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Keywords = N-substituted phenylalanine derivatives

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21 pages, 5906 KiB  
Article
Ultrasound-Enhanced Gelation of Stimuli-Responsive and Biocompatible Phenylalanine-Derived Hydrogels
by Eduardo Buxaderas, Yanina Moglie, Aarón Baz Figueroa, Juan V. Alegre-Requena, Santiago Grijalvo, César Saldías, Raquel P. Herrera, Eugenia Marqués-López and David Díaz Díaz
Gels 2025, 11(3), 160; https://doi.org/10.3390/gels11030160 - 23 Feb 2025
Viewed by 781
Abstract
Stimuli-responsive materials, particularly supramolecular hydrogels, exhibit a dynamic adaptability to external factors such as pH and ultrasound. Among these, phenylalanine (Phe)-derived hydrogels are promising due to their biocompatibility, biodegradability, and tunable properties, making them ideal for biomedical applications. This study explores the effects [...] Read more.
Stimuli-responsive materials, particularly supramolecular hydrogels, exhibit a dynamic adaptability to external factors such as pH and ultrasound. Among these, phenylalanine (Phe)-derived hydrogels are promising due to their biocompatibility, biodegradability, and tunable properties, making them ideal for biomedical applications. This study explores the effects of pH and ultrasound on the gelation properties of N-substituted Phe derivatives, with a primary focus on the role of ultrasound in optimizing the gelation process. A series of N-substituted Phe derivatives were synthesized via reductive amination and hydrolysis. Hydrogel formation was possible with two of these compounds, namely G1 and G2, using the following two methods: heating–cooling (H–C) and heating–ultrasound–cooling (H–US–C). The critical gelation concentration (CGC), gelation kinetics, thermal stability (Tgel), and viscoelastic properties were assessed. Morphological and cytotoxicity analyses were performed to confirm the suitability of these gels for biomedical applications. Both G1 and G2 derivatives demonstrated enhanced gelation under the H–US–C protocol compared to H–C, with notable reductions in CGC (up to 47%) and gelation time (by over 90%). Ultrasound-induced gels led to an improved network density and stability, while maintaining thermal reversibility and mechanical properties comparable to those of hydrogels formed without ultrasound. Cytotoxicity studies confirmed a high biocompatibility, with cell viability rates above 95% across the tested concentrations. Given the similar rheological and morphological properties of the hydrogels regardless of the preparation method, drug release experiments were performed with representative gel samples and demonstrated the efficient encapsulation and controlled release of 5-fluorouracil and methotrexate from the hydrogels, supporting their potential as pH-responsive drug delivery platforms. This study highlights the role of ultrasound as a powerful tool for accelerating and optimizing the gelation process of supramolecular hydrogels, which is particularly relevant for applications requiring rapid gel formation. The developed Phe-based hydrogels also demonstrate promising characteristics as drug delivery systems. Full article
(This article belongs to the Special Issue Gels: 10th Anniversary)
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22 pages, 5060 KiB  
Article
Activity and Selectivity of Novel Chemical Metallic Complexes with Potential Anticancer Effects on Melanoma Cells
by Maria Camilla Ciardulli, Annaluisa Mariconda, Marco Sirignano, Erwin Pavel Lamparelli, Raffaele Longo, Pasqualina Scala, Raffaella D’Auria, Antonietta Santoro, Liberata Guadagno, Giovanna Della Porta and Pasquale Longo
Molecules 2023, 28(12), 4851; https://doi.org/10.3390/molecules28124851 - 19 Jun 2023
Cited by 5 | Viewed by 2407
Abstract
Human malignant melanoma cells from lymph node metastatic site (MeWo) were selected for testing several synthesized and purified silver(I) and gold(I) complexes stabilized by unsymmetrically substituted N-heterocyclic carbene (NHC) ligands, called L20 (N-methyl, N′-[2-hydroxy ethylphenyl]imidazol-2-ylide) and M1 (4,5-dichloro, N-methyl, N′-[2-hydroxy ethylphenyl]imidazol-2-ylide), having halogenide [...] Read more.
