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Psammaplin A (PsA), a symmetrical bromotyrosine-derived disulfide marine metabolite, has been reported could inhibit HDAC1/2/3 through its thiol monomer. Inspired by the disuflide bond structure of this marine natural product, we designed and synthesized a series of PsA analogues, in which the disulfide bond of PsA was replaced with diselenide bond or cyclic disulfide/diselenide/selenenylsulfide motifs. We also studied the HDAC inhibition, cell growth inhibition, and apoptosis induction of these PsA analogues. The results showed that, all the synthetic diselenide analogues and cyclic selenenyl sulfide compounds exhibited better antiproferative activity than their counterpart of disulfide analogues. Among the prepared analogues, diselenide analogue P-503 and P-116 significantly increased the ability of inhibiting HDAC6 and induced apoptosis and G2/M cell cycle arrest. However, cyclic selenenylsulfides analogues P-111 lost its HDAC inhibitory ability and exhibited no effect on cell cycle and apoptosis, indicating that the anti-proliferative mechanism of cyclic selenenylsulfides analogues has changed., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The therapy of the clear cell renal cell carcinoma (ccRCC) is crucial for the human healthcare due to its easy metastasis and recurrence, as well as resistance to radiotherapy and chemotherapy. In this work, we propose the synthesis of MoS 2 @red phosphorus (MoS 2 @RP) heterojunction to induce synergistic photodynamic and photothermal therapy (PDT/PTT) of ccRCC. The MoS 2 @RP heterojunction exhibits enhanced spectra absorption in the NIR range and produce local heat-increasing under the NIR laser irradiation compared with pure MoS 2 and RP. The high photocatalytic activity of the MoS 2 @RP heterojunction contributes to effective transferring of the photo-excited electrons from the RP to MoS 2 , which promotes the production of various types of radical oxygen species (ROS) to kill the ccRCC cells. After the NIR irradiation, the MoS 2 @RP can effectively induce the apoptosis in the ccRCC cells through localized hyperthermia and the generation of ROS, while exhibiting low cytotoxicity towards normal kidney cells. In comparison to MoS 2 , the MoS 2 @RP heterojunction shows an approximate increase of 22 % in the lethality rate of the ccRCC cells and no significant change in toxicity towards normal cells. Furthermore, the PDT/PTT treatment using the MoS 2 @RP heterojunction effectively eradicates a substantial number of deep-tissue ccRCC cells in vivo without causing significant damage to major organs. This study presents promising effect of the MoS 2 @RP heterojunction-based photo-responsive therapy for effective ccRCC treatment., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Antibacterial materials have been rapidly emerging as a primary component in the mitigation of bacterial pathogens, and green functional materials play a vital role in the antibacterial field. In this study, biocompatible hydroxyapatite nanowires (HANW) was used as a carrier, a coral rod-like nanowires hybrid of MoS 2 and HANW (CR-MoS 2 @HANW) was synthesized via a facile two-step hydrothermal approach. After being characterized by scanning electron microscope (SEM), energy dispersive spectrometer (EDS), X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), fourier transform infrared spectroscopy (FT-IR), Brunauer-Emmet-Teller (BET) and thermogravimetric (TG) analysis, the antibacterial activity and environmental compatibility were assessed. It was found that MoS 2 nanosheets were in-situ assembled onto surface of HA nanowires, and the obtained nanohybrid exhibited excellent stability. CR-MoS 2 @HANW endowed a desirable long-term antibacterial activity against both gram-negative E. coli and gram-positive S. aureus. It was sufficient to inhibit the growth of bacteria within 72 h, and nanohybrids effectively promoted the growth of plants. In summary, the combination of MoS 2 and HANW created a novel eco-friendly nanohybrids that could be applied as a promising multi-functional green antisepsis. And the CR-MoS 2 @HANW possessed enormous potential for biomedical applications., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Disulfide-rich peptides and proteins are among the most fascinating bioactive molecules. The difficulties associated with the preparation of these targets have prompted the development of various chemical strategies. Nevertheless, the production of these targets remains very challenging or elusive. Recently, we introduced a strategy for one-pot disulfide bond formation, tackling most of the previous limitations. However, the effect of the order of oxidation remained an underexplored issue. Herein we report on the complete synthetic flexibility of the approach with respect to the order of oxidation of three disulfide bonds in targets that lack the knot motif. In contrast, our study reveals an essential order of disulfide bond formation in the EETI-II knotted miniprotein. This synthetic strategy was applied for the synthesis of novel analogues of the plectasin antimicrobial peptide with enhanced activities against methicillin-resistant Staphylococcus aureus (MRSA), a notorious human pathogen., (© 2021 Wiley-VCH GmbH.)

The simulation of human brain neurons by synaptic devices could be an effective strategy to break through the notorious "von Neumann Bottleneck" and "Memory Wall". Herein, opto-electronic synapses based on layered hafnium disulfide (HfS 2 ) transistors have been investigated. The basic functions of biological synapses are realized and optimized by modifying pulsed light conditions. Furthermore, 2 × 2 pixel imaging chips have also been developed. Two-pixel visual information is illuminated on diagonal pixels of the imaging array by applying light pulses (λ = 405 nm) with different pulse frequencies, mimicking short-term memory and long-term memory characteristics of the human vision system. In addition, an optically/electrically driven neuromorphic computation is demonstrated by machine learning to classify hand-written numbers with an accuracy of about 88.5%. This work will be an important step toward an artificial neural network comprising neuromorphic vision sensing and training functions.

