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The self-assembly of nanometric structures from molecular building blocks is an effective way to make new functional materials for biological and technological applications. In this work, four symmetrical bolaamphiphiles based on dehydrodipeptides (phenylalanyldehydrophenylalanine and tyrosyldehydrophenylalanine) linked through phenyl or naphthyl linkers (terephthalic acid and 2,6-naphthalenedicarboxylic acid) were prepared, and their self-assembly properties were studied. The results showed that all compounds, with the exception of the bolaamphiphile of tyrosyldehydrophenylalanine and 2,6-naphthalene dicarboxylic acid, gave self-standing hydrogels with critical gelation concentrations of 0.3 wt % and 0.4 wt %, using a pH trigger. The self-assembly of these hydrogelators was investigated using STEM microscopy, which revealed a network of entangled fibers. According to rheology, the dehydrodipeptide bolaamphiphilic hydrogelators are viscoelastic materials with an elastic modulus G' that falls in the range of native tissue (0.37 kPa brain-4.5 kPa cartilage). In viability and proliferation studies, it was found that these compounds were non-toxic toward the human keratinocyte cell line, HaCaT. In sustained release assays, we studied the effects of the charge present on model drug compounds on the rate of cargo release from the hydrogel networks. Methylene blue (MB), methyl orange (MO), and ciprofloxacin were chosen as cationic, anionic, and overall neutral cargo, respectively. These studies have shown that the hydrogels provide a sustained release of methyl orange and ciprofloxacin, while methylene blue is retained by the hydrogel network., Portugal2020, Compete2020, FEDER. PTDC/QUI-QOR/29015/2017. UIDB/04650/2020. UIDB/50006/2020. UID/QUI/00686/2019. UID/CTM/50025/2019. SFRH/BD/144017/2019

Supramolecular hydrogels are highly promising for biomedical materials owing to the wide array of properties that can be tailored and modulated. The combination with plasmonic/magnetic nanoparticles into plasmonic magnetogels further improve its potential in biomedical applications, through the combination of complementary strategies, such as photothermia, magnetic hyperthermia, photodynamic therapy and magnetic-guided drug delivery. Here, a new dehydropeptide hydrogelator, Npx-L-Met-Z-ΔPhe-OH, was developed and combined with two different plasmonic/magnetic nanoparticles architectures: core/shell manganese ferrite/gold nanoparticles or gold-decorated manganese ferrite nanoparticles with ca. 55 nm and 45 nm size, respectively. The characterization of magnetogels were performed by HR-TEM, FTIR, circular dichorism and rheological assays. The gels were tested as nanocarriers for a model antitumor drug, the natural compound curcumin. The incorporation of the drug in magnetogel matrices was confirmed through fluorescence-based techniques (FRET, fluorescence anisotropy and quenching). The curcumin release profiles were studied with and without excitation of the gold plasmon band. The transport of curcumin from magnetogels towards biomembrane models (small unilamellar vesicles) was assessed by FRET between the fluorescent drug and the lipid probe Nile Red. The developed magnetogels showed promising results for photothermia and photo-triggered drug release. The magnetogels bearing gold-decorated nanoparticles showed the best photothermia properties, while the ones containing core/shell nanoparticles had the best photoinduced curcumin release., This work was supported by the Portuguese Foundation for Science and Technology (FCT) in the framework of the Strategic Funding of CF-UM-UP (UID/FIS/04650/2019) and CQUM (UID/QUI/00686/ 2019). FCT, FEDER, PORTUGAL2020 and COMPETE2020 are also acknowledged for funding under research projects PTDC/QUIQFI/28020/2017 (POCI-01-0145-FEDER-028020) and PTDC/QUIQOR/29015/2017 (POCI-01-0145-FEDER-029015). The magnetic measurements were supported by projects UTAP-EXPL/NTec/0046/2017, NORTE-01-0145-FEDER-028538 and PTDC/FIS-MAC/29454/2017. Authors gratefully acknowledge Dr L. M. Vieira for carrying out the FTIR measurements at the Infrared Spectroscopy Lab. of the Centre of Physics, Univ. Minho.