Human malignant melanoma cells from lymph node metastatic site (MeWo) were selected for testing several synthesized and purified silver(I) and gold(I) complexes stabilized by unsymmetrically substituted N-heterocyclic carbene (NHC) ligands, called L20 (N-methyl, N′-[2-hydroxy ethylphenyl]imidazol-2-ylide) and M1 (4,5-dichloro, N-methyl, N′-[2-hydroxy ethylphenyl]imidazol-2-ylide), having halogenide (Cl or I) or aminoacyl (Gly=N-(tert-Butoxycarbonyl)glycinate or Phe=(S)-N-(tert-Butoxycarbonyl)phenylalaninate) counterion. For AgL20, AuL20, AgM1 and AuM1, the Half-Maximal Inhibitory Concentration (IC50) values were measured, and all complexes seemed to reduce cell viability more effectively than Cisplatin, selected as control. The complex named AuM1 was the most active just after 8 h of treatment at 5 μM, identified as effective growth inhibition concentration. AuM1 also showed a linear dose and time-dependent effect. Moreover, AuM1 and AgM1 modified the phosphorylation levels of proteins associated with DNA lesions (H2AX) and cell cycle progression (ERK). Further screening of complex aminoacyl derivatives indicated that the most powerful were those indicated with the acronyms: GlyAg, PheAg, AgL20Gly, AgM1Gly, AuM1Gly, AgL20Phe, AgM1Phe, AuM1Phe. Indeed, the presence of Boc-Glycine (Gly) and Boc-L-Phenylalanine (Phe) showed an improved efficacy of Ag main complexes, as well as that of AuM1 derivatives. Selectivity was further checked on a non-cancerous cell line, a spontaneously transformed aneuploid immortal keratinocyte from adult human skin (HaCaT). In such a case, AuM1 and PheAg complexes resulted as the most selective allowing HaCaT viability at 70 and 40%, respectively, after 48 h of treatment at 5 μM. The same complexes tested on 3D MeWo static culture induced partial spheroid disaggregation after 24 h of culture, with almost half of the cells dead. Full article
(This article belongs to the Special Issue Design, Synthesis, and Evaluation of Anticancer Drugs)
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13 pages, 1229 KiB  
Article
Asperopiperazines A and B: Antimicrobial and Cytotoxic Dipeptides from a Tunicate-Derived Fungus Aspergillus sp. DY001
by Diaa T. A. Youssef, Lamiaa A. Shaala and Grégory Genta-Jouve
Mar. Drugs 2022, 20(7), 451; https://doi.org/10.3390/md20070451 - 10 Jul 2022
Cited by 11 | Viewed by 3344
Abstract
Investigation of the cytotoxic fractions of the ethyl acetate extract of the fermentation broth of the tunicate-derived Aspergillus sp. DY001 afforded two new dipeptides, asperopiperazines A and B (1 and 2), along with the previously reported compounds (+)-citreoisocoumarin (3) [...] Read more.