Development of proteolysis targeting chimeras (PROTACs) is emerging as a promising strategy for targeted protein degradation. However, the drug development using the heterobifunctional PROTAC molecules is generally limited by poor membrane permeability, low in vivo efficacy and indiscriminate distribution. Herein an aptamer-PROTAC conjugation approach was developed as a novel strategy to improve the tumor-specific targeting ability and in vivo antitumor potency of conventional PROTACs. As proof of concept, the first aptamer-PROTAC conjugate (APC) was designed by conjugating a BET-targeting PROTAC to the nucleic acid aptamer AS1411 (AS) via a cleavable linker. Compared with the unmodified BET PROTAC, the designed molecule (APR) showed improved tumor targeting ability in a MCF-7 xenograft model, leading to enhanced in vivo BET degradation and antitumor potency and decreased toxicity. Thus, the APC strategy may pave the way for the design of tumor-specific targeting PROTACs and have broad applications in the development of PROTAC-based drugs., (© 2021 Wiley-VCH GmbH.)

Breast cancer stem cell (BCSC) properties are correlated with the malignancy of tumor cells. Sulforaphane (SFN), a natural isothiocyanate, has anti-cancer effects. However, SFN is an oil-like, hydrophobic and unstable substance. To enhance the inhibitory effect of SFN on BCSC-like properties, the mineralized hyaluronic acid-SS-tetradecyl nano-carriers (M-HA-SS-TA) were prepared. The nano-carriers possessed high SFN entrapment rate (92.36%) and drug-loading efficiency (33.64%). The carriers were responsive to the high reducing and mild acidic tumor micro-environment, leading to rapid SFN releasing from SFN-loaded nano-drug (SFN/M-HA-SS-TA). Through the specific recognition of breast cancer cells bearing CD44 + by HA, M-HA-SS-TA nano-carriers showed excellent tumor-targeting ability. Moreover, compared with free SFN, SFN/M-HA-SS-TA showed much stronger inhibition on the BCSC-like properties (invasiveness, self-renewal and tumor growth) both in vitro and in vivo. Together, these results suggested M-HA-SS-TA nano-carriers were promising platforms for tumor-targeted delivery of SFN, enhancing the therapeutic efficacy against BCSC-like properties by SFN., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Plasma membrane (PM) is the turntable of various reactions that regulate essential functionalities of cells. Among these reactions, the thiol disulfide exchange (TDE) reaction plays an important role in cellular processes. We herein designed a selective probe, called membrane reduction probe (MRP), that is able to report TDE activity at the PM. MRP is based on a green emitting BODIPY PM probe connected to rhodamine through a disulfide bond. MRP is fluorogenic as it is turned off in aqueous media due to aggregation-caused quenching, and once inserted in the PM, it displays a bright red signal due to an efficient fluorescence energy resonance transfer (FRET) between the BODIPY donor and the rhodamine acceptor. In the PM model, the MRP can undergo TDE reaction with external reductive agents as well as with thiolated lipids embedded in the bilayer. Upon TDE reaction, the FRET is turned off and a bright green signal appears allowing a ratiometric readout of this reaction. In cells, the MRP quickly labeled the PM and was able to probe variations of TDE activity using ratiometric imaging. With this tool in hand, we were able to monitor variations of TDE activity at the PM under stress conditions, and we showed that cancer cell lines presented a reduced TDE activity at the PM compared to noncancer cells.

Molybdenum disulfide quantum dots (MoS2 QDs) have drawn increasing attention owing to their distinct optical properties and potential applications in many fields such as biosensing, photocatalysis and cell imaging. Elucidating the relationship between the surface chemistry of MoS2 QDs and their optical properties as well as biological behaviors is critical for their practical applications, which remain largely unclear. Herein, by adopting a sulfur vacancy modification strategy, a toolbox of MoS2 QDs functionalized with different thiolate ligands was prepared. The effect of surface chemistry on the optical properties of MoS2 QDs was systematically explored by various spectroscopic techniques, revealing the important role of surface ligands in defining their absorption band gap and luminescence quantum yield. Furthermore, cellular experiments showed that the cytotoxicity and intracellular fate (i.e., lysosomal accumulation) of MoS2 QDs are closely related to the properties of surface ligands. Our results underscore the important roles of surface ligands in regulating the properties and biological interactions of these QDs, which will facilitate the future development of MoS2-based materials with precisely controlled functions for biomedical applications.

Altered redox homeostasis as a hallmark of cancer cells is exploited by cancer cells for growth and survival. The thioredoxin (Trx), an important regulator in maintaining the intracellular redox homeostasis, is cumulatively recognized as a promising target for the development of anticancer drugs. Herein, we synthesized 72 disulfides and evaluated theirinhibition for Trx and antitumor activity. First, we established an efficient and fast method to screen Trx inhibitors by using the probe NBL-SS that was developed by our group to detect Trx function in living cells. After an initial screening of the Trx inhibitory activity of these compounds, 8 compounds showed significant inhibition activity against Trx. We then evaluated the cytotoxicity of these 8 disulfides, compounds 68 and 69 displayed high cytotoxicity to HeLa cells, but less sensitive to normal cell lines. Next, we performed kinetic studies of both two disulfides, 68 had faster inhibition of Trx than 69. Further studies revealed that 68 led to the accumulation of reactive oxygen species and eventually induced apoptosis of Hela cells via inhibiting Trx. The establishment of a method for screening Trx inhibitors and the discovery of 68 with remarkable Trx inhibition provide support for the development of anticancer candidates with Trx inhibition., (Copyright © 2021 Elsevier Inc. All rights reserved.)