Self-assembled peptide-based hydrogels are promising materials for biomedical research owing to biocompatibility and similarity to the extracellular matrix, amenable synthesis and functionalization and structural tailoring of the rheological properties. Wider developments of self-assembled peptide-based hydrogels in biomedical research and clinical translation are hampered by limited commercial availability allied to prohibitive costs. In this work a focused library of Cbz-protected dehydrodipeptides Cbz-L-Xaa-Z-ΔPhe-OH (Xaa= Met, Phe, Tyr, Ala, Gly) was synthesised and evaluated as minimalist hydrogels. The Cbz-L-Met-Z-ΔPhe-OH and Cbz-L-Phe-Z-ΔPhe-OH hydrogelators were comprehensively evaluated regarding molecular aggregation and self-assembly, gelation, biocompatibility and as drug carriers for delivery of the natural compound curcumin and the clinically important antitumor drug doxorubicin. Drug release profiles and FRET studies of drug transport into small unilamellar vesicles (as biomembrane models) demonstrated that the Cbz-protected dehydropeptide hydrogels are effective nanocarriers for drug delivery. The expedite and scalable synthesis (in 3 steps), using commercially available reagents and amenable reaction conditions, makes Cbz-protected dehydrodipeptide hydrogels, widely available at affordable cost to the research community.

Graphical abstract 6″-Triazole-substituted-α-galactosyl ceramides 12a–f, 13, 14 and 15 have been synthesised. Along with azide precursor 11, their ability to activate iNKT cells and stimulate the production of IL-2 cytokines in vitro, and IFN-γ and IL-4 cytokines in vivo, has been evaluated., Huisgen [3+2] dipolar cycloaddition of 6″-azido-6″-deoxy-α-galactosyl ceramide 11 with a range of alkynes (or a benzyne precursor) yielded a series of triazole-containing α-galactosyl ceramide (α-GalCer) analogues in high yield. These α-GalCer analogues and the precursor azide 11 were tested for their ability to activate iNKT cells and stimulate IL-2 cytokine secretion in vitro, and IFN-γ and IL-4 cytokine secretion in vivo. Some of these analogues, specifically 11, 12b, 12f and 13, were more potent IL-2 stimulators than the prototypical CD1d agonist, α-GalCer 1. In terms of any cytokine bias, most of the triazole-containing analogues exhibited a small Th2 cytokine-biasing response relative to that shown by α-GalCer 1. In contrast, the cycloaddition precursor, namely azide 11, provided a small Th1 cytokine-biasing response.

A concise route to the 6-azido-6-deoxy-α-galactosyl-phytosphingosine derivative 9 is reported. Orthogonal protection of the two amino groups allows elaboration of 9 into a range of 6-N-derivatized α-galactosyl ceramides by late-stage introduction of the acyl chain of the ceramide and the 6-N-group in the sugar head-group. Biologically active glycolipids 6 and 8 have been synthesized to illustrate the applicability of the approach.

Three gamma-(amino)silyl-substituted allylsilanes 14a-c have been prepared in three steps from the corresponding dialkyldichlorosilane. The aminosilyl group has been used to link this allylsilane nucleophile to a series of beta-hydroxy aldehydes through a silyl ether temporary connection. The size of the alkyl substituents at the silyl ether tether governs the outcome of the reaction on exposure to acid. Thus, treatment of aldehyde (E)-9aa, which contains a dimethylsilyl ether connection between the aldehyde and allylsilane, with a range of Lewis and Brønsted acid activators provides an (E)-diene product. The mechanism of formation of this undesired product is discussed. Systems containing a sterically more bulky diethylsilyl ether connection react differently: thus in the presence of TMSOTf and a Brønsted acid scavenger, intramolecular allylation proceeds smoothly to provide two out of the possible four diastereoisomeric oxasilacycles, 23 (major) and 21 (minor). A diene product again accounts for the remaining mass balance in the reaction. This side product can be completely suppressed by using a sterically even more bulky diisopropylsilyl ether connection in the cyclization precursor, although this is now at the expense of a slight erosion in the 1,3-stereoinduction in the allylation products. The sense of 1,3-stereoinduction observed in these intramolecular allylations has been rationalized by using an electrostatic argument, which can also explain the stereochemical outcome of a number of related reactions. Levels of 1,4-stereoinduction in the intramolecular allylation are more modest but can be significantly improved in some cases by using a tethered (Z)-allylsilane in place of its (E)-stereoisomer. Oxidation of the major diastereoisomeric allylation product 23 under Tamao-Kumada conditions provides an entry into stereodefined 1,2-anti-2,4-syn triols 28.

