Search Results (64)

A library of neoisopulegol-based amino and thiol adducts was developed from (+)-neoisopulegol, derived from commercially available (−)-isopulegol. Michael addition of different nucleophiles towards its highly active α,β-unsaturated γ-lactone motif was accomplished, resulting in diverse amino and thiol analogs in stereoselective reactions. Then, the lactone ring was opened, with NH₃ and benzylamine furnishing primary amide and N-benzyl-substituted amide derivatives, respectively. The in vitro antimicrobial effect of prepared compounds was also explored. The results revealed that naphthylmethyl-substituted β-aminolactone, the most promising compound, displayed selective inhibition for the Gram-positive bacteria S. aureus with an MIC (minimum inhibitory concentration) value of 12.5 μM. A docking study was performed to interpret the obtained results. Full article

Plant tendrils exhibit intriguing tropism motions like bending, twisting, and coiling. Herein, we report the application of a liquid crystal elastomer (LCE) to make a light-sensitive and biomimetic coil to replicate behaviors of plant tendrils. The LCE coil consists of diacrylate azobenzene, diacrylate mesogens, and thiol-based spacers. These components are first mixed to form a highly viscous prepolymer solution through a thiol-acrylate Michael addition reaction. Subsequently, an extrusion–rolling process is developed to draw the viscous solution into a coil, which is mechanically stretched in a single direction to align mesogens in the LCE. Finally, the coil is photopolymerized under UV light to form an LCE coil with a diameter of 375 µm. The LCE coil possesses good rigidity and flexibility and shows movement upon light exposure. For example, the LCE coil shows a reversible bending up to 120° to 365 nm UV and 30% contraction to 455 nm visible light, respectively, due to trans-cis photoisomerization of azobenzene derivatives. When the coil is irradiated with UV light with an intensity up to 10 mW cm⁻², it can twist and coil up. It can also wrap around the UV light tube in 6 s, similar to a plant tendril. This type of light-responsive coil has great potential in making biomimetic plants or soft robotics. Full article

Conventional hair-straightening methods that use chemical treatments to break disulfide bonds cause severe damage to the hair shaft, leading to weakened hair that is prone to reverting to its curly form in high humidity. Therefore, a unique haircare coating technology is required to protect hair integrity and provide a long-lasting straightening effect. Herein, we designed a hair-straightening technology by integrating a nature-inspired polyphenol–inorganic sulfate (PIS) redox agent into formulated shampoo, which achieves a desirable straightening effect through sulfate-induced disulfide breakage while preserving hair integrity through a polyphenol-reinforced structure. The interaction between polyphenols and residual thiols from the straightening process maintained a long-lasting straight hair structure and hair strength. Ellman’s assay showed a lower free thiol content from reductant-induced damaged keratin in PIS shampoo-treated hair than in sulfate-treated hair as the polyphenol–thiol bond was formed through the Michael addition reaction, thereby restoring the natural structure of the hair and enhancing its mechanical properties. Owing to the polyphenol coating, PIS shampoo-treated hair exhibited an antistatic effect and high hydrophobicity, indicating healthy hair. Furthermore, the polyphenol coating effectively scavenged radical oxygen species (ROS) in the hair, thereby improving damage protection. Thus, PIS shampoo offers an alternative approach for effective hair straightening. Full article

Succination is a non-enzymatic post-translational modification of cysteine (Cys) residues, resulting in the formation of S-(2-succino)cysteine (2SC). While hundreds of 2SC-modified proteins have been identified and are associated with the dysfunction of proteins, the underlying molecular mechanisms remain poorly understood. Conventional methods for synthesizing succinated compounds, such as 2SC, often require prolonged reaction times and/or HCl hydrolysis. In this study, we present a rapid and efficient synthesis method for succinated compounds using maleic anhydride, enabling more effective in vivo studies of succination mechanisms. This method was tested on thiol compounds with varying molecular weights, including Cys derivatives, Cys-containing peptides, and reduced bovine serum albumin. By incubating these compounds in an aqueous buffer with maleic anhydride dissolved in an organic solvent like diethyl ether, we achieved significantly improved succination efficiency compared to conventional methods. The succination efficiency using maleic anhydride surpassed that of fumaric acid or maleic acid. Notably, this approach facilitated the succination of amino acids, peptides, and proteins within minutes at 25 °C, without requiring acid hydrolysis. Our findings provide a straightforward, time-efficient strategy for synthesizing succinated thiol compounds, offering a valuable tool to enhance the understanding of succination’s molecular mechanisms and its role in protein function and dysfunction. Full article