In this work, a label-free and highly sensitive fluorescence assay was constructed for microRNA detection. Nicking-enhanced rolling circle amplification (RCA) induced by G-quadruplex formation is coupled with inner filter effect (IFE)-based quenching effects of MoS 2 quantum dots (MoS 2 QDs). The padlock probe contains a recognition sequence to target microRNA and an accessible nicking site. The padlock probe is cyclized upon hybridization with target microRNA. Sequentially, amplification initiates a production of a long-concatenated sequence of circular probes. Abundant G-quadruplex sequences are produced via the nicking process and then used as the trigger to initiate the next RCA. In the presence of hemin, numerous hemin/G-quadruplex DNAzymes are formed, which catalyze the oxidation of o -phenylenediamine (OPD) into the colored product 2,3-diaminophenazine, resulting in quenching of the fluorescence of MoS 2 QDs. This sensing strategy enables detection of microRNA let-7a with high selectivity and a detection limit of 4.6 fM. The as-prepared sensor was applied for detecting microRNA let-7a in dilute human serum samples and achieved a satisfactory recovery rate, demonstrating its potential in clinic diagnosis of microRNA-associated disease and biochemical research.

Tridegin is a 66mer cysteine-rich coagulation factor XIIIa (FXI-IIa) inhibitor from the giant amazon leech Haementeria ghilianii of yet unknown disulfide connectivity. This study covers the structural and functional characterization of five different 3-disulfide-bonded tridegin isomers. In addition to three previously identified isomers, one isomer containing the inhibitory cystine knot (ICK, knottin) motif, and one isomer with the leech antihemostatic protein (LAP) motif were synthesized in a regioselective manner. A fluorogenic enzyme activity assay revealed a positive correlation between the constriction of conformational flexibility in the N-terminal part of the peptide and the inhibitory potential towards FXI-IIa with clear differences between the isomers. This observation was supported by molecular dynamics (MD) simulations and subsequent molecular docking studies. The presented results provide detailed structure-activity relationship studies of different tridegin disulfide isomers towards FXI-IIa and reveal insights into the possibly existing native linkage compared to non-native disulfide tridegin species., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

Diaryl disulfides and diaryl thiosulfonates were synthesized with the two phenyl rings of all compounds bearing identical halide substituents. Because of structural similarity to the potent antimitotic natural product combretastatin A-4 (CA-4), the compounds were examined for inhibition of tubulin polymerization, and the thiosulfonates were more active than the disulfides. The nine thiosulfonates had IC 50 values ranging from 1.2 to 9.1 µM, as compared with 1.3 µM obtained with CA-4. The compounds thus ranged from equipotent with CA-4 to 7-fold less active. The nine disulfides had IC 50 values ranging from 1.2 to 5.1 µM, as compared with 0.54 µM obtained with CA-4. The compounds thus ranged from less than half as active as CA-4 to over 9-fold less active. The most active members of each group, 2 g and 3c, in the assembly assay were modeled into the colchicine site. Compound 3c had significant hydrophobic interactions with β-tubulin residues CYS 241 and ALA 250, and its thiosulfonate bridge made a hydrogen bond with β-tubulin residue ASN 258. Compound 2 g had hydrophobic interactions with β-tubulin residues ALA 250, CYS 241 and ALA 254, but there was no significant interaction of the disulfide bridge with tubulin., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

A bacterial and viral infection causes life threatening diseases owing to the abuse of antibiotics and the development of antibiotic resistance microbes. Currently, biopolymers have been considered as the most promising materials in the medical field. Herein, the biogenic chitosan-functionalized MoS 2 nanocomposite was prepared by the hydrothermal method with the liquid exfoliation process. The X-ray diffraction (XRD) results of chitosan-MoS 2 hybrid nanocomposite revealed that MoS 2 nanoparticle was found to be 42 nm with a hexagonal crystal structure. FTIR and Raman spectrum revealed that the nitrogen functionalities in the chitosan interacted with MoS 2 to form the nanocomposite. The XPS spectrum of chitosan-MoS 2 nanocomposite confirms that C, N, O, Mo, and S exist in the nanocomposite. Thermal gravimetric analysis (TGA) and Differential thermal analysis (DTA) analysis showed that the chitosan-MoS 2 nanocomposite has higher thermal stability up to 600 °C. In the antibacterial application the chitosan-MoS 2 hybrid nanocomposite shows zones of inhibition against S. aureus as 22, 28, and 32 mm, and against E. coli as 26, 30, and 35 mm. In the anticancer analysis, chitosan-MoS 2 hybrid nanocomposites showed a maximum cell inhibition of 65.45% at 100 μg/mL - 1 , resulting in the most significant MCF-7 cell inhibition., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The recent discovery of hydropersulfides (RSSH) in mammalian systems suggests their potential roles in cell signaling. However, the exploration of RSSH biological significance is challenging due to their instability under physiological conditions. Herein, we report the preparation, RSSH-releasing properties, and cytoprotective nature of alkylamine-substituted perthiocarbamates. Triggered by a base-sensitive, self-immolative moiety, these precursors show efficient RSSH release and also demonstrate the ability to generate carbonyl sulfide (COS) in the presence of thiols. Using this dually reactive alkylamine-substituted perthiocarbamate platform, the generation of both RSSH and COS is tunable with respect to half-life, pH, and availability of thiols. Importantly, these precursors exhibit cytoprotective effects against hydrogen peroxide-mediated toxicity in H9c2 cells and cardioprotective effects against myocardial ischemic/reperfusion injury, indicating their potential application as new RSSH- and/or COS-releasing therapeutics.

