Solvent Induced Disulfide Bond Formation in 2,5-dimercapto-1,3,4-thiadiazole

Disulfide bond formation is the decisive event in the protein folding to determine the conformation and stability of protein. To achieve this disulfide bond formation in vitro, we took 2,5-dimercapto-1,3,4-thiadiazole (DMcT) as a model compound. We found that disulfide bond formation takes place between two sulfhydryl groups of DMcT molecules in methanol. UV-Vis, FT-IR and mass spectroscopic as well as cyclic voltammetry were used to monitor the course of reaction. We proposed a mechanism for the solvent induced disulfide bond formation on the basis of the results we obtained

Lattice Imaging of Self-Assembled Monolayers of Partially Fluorinated Disulfides and Thiols on Sputtered Gold by Atomic Force Microscopy

The structure of self-assembled monolayers (SAMs) of various fluorinated disulfides, perfluoroalkylamide thiols, and a mixed alkyl perfluoroalkylamide disulfide on sputtered gold was studied by atomic force microscopy (AFM). AFM, performed both in air and in ethanol, revealed the monolayer structure with molecular resolution on the polycrystalline gold substrates. For all partially fluorinated disulfides containing ester groups, a hexagonal lattice with a lattice constant of 5.8-5.9 Å was found. A mixed alkyl perfluoroalkylamide disulfide formed a hexagonal lattice of a slightly larger lattice constant (6.1 Å), whereas the lattice observed for fluorinated thiols containing an amide group was either hexagonal (5.7-5.8 Å) or distorted hexatic (5.6, 6.2, 5.6 Å), depending on the length of the perfluoroalkane segment and the imaging force. The observed deviation from hexagonal symmetry is attributed to the distorting effect of hydrogen bonding between neighboring amide groups within the monolayer. For short perfluoroalkane segments the distortion is observed at low imaging forces, whereas for long perfluoroalkane segments significantly higher imaging forces are necessary in order to observe the distortion. The force dependence of the measured lattice symmetries for different chain lengths suggests that the AFM tip penetrates into the SAM and probes at least partially the interior of the SAM

Synthesis of mechanically strong waterborne poly(urethane-urea)s capable of self-healing at elevated temperatures

Although various chemistries have been introduced into polyurethanes in order to obtain self-healing abilities, implementing these materials in applications requiring high strength is challenging as strong materials imply a limited molecular motion, but without movement of polymer chains self-healing is not possible. Here, waterborne poly(urethane-urea)s (PU(U)s) based on aromatic disulfide compounds are developed which balance these contradictory requirements by presenting good mechanical properties at room temperature, while showing the mobility necessary for healing when moderately heated. The influence of hard monomers on the stability and mobility of the materials is investigated by scratch closure, cut healing and rheological measurements, so that the limits of the readily available aromatic disulfide compounds, bis(4-aminophenyl)- and bis(4-hydroxyphenyl)disulfide, can be determined. Subsequently, a modified aromatic disulfide compound, bis[4-(3'-hydroxypropoxy)phenyl]disulfide, with increased reactivity, solubility and flexibility is synthesized and incorporated into the PU backbone, so that materials with more attractive mechanical properties, reaching ultimate tensile strengths up to 23 MPa, and self-healing abilities at elevated temperatures could be obtained.The European Union’s Horizon 2020 research and innovation programme is accredited for the financial support through Project TRACKWAY-ITN 642514 under the Marie Sklodowska-Curie grant agreement. N.B. acknowledges the financial support obtained through the Post-Doctoral fellowship Juan de la Cierva - Incorporación (IJCI-2016-28442), from the Ministry of Economy and Competitiveness of Spai

Flexible aromatic disulfide monomers for high-performance self-healable linear and cross-linked poly(urethane-urea) coatings

Implementation of the self-healing concept in coatings is challenging because they have to combine mechanical strength and chain mobility. This challenge is addressed in this work by studying the effect of the polymer microstructure on the mechanical properties and self-healing ability of waterborne poly(urethane-urea) coatings containing aromatic disulfide dynamic bonds. The structural modifications studied are the concentration and flexibility of the aromatic disulfide units and the effect of cross-linking. The effects and limits of these structural changes on the mechanical properties of the polymers and their healability were determined via a combination of DMA measurements, tensile tests, and rheological and scratch closure experiments. It was found that the flexibility of the disulfide unit was key to develop more efficient self-healing materials which offer the necessary molecular mobility for self-healing while simultaneously maintaining a level of mechanical strength that are essential for coating applications.The European Union’s Horizon 2020 research and innovation programme is accredited for the financial support through Project TRACKWAY-ITN 642514 under the Marie Sklodowska-Curie grant agreement. N.B. acknowledges the financial support obtained through the Post-Doctoral fellowship Juan de la Cierva - Incorporación (IJCI-2016-28442), from the Ministry of Economy and Competitiveness of Spai

Synthetic Analogues of the Snail Toxin 6-Bromo-2-mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Modulation of Voltage-Gated Potassium Channels