The separation and purification of molecular compounds and their functionalized derivatives is a common challenge in organic synthesis. In particular, calix[4]resorcinarenes present a high potential for chemical derivatization at their upper edge by aminomethylation reactions, and these compounds and their derivatives require appropriate analytical methodologies for their analysis, separation, and purification. In this study, C-tetra(propyl)calix[4]resorcinarene was synthesized and functionalized with maleimide groups by optimized aminomethylation reactions, obtaining a mixture of mono-, di-, tri-, and tetrasubstituted compounds. Initial separation by RP-HPLC with a core-shell column showed poorly resolved peaks, indicating a loss of separation efficiency. Therefore, a monolithic C18 column was used, which significantly improved the separation, thanks to its larger pore volume and continuous structure facilitating the diffusion of these bulky molecules, notably improving efficiency. Finally, the six compounds functionalized with maleimide groups were efficiently separated and enriched by RP-SPE by analytical method transfer, and the two peptides of six and the thirteen residues derived from LfcinB (20–25): RRWQWR were synthesized by SPPS-Fmoc/tBu and purified. These were modularly linked by the Michael thiol-maleimide addition reaction obtaining six (peptide)_n-resorcinarene conjugates. The analytical method by RP-HPLC with a monolithic C18 column, the separation and purification by RP-SPE were used transversally in all the steps to obtain compounds with adequate purities and quantities. Finally, the antibacterial activities of the six conjugates were evaluated against E. coli and E. faecalis strains, and it was determined that three aminomethylated compounds and one monosubstituted conjugate showed activity against E. faecalis. Our work established a new modular conjugation strategy between calix[4]resorcinarenes and peptides by thiol-maleimide click chemistry, and a methodology of separation, purification, and enrichment for these products by RP-HPLC and RP-SPE, which permitted us to obtain quantities with purities appropriate for their characterization by NMR, LC-MS and antibacterial activity assays. Full article

In vitro relative cytotoxicity (IC₅₀ (IIb)/IC₅₀ (IIIb) of (E)-3-(4′-methylbenzylidene)-4-chromanone (IIIb) towards human Molt 4/C8 and CEM T-lymphocytes showed a >50-fold increase in comparison to those of the respective tetralone derivative (IIb). On the other hand, such an increase was not observed in the analogous 4-OCH₃ (IIc and IIIc) derivatives. In order to study whether thiol reactivity—as a possible basis of the mechanism of action—correlates with the observed cytotoxicities, the kinetics of the non-enzyme catalyzed reactions with reduced glutathione (GSH) and N-acetylcysteine (NAC) of IIIb and IIIc were investigated. The reactivity of the compounds and the stereochemical outcome of the reactions were evaluated using high-pressure liquid chromatography-mass spectrometry (HPLC-MS). Molecular modeling calculations were performed to rationalize the unexpectedly higher thiol reactivity of the chromanones (III) compared to the carbocyclic analog tetralones (II). The results indicate the possible role of spontaneous thiol reactivity of compounds III in their recorded biological effects. Full article

A novel and controllable synthesis of thioacetals/thioketals and β-sulfanyl ketones mediated by the reaction of aldehyde/acetone with thiols has been developed. In this protocol, β-sulfanyl ketones can be generated without the prior preparation of α, β-unsaturated carbonyl compounds. A variety of thiols reacted with aldehyde/acetone and provided the corresponding thioacetals/thioketals and β-sulfanyl ketones in good to excellent yields, respectively. This protocol is operationally simple, mild, and atom-economical, providing controllable access to thioacetals/thioketals and thia-Michael addition products under mild conditions. Full article

Sphaerococcenol A is a cytotoxic bromoditerpene biosynthesized by the red alga Sphaerococcus coronopifolius. A series of its analogues (1–6) was designed and semi-synthesized using thiol-Michael additions and enone reduction, and the structures of these analogues were characterized by spectroscopic methods. Cytotoxic analyses (1–100 µM; 24 h) were accomplished on A549, DU-145, and MCF-7 cells. The six novel sphaerococcenol A analogues displayed an IC₅₀ range between 14.31 and 70.11 µM on A549, DU-145, and MCF-7 malignant cells. Compound 1, resulting from the chemical addition of 4-methoxybenzenethiol, exhibited the smallest IC₅₀ values on the A549 (18.70 µM) and DU-145 (15.82 µM) cell lines, and compound 3, resulting from the chemical addition of propanethiol, exhibited the smallest IC₅₀ value (14.31 µM) on MCF-7 cells. The highest IC₅₀ values were exhibited by compound 4, suggesting that the chemical addition of benzylthiol led to a loss of cytotoxic activity. The remaining chemical modifications were not able to potentiate the cytotoxicity of the original compounds. Regarding A549 cell viability, analogue 1 exhibited a marked effect on mitochondrial function, which was accompanied by an increase in ROS levels, Caspase-3 activation, and DNA fragmentation and condensation. This study opens new avenues for research by exploring sphaerococcenol A as a scaffold for the synthesis of novel bioactive molecules. Full article