An inverse electron demand Diels-Alder reaction between tetrazine and trans-cyclooctene (TCO) holds great promise for protein modification and manipulation. Herein, we report the design and synthesis of a tetrazine-based disulfide rebridging reagent, which allows the site-selective installation of a tetrazine group into disulfide-containing peptides and proteins such as the hormone somatostatin (SST) and the antigen binding fragment (Fab) of human immunoglobulin G (IgG). The fast and efficient conjugation of the tetrazine modified proteins with three different TCO-containing substrates to form a set of bioconjugates in a site-selective manner was successfully demonstrated for the first time. Homogeneous, well-defined bioconjugates were obtained underlining the great potential of our method for fast bioconjugation in emerging protein therapeutics. The formed bioconjugates were stable against glutathione and in serum, and they maintained their secondary structure. With this work, we broaden the scope of tetrazine chemistry for site-selective protein modification to prepare well-defined SST and Fab conjugates with preserved structures and good stability under biologically relevant conditions.

Platinum(iv) complexes with a heterocyclic ligand and an ancillary ligand have been investigated and applied for treating various tumour cell lines. Another application of the Pt(iv) complexes in forming peptide disulfide bonds was investigated in this work. For development of Pt(iv) complex chemistry for disulfide bond formation in peptides, two Pt(iv) complexes, [PtCl 2 (phen)(en)]Cl 2 and [PtCl 2 (bpy)(en)]Cl 2 , were synthesized and characterized using elemental analysis, ESI-MS and NMR. Subsequently, they were investigated as oxidants for the formation of disulfide bonds in various peptides. Excellent purities and yields of disulfide-containing peptides were achieved when the reactions were carried out in aqueous solution. The reactions were completed rapidly in a wide range of pH values even in acidic medium at room temperature. An intramolecular disulfide bond was formed in each of the peptides in a solution containing two dithiol-containing peptides, making the Pt(iv) complexes useful for generating disulfide-containing peptide libraries. In addition, the two Pt(iv) complexes can be used as oxidants for the synthesis of disulfide bonds on a resin, which is a more convenient method to synthesize disulfide-containing peptides through automation.

Nucleosomes, the basic unit of chromatin, contain a protein core of histone proteins, which are heavily posttranslationally modified. These modifications form a combinatorial language which defines the functional state of the underlying genome. As each histone type exists in two copies in a nucleosome, the modification patterns can differ between the individual histones, resulting in asymmetry and increasing combinatorial complexity. To systematically explore the regulation of chromatin regulatory enzymes (writers, erasers, or readers), chemically defined nucleosomes are required. We have developed strategies to chemically modify histones and control nucleosome assembly, thereby enabling the reconstitution of asymmetric histone modification patterns. Here, we report a detailed protocol for the modular assembly of such nucleosomes. Employing a three-segment ligation strategy for the semisynthesis of H3, coupled with the use of the protease cleavable "lnc-tag," we provide an efficient and traceless method for the controlled semisynthesis and reconstitution of asymmetrically modified nucleosomes.

Persulfides have been considered as potential signaling compounds similar to the H 2 S in "S-persulfidation", a sulfur-mediated redox cycle. The research of this sulfur-mediated species is hindered because of the lack of efficient persulfide donors. In this current study, we have developed one- and two-photon-activated persulfide donors based on an o -nitrobenzyl (ONB) phototrigger, which releases the biologically active persulfide ( N -acetyl l-cysteine persulfide, NAC-SSH) in a spatiotemporal manner. Next, we have demonstrated the detection of persulfide release both qualitatively and quantitatively using the well-known "turn on" fluorescence probe, that is, monobromobimane, and the trapping agent, that is, 2,4-dinitrofluorobenzene, respectively. Furthermore, we examined the cytotoxicity of synthesized persulfide donors on HeLa cells and the cytoprotective ability in the highly oxidizing cellular environment.

The fast and accurate real-time monitoring of hydrogen peroxide (H 2 O 2 ) secreted from living cells plays a critical role in clinical diagnosis and management. Herein, we report low-cost and self-supported MoS 2 nanosheet arrays for non-enzymatic eletrochemical H 2 O 2 detection. Under the optimal test conditions, such MoS 2 electrodes exhibit extremely promising electrocatalytic performance with a low detection limit of 1.0 μM (S/N = 3) and an excellent sensitivity of 5.3 mA mM -1 cm -2 . Furthermore, the detection of the trace amount of H 2 O 2 secreted from live A549 cancer cells was successfully performed with this biosensor.

Insulin is the principal hormone involved in the regulation of metabolism and has served a seminal role in the treatment of diabetes. Building upon advances in insulin synthetic methodology, we have developed a straightforward route to novel insulins containing a fourth disulfide bond in a [3 + 1] fashion establishing the first disulfide scan of the hormone. All the targeted analogs accommodated the constraint to demonstrate an unexpected conformational flexibility of native insulin. The bioactivity was established for the constrained (4-DS) and unconstrained (3-DS) analogs by in vitro methods, and extended to in vivo study for select peptides. We also identified residue B10 as a preferred anchor to introduce a tether that would regulate insulin bioactivity. We believe that the described [3 + 1] methodology might constitute the preferred approach for performing similar disulfide scanning in peptides that contain multiple disulfides.

The delivery of therapeutic agents into target cells is a challenging task. Cell penetration and intracellular targeting were recently addressed with biodegradable cell-penetrating poly(disulfide)s (CPDs). Cellular localization is determined by the length of these polymers, emphasizing the significance of initial chain length and the kinetics of intracellular depolymerization for targeted delivery. In the present study, the kinetics of CPD polymer growth and degradation were monitored in a single-molecule nanoreactor. The chain lengths achievable under synthetic conditions with high concentrations of dithiolanes were then predicted by using the rate constants. For example, CPDs comprising 40 units are generated in 1 s at pH 7.4 and 0.3 s at pH 8.4 at dithiolane concentrations of 200 mM. The rate constants for degradation suggest that the main depolymerization pathway in the cell is by monomer removal by self-cyclization, rather than by intrachain cleavage by endogenous thiols.