Investigation of the cytotoxic fractions of the ethyl acetate extract of the fermentation broth of the tunicate-derived Aspergillus sp. DY001 afforded two new dipeptides, asperopiperazines A and B (1 and 2), along with the previously reported compounds (+)-citreoisocoumarin (3) and (−)-6,8-di-O-methylcitreoisocoumarin (4). Analyses of the 1D and 2D NMR spectroscopic data of the compounds supported their structural assignments. Asperopiperazine A (1) is a cyclic dipeptide of leucine and phenylalanine moieties, which are substituted with an N-methyl and an N-acetyl group, respectively. On the other hand, asperopiperazine B (2) is a cyclic dipeptide of proline and phenylalanine moieties with a hydroxyl group at C-2 of the proline part. The absolute configuration of the amino acid moieties in 1 and 2 were determined by Marfey’s analyses and DFT NMR chemical shift calculations, leading to their assignment as cyclo(l-NMe-Leu-l-NAc-Phe) and cyclo(d-6-OH-Pro-l-Phe), respectively. Asperopiperazines A and B displayed higher antimicrobial effects against Escherichia coli and Staphylococcus aureus than Candida albicans. Furthermore, compounds 14 displayed variable growth inhibitory effects towards HCT 116 and MDA-MB-231 cells, with asperopiperazine A as the most active one towards HCT 116. Full article
(This article belongs to the Special Issue Antimicrobial and Antiviral Agents from Marine Sources)
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19 pages, 2352 KiB  
Article
Phenylalanine-Based AMPA Receptor Antagonist as the Anticonvulsant Agent with Neuroprotective Activity—In Vitro and In Vivo Studies
by Gniewomir Latacz, Kinga Sałat, Anna Furgała-Wojas, Adrian Martyniak, Agnieszka Olejarz-Maciej, Ewelina Honkisz-Orzechowska and Ewa Szymańska
Molecules 2022, 27(3), 875; https://doi.org/10.3390/molecules27030875 - 27 Jan 2022
Cited by 8 | Viewed by 3398
Abstract
Trying to meet the multitarget-directed ligands strategy, a series of previously described aryl-substituted phenylalanine derivatives, reported as competitive antagonists of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, were screened in vitro for their free-radical scavenging and antioxidant capacity in two different assays: ferric reducing antioxidant power [...] Read more.
Trying to meet the multitarget-directed ligands strategy, a series of previously described aryl-substituted phenylalanine derivatives, reported as competitive antagonists of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, were screened in vitro for their free-radical scavenging and antioxidant capacity in two different assays: ferric reducing antioxidant power (FRAP) and oxygen radical absorbance capacity fluorescent (ORAC-FL) assays. The most active antioxidants 1 and 8 were further examined to evaluate their neuroprotective properties in vitro. In this study, compound 1 showed a significant neuroprotective effect against the neurotoxin 6-hydroxydopamine in neuroblastoma SH-SY5Y and IMR-32 cell lines. Both compounds also showed prevention from high levels of reactive oxygen species (ROS) in SH-SY5Y cells. Furthermore, the desired monoamine oxidase B (MAO-B) inhibition effect (IC50 = 278 ± 29 nM) for 1 was determined. No toxic effects up to 100 µM of 1 and 8 against neuroblastoma cells were observed. Furthermore, in vivo studies showed that compound 1 demonstrated significant anticonvulsant potential in 6-Hz test, but in neuropathic pain models its antiallodynic and antihyperalgesic properties were not observed. Concluding, the compound 1 seems to be of higher importance as a new phenylalanine-based lead candidate due to its confirmed promise in in vitro and in vivo anticonvulsant activity. Full article
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20 pages, 8913 KiB  
Article
Identification and Target-Modification of SL-BBI: A Novel Bowman–Birk Type Trypsin Inhibitor from Sylvirana latouchii
by Xi Chen, Dong Chen, Linyuan Huang, Xiaoling Chen, Mei Zhou, Xinping Xi, Chengbang Ma, Tianbao Chen and Lei Wang
Biomolecules 2020, 10(9), 1254; https://doi.org/10.3390/biom10091254 - 28 Aug 2020
Cited by 12 | Viewed by 3528
Abstract
The peptides from the ranacyclin family share similar active disulphide loop with plant-derived Bowman–Birk type inhibitors, some of which have the dual activities of trypsin inhibition and antimicrobial. Herein, a novel Bowman–Birk type trypsin inhibitor of the ranacyclin family was identified from the [...] Read more.