Drugs do not act solely by canonical ligand–receptor binding interactions. Amphiphilic drugs partition into membranes, thereby perturbing bulk lipid bilayer properties and possibly altering the function of membrane proteins. Distinguishing membrane perturbation from more direct protein–ligand interactions is an ongoing challenge in chemical biology. Herein, we present one strategy for doing so, using dimeric 6-bromo-2-mercaptotryptamine (BrMT) and synthetic analogues. BrMT is a chemically unstable marine snail toxin that has unique effects on voltage-gated K+ channel proteins, making it an attractive medicinal chemistry lead. BrMT is amphiphilic and perturbs lipid bilayers, raising the question of whether its action against K+ channels is merely a manifestation of membrane perturbation. To determine whether medicinal chemistry approaches to improve BrMT might be viable, we synthesized BrMT and 11 analogues and determined their activities in parallel assays measuring K+ channel activity and lipid bilayer properties. Structure–activity relationships were determined for modulation of the Kv1.4 channel, bilayer partitioning, and bilayer perturbation. Neither membrane partitioning nor bilayer perturbation correlates with K+ channel modulation. We conclude that BrMT’s membrane interactions are not critical for its inhibition of Kv1.4 activation. Further, we found that alkyl or ether linkages can replace the chemically labile disulfide bond in the BrMT pharmacophore, and we identified additional regions of the scaffold that are amenable to chemical modification. Our work demonstrates a strategy for determining if drugs act by specific interactions or bilayer-dependent mechanisms, and chemically stable modulators of Kv1 channels are reported

Review

The chalcogen elements oxygen, sulfur, and selenium are essential constituents of side chain functions of natural amino acids. Conversely, no structural and biological function has been discovered so far for the heavier and more metallic tellurium element. In the methionine series, only the sulfur-containing methionine is a proteinogenic amino acid, while selenomethionine and telluromethionine are natural amino acids that are incorporated into proteins most probably because of the tolerance of the methionyl-tRNA synthetase; so far, methoxinine the oxygen analogue has not been discovered in natural compounds. Similarly, the chalcogen analogues of tryptophan and phenylalanine in which the benzene ring has been replaced by the largely isosteric thiophene, selenophene, and more recently, even tellurophene are fully synthetic mimics that are incorporated with more or less efficiency into proteins via the related tryptophanyl- and phenylalanyl-tRNA synthetases, respectively. In the serine/cysteine series, also selenocysteine is a proteinogenic amino acid that is inserted into proteins by a special translation mechanism, while the tellurocysteine is again most probably incorporated into proteins by the tolerance of the cysteinyl-tRNA synthetase. For research purposes, all of these natural and synthetic chalcogen amino acids have been extensively applied in peptide and protein research to exploit their different physicochemical properties for modulating structural and functional properties in synthetic peptides and rDNA expressed proteins as discussed in the following review

Straightforward synthesis of functionalized cyclic polymers in high yield via RAFT and thiolactone-disulfide chemistry

An efficient synthetic pathway toward cyclic polymers based on the combination of thiolactone and disulfide chemistry has been developed. First, heterotelechelic linear polystyrene (PS) containing an alpha-thiolactone (TLa) and an omega-dithiobenzoate group was synthesized via reversible addition-fragmentation chain transfer (RAFT) polymerization, employing a newly designed TLa-bearing chain transfer agent (CTA). The subsequent reaction of this heterotelechelic polymer with an amine, which acts as a nucleophile for both the TLa and dithiobenzoate units, generated the alpha,omega-thiol-telechelic PS under ambient conditions without the need for any catalyst or other additives. The arrangement of thiols under a high dilution afforded single cyclic PS (c-PS) through an oxidative disulfide linkage. The cyclic PS (c-PS) disulfide ring formation was evidenced by SEC, MALDI-TOF MS and H-1-NMR characterization. Moreover, we demonstrated a controlled ring opening via either disulfide reduction or thiol-disulfide exchange to enable easy and clean topology transformation. Furthermore, to illustrate the broad utility of this synthetic methodology, different amines including functional ones were employed, allowing for the one-step preparation of functionalized cyclic polymers with high yields

SUN/KASH interactions facilitate force transmission across the nuclear envelope.

LINC complexes (Linker of Nucleoskeleton and Cytoskeleton), consisting of inner nuclear membrane SUN (Sad1, UNC-84) proteins and outer nuclear membrane KASH (Klarsicht, ANC-1, and Syne Homology) proteins, are essential for nuclear positioning, cell migration and chromosome dynamics. To test the in vivo functions of conserved interfaces revealed by crystal structures, Cain et al used a combination of Caenorhabditis elegans genetics, imaging in cultured NIH 3T3 fibroblasts, and Molecular Dynamic simulations, to study SUN-KASH interactions. Conserved aromatic residues at the -7 position of the C-termini of KASH proteins and conserved disulfide bonds in LINC complexes play important roles in force transmission across the nuclear envelope. Other properties of LINC complexes, such as the helices preceding the SUN domain, the longer coiled-coils spanning the perinuclear space and higher-order organization may also function to transmit mechanical forces generated by the cytoskeleton across the nuclear envelope