This study is about (1) nanomanufacturing (focusing on microfluidic-assisted nanoprecipitation), (2) advanced colloid characterization (focusing on field flow fractionation), and (3) the possible restructuring of surface disulfides. Disulfides are dynamic and exchangeable groups, and here we specifically focus, first, on their use to introduce biofunctional groups and, second, on their re-organization, which may lead to variable surface chemistries and uncontrolled cell interactions. The particles were obtained via microfluidic-assisted (flow-focused) nanoprecipitation of poly(ethylene glycol)- b -poly(ε-caprolactone) bearing or not a 2-pyridyl disulfide (PDS) terminal group, which quantitatively exchanges with thiols in solution. In this study, we have paid specific attention to size characterization, thereby also demonstrating the limitations of dynamic light scattering (DLS) as a stand-alone technique. By using asymmetric flow field flow fractionation coupled with DLS, static light scattering (SLS), and refractive index detectors, we show that relatively small amounts of >100 nm aggregates (cryogenic transmission electron microscopy and SLS/DLS comparison suggesting them to be wormlike micelles) dominated the stand-alone DLS results, whereas the "real" size distributions picked <50 nm. Our key result is that the kinetics of the conjugation based on PDS-thiol exchange was controlled by the thiol p K a , and this also determined the rate of the exchange between the resulting disulfides and glutathione (GSH). In particular, more acidic thiols (e.g., peptides, where a cysteine is flanked by cationic residues) react faster with PDS, but their disulfides hardly exchange with GSH; the reverse applies to thiols with a higher p K a . Disulfides that resist against restructuring via thiol-disulfide exchange allow for a stable bioconjugation, although they may be bad news for payload release under reducing conditions. However, experiments of both thiol release and nanoparticles uptake in cells (HCT116) show that also the disulfides formed from less-acidic and, therefore, less-reactive, and more exchangeable thiols were stable for at least a few hours even in a GSH-rich (10 mM) environment; this suggests a sufficiently long stability of surface groups to achieve, for example, a cell-targeting effect.

Phosphatidylcholine is the main component of liposomes and other phospholipid-based nanocarriers in drug delivery. However, the functions and applications of these nanocarriers are extremely limited by conventional phospholipids. Here we report novel disulfide phosphatidylcholines (SS-PCs) and SS-PC based liposomes (SS-LPs) used as alternatives to traditional phospholipids and liposomes.

Prostate cancer (PCa) is the most common malignancy in men and is the leading cause of cancer-related male mortality. A disulfide cyclic peptide ligand [CTVRTSADC] 1 has been previously found to target extra domain B of fibronectin (EDB-FN) in the extracellular matrix that can differentiate aggressive PCa from benign prostatic hyperplasia. We synthesized and optimized the stability of ligand 1 by amide cyclization to obtain [KTVRTSADE] 8 using Fmoc/tBu solid-phase chemistry. Optimized targeting ligand 8 was found to be stable in phosphate buffered saline (PBS, pH 6.5, 7.0, and 7.5) and under redox conditions, with a half-life longer than 8 h. Confocal microscopy studies demonstrated increased binding of ligand 8 to EDB-FN compared to ligand 1 . Therefore, we hypothesized that the EDB-FN targeted peptides ( 1 and 8 ) conjugated with an anticancer drug via a hydrolyzable linker would provide selective cytotoxicity to the cancer cells. To test our hypothesis, we selected both the normal prostate cell line, RWPE-1, and the cancerous prostate cell lines, PC3, DU-145, LNCaP, and C4-2, to evaluate the anticancer activity of synthesized peptide-drug conjugates. Docetaxel (Doce) and doxorubicin (Dox) were used as anticancer drugs. Dox conjugate 13 containing disulfide linkage showed comparable cytotoxicity versus Dox after 72 h incubation in all the cancer cell lines, whereas it was found to be less cytotoxic on RWPE-1, suggesting that it can act as a Dox prodrug. Doce conjugate 14 was found to be less cytotoxic in all the cell lines as compared to drug alone.

In nature, individual histones in the same nucleosome can carry identical (symmetric) or different (asymmetric) post-translational modification (PTM) patterns, increasing the combinatorial complexity. Embryonic stem cells exhibit "bivalent" nucleosomes, some of which are marked by an asymmetric arrangement of H3K36me3 (an activating PTM) and H3K27me3 (a repressive PTM). Here we describe a modular synthetic method to access such asymmetrically modified nucleosomes and show that H3K36me3 inhibits the activity of the methyltransferase PRC2 locally while still prolonging its chromatin binding time., (© 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Two-dimensional (2D) layered nanomaterials have triggered an intensive interest due to the fascinating physiochemical properties with the exceptional physical, optical and electrical characteristics that transpired from the quantum size effect of their ultra-thin structure. Among the family of 2D nanomaterials, molybdenum disulfide (MoS 2 ) features distinct characteristics related to the existence of direct energy bandgap, which significantly lowers the leakage current and surpasses other 2D materials. In this overview, we expatiate the novel strategies to synthesize MoS 2 that cover techniques such as liquid exfoliation, chemical vapour deposition, mechanical exfoliation, hydrothermal reaction, and Van Der Waal epitaxial growth on the substrate. We extend the discussion on the recent progress in biosensing applications of the produced MoS 2 , highlighting the important surface-to-volume of ultrathin MoS 2 structure, which enhances the overall performance of the devices. Further, envisioned the missing piece with the current MoS 2 -based biosensors towards developing the future strategies., (Copyright © 2019 Elsevier B.V. All rights reserved.)