The peptides from the ranacyclin family share similar active disulphide loop with plant-derived Bowman–Birk type inhibitors, some of which have the dual activities of trypsin inhibition and antimicrobial. Herein, a novel Bowman–Birk type trypsin inhibitor of the ranacyclin family was identified from the skin secretion of broad-folded frog (Sylvirana latouchii) by molecular cloning method and named as SL-BBI. After chemical synthesis, it was proved to be a potent inhibitor of trypsin with a Ki value of 230.5 nM and showed weak antimicrobial activity against tested microorganisms. Modified analogue K-SL maintains the original inhibitory activity with a Ki value of 77.27 nM while enhancing the antimicrobial activity. After the substitution of active P1 site to phenylalanine and P2′ site to isoleucine, F-SL regenerated its inhibitory activity on chymotrypsin with a Ki value of 309.3 nM and exhibited antiproliferative effects on PC-3, MCF-7 and a series of non-small cell lung cancer cell lines without cell membrane damage. The affinity of F-SL for the β subunits in the yeast 20S proteasome showed by molecular docking simulations enriched the understanding of the possible action mode of Bowman–Birk type inhibitors. Further mechanistic studies have shown that F-SL can activate caspase 3/7 in H157 cells and induce apoptosis, which means it has the potential to become an anticancer agent. Full article
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14 pages, 10130 KiB  
Article
Synthesis of diN-Substituted Glycyl-Phenylalanine Derivatives by Using Ugi Four Component Reaction and Their Potential as Acetylcholinesterase Inhibitors
by Luis Prent-Peñaloza, Alexander F. De la Torre, José L. Velázquez-Libera, Margarita Gutiérrez and Julio Caballero
Molecules 2019, 24(1), 189; https://doi.org/10.3390/molecules24010189 - 6 Jan 2019
Cited by 3 | Viewed by 5571
Abstract
Ugi four component reaction (Ugi-4CR) isocyanide-based multicomponent reactions were used to synthesize diN-substituted glycyl-phenylalanine (diNsGF) derivatives. All of the synthesized compounds were characterized by spectroscopic and spectrometric techniques. In order to evaluate potential biological applications, the synthesized compounds were tested in computational models [...] Read more.
Ugi four component reaction (Ugi-4CR) isocyanide-based multicomponent reactions were used to synthesize diN-substituted glycyl-phenylalanine (diNsGF) derivatives. All of the synthesized compounds were characterized by spectroscopic and spectrometric techniques. In order to evaluate potential biological applications, the synthesized compounds were tested in computational models that predict the bioactivity of organic molecules by using only bi-dimensional molecular information. The diNsGF derivatives were predicted as cholinesterase inhibitors. Experimentally, all of the synthesized diNsGF derivatives showed moderate inhibitory activities against acetylcholinesterase (AChE) and poor activities against butyrylcholinesterase (BuChE). Compound 7a has significant activity and selectivity against AChE, which reveals that the diNsGF scaffold could be improved to reach novel candidates by combining other chemical components of the Ugi-4CR in a high-throughput combinatorial screening experiment. Molecular docking experiments of diNsGF derivatives inside AChE suggest that these compounds placed the phenylalanine group at the peripheral site of AChE. The orientations and chemical interactions of diNsGF derivatives were analyzed, and the changeable groups were identified for future exploration of novel candidates that could lead to the improvement of diNsGF derivative inhibitory activities. Full article
(This article belongs to the Special Issue Design and Synthesis of Bioactive Compounds)
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11 pages, 1455 KiB  
Article
Design, Synthesis, and Evaluation of Amphiphilic Cyclic and Linear Peptides Composed of Hydrophobic and Positively-Charged Amino Acids as Antibacterial Agents
by Neda Riahifard, Saghar Mozaffari, Taibah Aldakhil, Francisco Nunez, Qamar Alshammari, Saud Alshammari, Jason Yamaki, Keykavous Parang and Rakesh Kumar Tiwari
Molecules 2018, 23(10), 2722; https://doi.org/10.3390/molecules23102722 - 22 Oct 2018
Cited by 38 | Viewed by 7125
Abstract
Antimicrobial peptides (AMPs) contain amphipathic structures and are derived from natural resources. AMPs have been found to be effective in treating the infections caused by antibiotic-resistant bacteria (ARB), and thus, are potential lead compounds against ARB. AMPs’ physicochemical properties, such as cationic nature, [...] Read more.