Non-enzyme-catalyzed thiol addition onto the α,β-unsaturated carbonyl system is associated with several biological effects. Kinetics and diastereoselectivity of non-enzyme catalyzed nucleophilic addition of reduced glutathione (GSH) and N-acetylcysteine (NAC) to the six-membered cyclic chalcone analogs 2a and 2b were investigated at different pH values (pH 3.2, 7.4 and 8.0). The selected compounds displayed in vitro cancer cell cytotoxicity (IC₅₀) of different orders of magnitude. The chalcones intrinsically reacted with both thiols under all incubation conditions. The initial rates and compositions of the final mixtures depended both on the substitution and the pH. The stereochemical outcome of the reactions was evaluated using high-pressure liquid chromatography with UV detection (HPLC-UV). The structures of the formed thiol-conjugates and the retro-Michael products (Z)-2a and (Z)-2b were confirmed by high-pressure liquid chromatography-mass spectrometry (HPLC-MS). Frontier molecular orbitals and the Fukui function calculations were carried out to investigate their effects on the six-membered cyclic analogs. Data were compared with those obtained with the open-chain (1) and the seven-membered (3) analogs. The observed reactivities do not directly relate to the difference in in vitro cancer cell cytotoxicity of the compounds. Full article

The study delves into the use of the thiol-yne click reaction to enhance (bio)conjugation methodologies, particularly focusing on immobilizing biomolecules onto PLLA surfaces. The thiol-yne click reaction, known for its efficiency, selectivity, and versatility in forming carbon-sulfur bonds under mild conditions without transition metal catalysts, is explored for conjugating the fluorophore dansyl onto PLLA surfaces. This approach aims to broaden bioconjugation strategies beyond traditional methods like the Michael-type reaction, expanding their applicability to diverse biomolecules. Utilizing a photoinitiator and specific light for photo-immobilization, the thiol-yne click reaction offers spatial and temporal control, with the absence of transition metal catalysts mitigating concerns of cytotoxicity and metal contamination, rendering it suitable for biomedical applications. The objectives of this research encompass demonstrating the feasibility of the thiol-yne click reaction for surface functionalization and enriching bioconjugation strategies for tailoring PLLA surfaces, ultimately advancing biomedical technologies through precise control over surface properties and functionality. For this purpose, PLLA surfaces were activated through hydrolysis and amidation to introduce the activated alkyne moiety (PLLA-Alkyne), followed by photo-induced dansyl immobilization (PLLA-Dns) with Irgacure 651. Various surface characterization techniques, including SEM, WCA, XPS, ATR-FTIR, and fluorescence microscopy and spectroscopy, validated the successful conjugation. This metal-free method preserves the material’s bulk properties while enabling thiol-containing molecule immobilization. Full article

Polymer nanogels—considered as nanoscale hydrogel particles—are attractive for biological and biomedical applications due to their unique physicochemical flexibility. However, the aggregation or accumulation of nanoparticles in the body or the occurrence of the body’s defense reactions still pose a research challenge. Here, we demonstrate the fabrication of degradable nanogels using thermoresponsive, cytocompatible poly[oligo(ethylene glycol) methacrylate]s-based copolymers (POEGMA). The combination of POEGMA’s beneficial properties (switchable affinity to water, nontoxicity, non-immunogenicity) along with the possibility of nanogel degradation constitute an important approach from a biological point of view. The copolymers of oligo(ethylene glycol) methacrylates were partially modified with short segments of degradable oligo(lactic acid) (OLA) terminated with the acrylate group. Under the influence of temperature, copolymers formed self-assembled nanoparticles, so-called mesoglobules, with sizes of 140–1000 nm. The thermoresponsive behavior of the obtained copolymers and the nanostructure sizes depended on the heating rate and the presence of salts in the aqueous media. The obtained mesoglobules were stabilized by chemical crosslinking via thiol-acrylate Michael addition, leading to nanogels that degraded over time in water, as indicated by the DLS, cryo-TEM, and AFM measurements. Combining these findings with the lack of toxicity of the obtained systems towards human fibroblasts indicates their application potential. Full article