A metal-inorganic composite, comprises of silver-molybdenum disulfide nanosheets (Ag@MoS 2 ) was synthesized at low temperature. The Ag@MoS 2 composite was drop-casted onto a glassy carbon electrode (GCE) for a highly selective dopamine (DA) detection in the presence of interfering compounds such as uric acid (UA) and ascorbic acid (AA). The physicochemical analysis of the nanosheets was carried out with X-ray diffraction, transmission electron microscopy and X-ray photoelectron spectroscopy. The as-prepared Ag@MoS 2 -modified GCE displayed excellent electrocatalytic activity toward DA oxidation, with a 0.2 μM detection limit at a signal-to-noise ratio of 3 and an extensive linear detection range from 1 μM to 500 μM (R 2  = 0.9983). The fabricated non-enzymatic electrochemical sensor demonstrated superior selectivity and stability for the detection of DA with the removal of AA and UA interfering compounds., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Large-area, ultrathin flexible tactile sensors with conformal adherence are becoming crucial for advances in wearable electronics, electronic skins and biorobotics. However, normal passive tactile sensors suffer from high crosstalk, resulting in inaccurate sensing, which consequently limits their use in such advanced applications. Active-matrix-driven tactile sensors could potentially overcome such hurdles, but it demands the high performance and reliable operations of the thin-film-transistor array that could efficiently control integrated pressure gauges. Herein, we utilized the benefit of the semiconducting and mechanical excellence of MoS 2 and placed it between high- k Al 2 O 3 dielectric sandwich layers to achieve the high and reliable performance of MoS 2 -based back-plane circuitry and strain sensor. This strategical combination reduces the fabrication complexity and enables the demonstration of an all MoS 2 -based large area (8 × 8 array) active-matrix tactile sensor offering a wide sensing range (1-120 kPa), sensitivity value (Δ R/ R 0 : 0.011 kPa -1 ), and a response time (180 ms) with excellent linearity. In addition, it showed potential in sensing multitouch accurately, tracking a stylus trajectory, and detecting the shape of an external object by grasping it using the palm of the human hand.

An adamantane-containing zwitterionic copolymer poly(2-(methacryloyloxy)ethyl phosphorylcholine)- co-poly(2-(methacryloyloxy)ethyl adamantane-1-carboxylate) (poly(MPC- co-MAda)) was prepared by reversible addition-fragmentation chain transfer (RAFT) polymerization. The hydrophobic photosensitizer chlorin e6 (Ce6) was conjugated to β-cyclodextrin (β-CD) by glutathione (GSH)-sensitive disulfide bonds. The Ce6 conjugated supramolecular prodrug nanocarriers were fabricated due to the host-guest interaction between adamantane and β-CD, which was confirmed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The Ce6 conjugated prodrug nanocarriers showed reduction-responsive release of Ce6, which could result in the activation of Ce6. The generation of cytotoxic reactive oxygen species (ROS) was significantly enhanced due to the activation of Ce6. In additiona, the Ce6 conjugated prodrug nanocarriers could effectively inhibit the proliferation of cancer cells upon light irradiation.

The goal of this study is to develop a simple one-pot method for the synthesis of a zwitterionic small molecule bearing disulfide moiety, which can effectively inhibit nonspecific protein adsorption on macroscopic and nanoscopic gold surfaces. To this end, the optimal molecular structure of a pyridine disulfide derivative was explored and a zwitterionic small molecule was successfully synthesized from the tertiary amine residue on the pyridine ring through a one-pot method. The coating conditions of the synthesized zwitterionic molecules on the gold surface were optimized through contact angle measurements, and the strong interactions between the gold surface and the disulfide moiety of the zwitterion small molecule were confirmed by surface plasmon resonance (SPR) analysis and X-ray photoelectron spectroscopy. The antibiofouling properties of the coated gold surface were analyzed by fluorescence microscopic observations after contacting with FITC-labeled bovine serum albumin (BSA) and SPR sensor as contacting with BSA solution. In addition, the effect of zwitterion-coating on the salt stability of and protein adsorption on nanoscopic gold surfaces were examined through a NaCl stability test and BSA adsorption test, respectively. From the obtained results, it was confirmed that the simply synthesized zwitterionic small molecule was effective in inhibiting nonspecific protein adsorption on macroscopic and nanoscopic gold surfaces; further, it enhanced the salt stability of gold nanoparticle surfaces.

Staphylococcus aureus is a WHO Priority II pathogen for its capability to cause acute to chronic infections and to resist antibiotics, thus severely impacting healthcare systems worldwide. In this context, it is urgently desired to discover novel molecules to thwart the continuing emergence of antimicrobial resistance. Disulphide containing small molecules has gained prominence as antibacterials. As their conventional synthesis requires tedious synthetic procedure and sometimes toxic reagents, a green and environmentally benign protocol for their synthesis has been developed through which a series of molecules were obtained and evaluated for antibacterial activity against ESKAPE pathogen panel. The hit compound was tested for cytotoxicity against Vero cells to determine its selectivity index and time-kill kinetics was determined. The activity of hit was determined against a panel of S. aureus multi-drug resistant clinical isolates. Also, its ability to synergize with FDA approved drugs was tested as was its ability to reduce biofilm. We identified bis(2-bromophenyl) disulphide (2t) as possessing equipotent antimicrobial activity against S. aureus including MRSA and VRSA strains. Further, 2t exhibited a selectivity index of 25 with concentration-dependent bactericidal activity, synergized with all drugs tested and significantly reduced preformed biofilm. Taken together, 2t exhibits all properties to be positioned as novel scaffold for anti-staphylococcal therapy., (© 2018 Wiley Periodicals, Inc.)