Antimicrobial peptides (AMPs) contain amphipathic structures and are derived from natural resources. AMPs have been found to be effective in treating the infections caused by antibiotic-resistant bacteria (ARB), and thus, are potential lead compounds against ARB. AMPs’ physicochemical properties, such as cationic nature, amphiphilicity, and their size, will provide the opportunity to interact with membrane bilayers leading to damage and death of microorganisms. Herein, AMP analogs of [R4W4] were designed and synthesized by changing the hydrophobicity and cationic nature of the lead compound with other amino acids to provide insights into a structure-activity relationship against selected model Gram-negative and Gram-positive pathogens. Clinical resistant strains of methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli (E. coli) were used in the studies. Our results provided information about the structural requirements for optimal activity of the [R4W4] template. When tryptophan was replaced with other hydrophobic amino acids, such as phenylalanine, tyrosine, alanine, leucine, and isoleucine, the antibacterial activities were significantly reduced with MIC values of >128 µg/mL. Furthermore, a change in stereochemistry caused by d-arginine, and use of N-methyltryptophan, resulted in a two-fold reduction of antibacterial activity. It was found that the presence of tryptophan is critical for antibacterial activity, and could not be substituted with other hydrophobic residues. The study also confirmed that cyclic peptides generally showed higher antibacterial activities when compared with the corresponding linear counterparts. Furthermore, by changing tryptophan numbers in the compound while maintaining a constant number of arginine, we determined the optimal number of tryptophan residues to be four, as shown when the number of tryptophan residues increased, a decrease in activity was observed. Full article
(This article belongs to the Special Issue Peptides in Chemical Biology and Drug Discovery)
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16 pages, 2365 KiB  
Article
Synthesis of Both Enantiomers of Chiral Phenylalanine Derivatives Catalyzed by Cinchona Alkaloid Quaternary Ammonium Salts as Asymmetric Phase Transfer Catalysts
by Lei Jin, Shuai Zhao and Xin Chen
Molecules 2018, 23(6), 1421; https://doi.org/10.3390/molecules23061421 - 12 Jun 2018
Cited by 7 | Viewed by 6059
Abstract
A practical synthesis of both enantiomers of unnatural phenylalanine derivatives by using two pseudoenantiomeric phase transfer catalysts is described. Through asymmetric α-alkylation of glycine Schiff base with substituted benzyl bromides and 1-(bromomethyl)naphthalene under the catalysis of O-allyl-N-(9-anthracenmethyl) cinchoninium bromide ( [...] Read more.
A practical synthesis of both enantiomers of unnatural phenylalanine derivatives by using two pseudoenantiomeric phase transfer catalysts is described. Through asymmetric α-alkylation of glycine Schiff base with substituted benzyl bromides and 1-(bromomethyl)naphthalene under the catalysis of O-allyl-N-(9-anthracenmethyl) cinchoninium bromide (1f) and O-allyl-N-(9-anthracenylmethyl)cinchonidium bromide (1i), respectively, a series of both (R)- and (S)-enantiomers of unnatural α-amino acid derivatives were obtained in excellent yields and enantioselectivity. The synthetic method is simple and scalable, and the stereochemistry of the products is fully predictable and controlled: the cinchonine-type phase transfer catalyst 1f resulted in (R)-α-amino acid derivatives, and the cinchonidine-type phase transfer catalyst 1i afforded (S)-α-amino acid derivatives. Full article
(This article belongs to the Collection Recent Advances in Organocatalysis)
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