MeSO(3)H effects the intramolecular allenylation of a series of aldehydes I to provide allenyl alcohol product 3 as a single diastereoisomer. Cyclization proceeds rapidly at -78 degrees C. However, when the reaction is performed at room temperature, aldehyde 1 provides enone product 7 instead. A mechanism for the formation of this product is proposed in which the initially formed allenyl alcohol, 3 undergoes dehydration to provide an allyl carbocation, which is trapped with water, thereby installing the enone.

Invariant natural killer T cells (iNKT cells) are restricted by CD1d molecules and activated upon CD1d-mediated presentation of glycolipids to T cell receptors (TCRs) located on the surface of the cell. Because the cytokine response profile is governed by the structure of the glycolipid, we sought a method for labeling various glycolipids to study their in vivo behavior. The prototypical CD1d agonist, α-galactosyl ceramide (α-GalCer) 1, instigates a powerful immune response and the generation of a wide range of cytokines when it is presented to iNKT cell TCRs by CD1d molecules. Analysis of crystal structures of the TCR-α-GalCer-CD1d ternary complex identified the α-methylene unit in the fatty acid side chain, and more specifically the pro-S hydrogen at this position, as a site for incorporating a label. We postulated that modifying the glycolipid in this way would exert a minimal impact on the TCR-glycolipid-CD1d ternary complex, allowing the labeled molecule to function as a good mimic for the CD1d agonist under investigation. To test this hypothesis, the synthesis of a biotinylated version of the CD1d agonist threitol ceramide (ThrCer) was targeted. Both diastereoisomers, epimeric at the label tethering site, were prepared, and functional experiments confirmed the importance of substituting the pro-S, and not the pro-R, hydrogen with the label for optimal activity. Significantly, functional experiments revealed that biotinylated ThrCer (S)-10 displayed behavior comparable to that of ThrCer 5 itself and also confirmed that the biotin residue is available for streptavidin and antibiotin antibody recognition. A second CD1d agonist, namely α-GalCer C20:2 4, was modified in a similar way, this time with a fluorescent label. The labeled α-GalCer C20:2 analogue (11) again displayed functional behavior comparable to that of its unlabeled substrate, supporting the notion that the α-methylene unit in the fatty acid amide chain should be a suitable site for attaching a label to a range of CD1d agonists. The flexibility of the synthetic strategy, and late-stage incorporation of the label, opens up the possibility of using this labeling approach to study the in vivo behavior of a wide range of CD1d agonists.

A series of 9 title compounds of type (III), (V), or (VII) is prepared and tested for the ability to stimulate the production of IL-2.

Two trisubstituted epimeric tetrahydrofurans, 1 and 2, have been synthesized in order to confirm the relative stereochemistry in the natural product aureonitol. The key step in the synthesis of 1 a...

The cycloaddition reaction of acylketenes with vinyl ethers affords an extremely direct route to 2,6-dideoxysugars and their methyl ethers. The lithium enolate of commercial 2,6,6-trimethyldioxinone 3 was fluorinated in good yield to afford fluorinated dioxinone 8. An illustrative range of fluorinated 2,6-dideoxysugar derivatives was prepared via the acetyl ketene-vinyl ether cycloadduct. Electronic structure calculations were carried out to investigate the effect of the fluorine atom on ease of formation and subsequent reaction of the (fluoroacetyl)ketene reactive intermediate. A single fluorine atom lowers the barrier to fragmentation by ca. 7.5 kJ mol(-1), consistent with experimental findings, but has almost no effect on the barrier to rate determining vinyl ether addition, or to oxoketene dimerisation.

Graphical abstract α-Glucosyl ceramides 4 and 5 have been synthesised and their ability to stimulate the activation and expansion of iNKT cells evaluated., α-Glucosyl ceramides 4 and 5 have been synthesised and evaluated for their ability to stimulate the activation and expansion of human iNKT cells. The key challenge in the synthesis of both target molecules was the stereoselective synthesis of the α-glycosidic linkage. Of the methods examined, glycosylation using per-TMS-protected glucosyl iodide 16 was completely α-selective and provided gram quantities of amine 11, from which α-glucosyl ceramides 4 and 5 were obtained by N-acylation. α-GlcCer 4, containing a C24 saturated acyl chain, stimulated a marked proliferation and expansion of human circulating iNKT cells in short-term cultures. α-GlcCer 5, which contains a C20 11,14-cis-diene acyl chain (C20:2), induced extremely similar levels of iNKT cell activation and expansion.