The prodrug strategy serves well in drug formulation and delivery. Two disulfide-based PEGylated prodrugs were developed and the drug reconversion upon different conditions were studied in detail. The reconversion-induced oversaturation phenomenon was firstly reported here. We found the prodrug can co-assemble with parent drug via π-π stacking into well-defined nanoparticles. The PEG layer of the self-assembled nanoparticles improved the stability of the PEGylated prodrug by reducing the contact with biological enzymes. The nanoparticles also show favorable antitumor efficacy, both in vitro and in vivo., (Copyright © 2018 Elsevier B.V. All rights reserved.)

A new DNA binding small molecule, NCD-CC is reported. NCD-CC has a NCD domain, which recognizes the G-G mismatch in a CGG/CGG triad, and a cysteinylcystein (CC) moiety. Dimerization of NCD-CC through intermolecular disulfide bond formation was accelerated in the presence of CGG repeat DNA.

Abnormal H 2 O 2 and cholesterol levels are closely related to many diseases. This work reports a facile process for the synthesis of oxidized glutathione (GSSG)-modified MoS 2 nanosheets (MoS 2 -GSSG NSs). The biocompatible MoS 2 -GSSG NSs have good dispersibility and high affinity to the substrate 3,3',5,5'-tetramethylbenzidine (TMB), which is beneficial for improving peroxidase-like catalytic activity of MoS 2 . The high peroxidase-like activity of MoS 2 -GSSG NSs was applied as a robust nanoplatform for low-cost, rapid, and highly effective colorimetric detection of H 2 O 2 and total/free cholesterol. Moreover, the peroxidase-like catalytic mechanism was studied by the steady-state kinetics method. The catalytic activity was remarkably high at a wide range of pH (2.4-7.0) and temperature values (25-70 °C). The cholesterol was catalyzed by cholesterol oxidase (ChOx) in the presence of O 2 to generate H 2 O 2 , which oxidized TMB to generate a blue-colored product (oxTMB) under the catalysis of MoS 2 -GSSG NSs. The detection limit (DL) of total cholesterol and H 2 O 2 was as low as 5.36 and 0.51 μm, respectively. The linear ranges for detecting cholesterol and H 2 O 2 were from 5.36 to 800 μm and from 0.51 to 50 μm, respectively. This method was also successfully applied to the detection of cholesterol in serum. The detection concentration of total cholesterol was consistent with that of the value detected by the blood biochemical method used in the clinic., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Polycaprolactone (PCL) networks with disulfide bonds are synthesized through a thiol-ene "click" reaction. The PCL networks have various functional properties, including self-healing, shape memory, reprocessability, and degradability. Pronouncedly, a healing efficiency of 92% on the yield strength of the PCL network is obtained after heating for 1 h at 60 °C. Meanwhile, the PCL networks show shape memory property with fixing ratio (R f ) and recovery ratio (R r ) at 98% and 95%, respectively. The PCL network still retains good mechanical properties after reprocessing cycles and can be fast-decomposed through a thiol-disulfide exchange reaction., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We describe a short total synthesis of ajoene, a major biologically active constituent of garlic. The instability of allicin as the only other known alternative starting material has led to the development of a reliable procedure for the synthesis of ajoene from simple building blocks that is also suitable for upscale operations., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The synergistic effect of two anticancer drugs can significantly overcome the multidrug resistance of tumor cells and improve the drug bioavailability. Herein, two different anticancer drugs, camptothecin and chlorambucil, are successfully connected together by a disulfide linkage to get a novel drug-drug conjugated prodrug (G). Using water-soluble pillar[6]arene (WP6) as a host molecule, a supramolecular host-guest complex WP6⊃G is formed, which can further self-assemble into supramolecular vesicles in aqueous solution. In the specific microenvironment of cancer cells, the disulfide linkage is destroyed and the two anticancer drugs can be released efficiently to achieve a better synergistic effect than a single anticancer drug. Notably, these prodrug nanocarriers can not only effectively kill the cancer cells but also obviously reduce the undesirable side effects on normal cells.

The development of delivery systems for small interfering RNA (siRNA) plays a key role in its clinical application. As the major delivery systems for siRNA, cationic polymer- or lipid-based vehicles are plagued by inherent issues. As proof of concept, a disulfide bond-containing amphiphilic Janus dendrimer (ssJD), which could be conveniently synthesized and readily scaled up with high reproducibility, was explored as a siRNA delivery system to circumvent these issues. The cationic hydrophilic head of this Janus dendrimer ensured strong and stable binding with negatively charged siRNA via electrostatic interactions, and the loaded siRNA was rapidly released from the obtained complexes under a redox environment. Therefore, after efficient internalization into tumor cells, redox-sensitive dendrimersome (RSDs)/siRNA exhibited significantly improved gene silencing efficacy.

