. The synthesis involved coupling heterocyclic carboxylic acids with trifluoroacetate salts of ethyl <span style="font-variant: small-caps;">l</span>-phenylalanyl-<span style="font-variant: small-caps;">l</span>-phenylalaninate and ethyl <span style="font-variant: small-caps;">l</span>-phenylalanyl- <span style="font-variant: small-caps;">l</span>-leucinate using HBTU and Et<sub>3</sub>N, producing the corresponding six <i>N</i>-heterocycle–dipeptide ester conjugates, which were then hydrolyzed to the carboxylic acids. These conjugates were subjected to gelation tests in water starting from 0.4 wt% concentration of the conjugates, using a pH-lowering method with GdL. Among them, only the conjugate of benzo[<i>b</i>]thiophene with <span style="font-variant: small-caps;">l</span>-Phe-<span style="font-variant: small-caps;">l</span>-Phe-OH formed a hydrogel, with a gelation critical concentration of 0.15 wt% (GdL 0.6%) and a final pH of 6.8, which is important for biological applications. The hydrogel was characterized by STEM, revealing nanofibers with an average thickness of 17 nm that assemble into a 3D network capable of trapping water. Further rheological analysis demonstrated its viscoelastic behavior (G′ = 3.03 × 10<sup>3</sup> Pa; G″ = 3.28 × 10<sup>2</sup> Pa), comparable to the extracellular matrix of certain human tissues, crucial for biomedical applications. |
| format | Article |
| id | doaj-art-07f01e7d68de4dd4889a09a40e58ac0a |
| institution | DOAJ |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-02-01 |
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| spelling | doaj-art-07f01e7d68de4dd4889a09a40e58ac0a2025-08-20T03:12:12ZengMDPI AGMolecules1420-30492025-02-0130486910.3390/molecules30040869Synthesis of <i>S</i>- and <i>N</i>,<i>S</i>-Heterocycle–Dipeptide Conjugates for Supramolecular Hydrogel FormationAna-Morgana G. P. Silva0Maria F. Martins1Carlos B. P. Oliveira2José A. Martins3Paula M. T. Ferreira4Maria-João R. P. Queiroz5Centro de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, PortugalCentro de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, PortugalCentro de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, PortugalCentro de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, PortugalCentro de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, PortugalCentro de Química, Universidade do Minho, Campus de Gualtar, 4710-057 Braga, PortugalSmall peptides with aromatic nuclei at the <i>N</i>-terminus have been shown to form bioactive, biocompatible, and biodegradable supramolecular peptide hydrogels. Novel heterocycle–dipeptide conjugates with potential biological activity or application as drug carriers were synthesized by using <i>S-</i>(benzo[<i>b</i>]thiophene) and <i>N</i>,<i>S-</i>(thieno [2,3-<i>b</i>]pyridine and thieno[2,3-<i>b</i>]quinoline) heterocycles as <i>N</i>-protective groups for dipeptides <span style="font-variant: small-caps;">l</span>-Phe-<span style="font-variant: small-caps;">l</span>-Phe and <span style="font-variant: small-caps;">l</span>-Phe-<span style="font-variant: small-caps;">l</span>-Leu. The synthesis involved coupling heterocyclic carboxylic acids with trifluoroacetate salts of ethyl <span style="font-variant: small-caps;">l</span>-phenylalanyl-<span style="font-variant: small-caps;">l</span>-phenylalaninate and ethyl <span style="font-variant: small-caps;">l</span>-phenylalanyl- <span style="font-variant: small-caps;">l</span>-leucinate using HBTU and Et<sub>3</sub>N, producing the corresponding six <i>N</i>-heterocycle–dipeptide ester conjugates, which were then hydrolyzed to the carboxylic acids. These conjugates were subjected to gelation tests in water starting from 0.4 wt% concentration of the conjugates, using a pH-lowering method with GdL. Among them, only the conjugate of benzo[<i>b</i>]thiophene with <span style="font-variant: small-caps;">l</span>-Phe-<span style="font-variant: small-caps;">l</span>-Phe-OH formed a hydrogel, with a gelation critical concentration of 0.15 wt% (GdL 0.6%) and a final pH of 6.8, which is important for biological applications. The hydrogel was characterized by STEM, revealing nanofibers with an average thickness of 17 nm that assemble into a 3D network capable of trapping water. Further rheological analysis demonstrated its viscoelastic behavior (G′ = 3.03 × 10<sup>3</sup> Pa; G″ = 3.28 × 10<sup>2</sup> Pa), comparable to the extracellular matrix of certain human tissues, crucial for biomedical applications.https://www.mdpi.com/1420-3049/30/4/869<i>S</i> and <i>N</i>,<i>S</i>-heterocyclesdipeptides<i>N</i>-heterocycle–dipeptide conjugateshydrogels |
| spellingShingle | Ana-Morgana G. P. Silva Maria F. Martins Carlos B. P. Oliveira José A. Martins Paula M. T. Ferreira Maria-João R. P. Queiroz Synthesis of <i>S</i>- and <i>N</i>,<i>S</i>-Heterocycle–Dipeptide Conjugates for Supramolecular Hydrogel Formation Molecules <i>S</i> and <i>N</i>,<i>S</i>-heterocycles dipeptides <i>N</i>-heterocycle–dipeptide conjugates hydrogels |
| title | Synthesis of <i>S</i>- and <i>N</i>,<i>S</i>-Heterocycle–Dipeptide Conjugates for Supramolecular Hydrogel Formation |
| title_full | Synthesis of <i>S</i>- and <i>N</i>,<i>S</i>-Heterocycle–Dipeptide Conjugates for Supramolecular Hydrogel Formation |
| title_fullStr | Synthesis of <i>S</i>- and <i>N</i>,<i>S</i>-Heterocycle–Dipeptide Conjugates for Supramolecular Hydrogel Formation |
| title_full_unstemmed | Synthesis of <i>S</i>- and <i>N</i>,<i>S</i>-Heterocycle–Dipeptide Conjugates for Supramolecular Hydrogel Formation |
| title_short | Synthesis of <i>S</i>- and <i>N</i>,<i>S</i>-Heterocycle–Dipeptide Conjugates for Supramolecular Hydrogel Formation |
| title_sort | synthesis of i s i and i n i i s i heterocycle dipeptide conjugates for supramolecular hydrogel formation |
| topic | <i>S</i> and <i>N</i>,<i>S</i>-heterocycles dipeptides <i>N</i>-heterocycle–dipeptide conjugates hydrogels |
| url | https://www.mdpi.com/1420-3049/30/4/869 |
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