With the aim to develop novel scaffolds for the sustained release of drugs, we initially developed an easy approach for the synthesis of α,ω-homobifunctional mercaptoacyl poly(alkyl oxide)s. This was based on the esterification of the terminal hydroxyl groups of poly(alkyl oxide)s with suitably S-4-methoxytrityl (Mmt)-protected mercapto acids, followed by the removal of the acid labile S-Mmt group. This method allowed for the efficient synthesis of the title compounds in high yield and purity, which were further used in the development of a thioether cross-linked liposome scaffold, by thia–Michael reaction of the terminal thiol groups with pre-formed nano-sized liposomes bearing maleimide groups on their surface. The reaction process was followed by ¹H-NMR, using a Carr–Purcell–Meiboom–Gill (CPMG) relaxation dispersion NMR experiment (¹H-NMR CPMG), which allowed for real-time monitoring and optimization of the reaction process. The thioether cross-linked liposomal scaffold that was synthesized was proven to preserve the nano-sized characteristics of the initial liposomes and allowed for the sustained release of calcein (which was used as a hydrophilic dye and a hydrophilic drug model), providing evidence for the efficient synthesis of a novel drug release scaffold consisting of nanoliposome building blocks. Full article

Thiols can react with readily available organic substrates under benign conditions, making them suitable for use in chemical, biological, physical, and materials and engineering research areas. In particular, the highly efficient thiol-based click reaction includes the reaction of radicals with electron-rich enes, Michael addition with electron-poor enes, carbonyl addition with isocyanate S_N2 ring opening with epoxies, and S_N2 nucleophilic substitution with halogens. This mini review provides insights into emerging venues for their industrial applications, especially for the applications of thiol-ene, thiol–isocyanate, and thiol–epoxy reactions, highlighting a brief chemistry of thiols as well as various approaches to polythiol synthesis. Full article

Juglone, a quinonic compound present in walnut extracts, was proposed as a restoring agent for hair keratin treated with permanent or discoloration processes. The proposed mechanism of restoration by juglone involves the formation of a Michael adduct between the quinone and the thiol moieties of cysteine residues. To this purpose, the first part of the present paper involved the spectroscopic study of the product of the reaction between juglone and N-acetyl-L-cysteine as a model compound. IR spectroscopy and Scanning Electron Microscopy (SEM) monitored the chemical and morphological variations induced by applying juglone to hair keratin. In order to simulate the most common hair treatments (i.e., permanent and discoloration), juglone was applied to hair that had been previously treated with a reducing agent, i.e., methyl thioglycolate (MT) or with bleaching agents (based on hydrogen peroxide and persulfates) followed by sodium hydrogen sulfite. IR spectroscopy allowed us to monitor the formation of Michael adducts between juglone and cysteine residues: the Michael adducts’ content was related to the cysteine content of the samples. In fact, MT and sodium hydrogen sulfite favored the reduction of the disulfide bonds and increased the content of free cysteine residues, which can react with juglone. SEM analyses confirmed the trend observed by IR spectroscopy since hair samples treated with juglone adopted a more regular hair surface and more imbricated scales, thus supporting the possible use of juglone as a restoring agent for damaged hair keratins. Full article

Hydrogel-based artificial scaffolds are essential for advancing cell culture models from 2D to 3D, enabling a more realistic representation of physiological conditions. These hydrogels can be customized through crosslinking to mimic the extracellular matrix. While the impact of extracellular matrix scaffolds on cell behavior is widely acknowledged, mechanosensing has become a crucial factor in regulating various cellular functions. cancer cells’ malignant properties depend on mechanical cues from their microenvironment, including factors like stiffness, shear stress, and pressure. Developing hydrogels capable of modulating stiffness holds great promise for better understanding cell behavior under distinct mechanical stress stimuli. In this study, we aim to 3D culture various cancer cell lines, including MCF-7, HT-29, HeLa, A549, BT-474, and SK-BR-3. We utilize a non-degradable hydrogel formed from alpha acrylate-functionalized dendritic polyglycerol (dPG) and thiol-functionalized 4-arm polyethylene glycol (PEG) via the thiol-Michael click reaction. Due to its high multivalent hydroxy groups and bioinert ether backbone, dPG polymer was an excellent alternative as a crosslinking hub and is highly compatible with living microorganisms. The rheological viscoelasticity of the hydrogels is tailored to achieve a mechanical stiffness of approximately 1 kPa, suitable for cell growth. Cancer cells are in situ encapsulated within these 3D network hydrogels and cultured with cell media. The grown tumor spheroids were characterized by fluorescence and confocal microscopies. The average grown size of all tumoroid types was ca. 150 µm after 25 days of incubation. Besides, the stability of a swollen gel remains constant after 2 months at physiological conditions, highlighting the nondegradable potential. The successful formation of multicellular tumor spheroids (MCTSs) for all cancer cell types demonstrates the versatility of our hydrogel platform in 3D cell growth. Full article