This work addresses the need for chemical tools that can selectively form cross-links. Contemporary thiol-selective cross-linkers, for example, modify all accessible thiols, but only form cross-links between a subset. The resulting terminal "dead-end" modifications of lone thiols are toxic, confound cross-linking-based studies of macromolecular structure, and are an undesired, and currently unavoidable, byproduct in polymer synthesis. Using the thiol pair of Cu/Zn-superoxide dismutase (SOD1), we demonstrated that cyclic disulfides, including the drug/nutritional supplement lipoic acid, efficiently cross-linked thiol pairs but avoided dead-end modifications. Thiolate-directed nucleophilic attack upon the cyclic disulfide resulted in thiol-disulfide exchange and ring cleavage. The resulting disulfide-tethered terminal thiolate moiety either directed the reverse reaction, releasing the cyclic disulfide, or participated in oxidative disulfide (cross-link) formation. We hypothesized, and confirmed with density functional theory (DFT) calculations, that mono- S-oxo derivatives of cyclic disulfides formed a terminal sulfenic acid upon ring cleavage that obviated the previously rate-limiting step, thiol oxidation, and accelerated the new rate-determining step, ring cleavage. Our calculations suggest that the origin of accelerated ring cleavage is improved frontier molecular orbital overlap in the thiolate-disulfide interchange transition. Five- to seven-membered cyclic thiosulfinates were synthesized and efficiently cross-linked up to 10 4 -fold faster than their cyclic disulfide precursors; functioned in the presence of biological concentrations of glutathione; and acted as cell-permeable, potent, tolerable, intracellular cross-linkers. This new class of thiol cross-linkers exhibited click-like attributes including, high yields driven by the enthalpies of disulfide and water formation, orthogonality with common functional groups, water-compatibility, and ring strain-dependence.

Gene silencing using small interfering RNA (siRNA) is a promising strategy for the treatment of multiple diseases. However, the low in vivo stability of siRNA, its poor pharmacokinetics and inability to penetrate inside cells limit its employment in the clinic. Here, we present a novel redox-sensitive micellar nanopreparation based on a triple conjugate of polyethylene glycol, polyethyleneimine and phosphatidylethanolamine, PEG-SS-PEI-PE (PSSPD). This non-toxic system efficiently condenses siRNA and specifically downregulates target green fluorescent protein (GFP) only under reducing conditions via intracellular siRNA release after de-shielding of PEG due to increased glutathione (GSH) levels characteristic of cancer cells.

The dimethyl disulfide (DMDS) adduct method is one of the more effective methods for determining double bond positions of dienoic acid. The DMDS method can be simply used to obtain the characteristic ions in which cleavage occurs between the methylthio group-added double-bond carbons as can be seen in the mass spectrum obtained using gas chromatography/electron ionization-mass spectrometry. In the case of the methylene-interrupted di-cis type and di-trans type dienoic acid, the DMDS addition reaction only occurs at one double-bond position, and cannot occur at the remaining double-bond position due to steric hindrance. As a result, two types of adducts are produced in the addition reaction. However, in the case of the methylene-interrupted mono-trans (mono-cis) type dienoic acid, the DMDS addition reaction only occurs at the cis-double bond. As a result, one type of adduct is produced in the addition reaction. In this report, we investigate the cause of the reaction selectivity by focusing on the addition reaction time., (© 2018 AOCS.)

Bicyclic peptides have been attractive scaffolds for developing high affinity reagents for biomacromolecules. Here we report a general phage-screening strategy for the development of bicyclic peptide ligands constrained with isomerically-forbidden disulfide bridges without elaborate chemical modifications and recourses to genetic code reprogramming.

Background: In our previous work, several piperazine derived bis(dialkylaminethiocarbonyl) disulfides and disulfide esters of dithiocarbamic acid have been synthesized and evaluated for their spermicidal and microbicidal efficacy. These studies have provided some promising compounds for developing a dually active vaginal microbicidal contraceptive which is under pre-clinical stage., Objective: The main objective of this study was the design synthesis and biological evaluation of bis(dialkylaminethiocarbonyl) disulfides (4-15) and 2,2'-disulfanediylbis (3-(substituted-1-yl) propane-2,1-diyl) disubstituted-1-carbodithioates (19-28) as non-surfactant molecules capable of eliminating Trichomonas vaginalis as well as irreversibly immobilizing 100% human sperm promptly., Method: Spermicidal, anti-trichomonas, cytotoxicity and biocompatibility study of the synthesized compounds was done as per the reported methodologies., Result: Among bis(dialkylaminethiocarbonyl) disulfides (4-15, Table 1), compound 4 (MEC 0.02 mM) was found to be the most desirable for spermicidal activity as it was 40 times more active than Nonoxynol-9 (N-9), and also active against Trichomonas vaginalis (MIC 0.02 &1.10 mM). 2, 2'-disulfanediylbis (3-(substituted- 1-yl) propane-2, 1-diyl) disubstituted-1-carbodithioates (19-28, Table 2), and compounds (19, 22, 23, and 24 MEC 0.05 mM) were sixteen times more active than N-9 with promising Trichomonacidal activity., Conclusion: This study suggested that the disulfide linkage alone and dithiocarbamate along with disulfide group within the same chemical entity impart the desired multiple activities of compounds., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

The worldwide outbreak of severe acute respiratory syndrome (SARS) in 2003 had caused a high rate of mortality. Main protease (M pro ) of SARS-associated coronavirus (SARS-CoV) is an important target to discover pharmaceutical compounds for the therapy of this life-threatening disease. During the course of screening new anti-SARS agents, we have identified that a series of unsymmetrical aromatic disulfides inhibited SARS-CoV M pro significantly for the first time. Herein, 40 novel unsymmetrical aromatic disulfides were synthesized chemically and their biological activities were evaluated in vitro against SARS-CoV M pro . These novel compounds displayed excellent IC 50 data in the range of 0.516-5.954 μM. Preliminary studies indicated that these disulfides are reversible and mpetitive inhibitors. A possible binding mode was generated via molecular docking simulation and a comparative field analysis (CoMFA) model was constructed to understand the structure-activity relationships. The present research therefore has provided some meaningful guidance to design and identify anti-SARS drugs with totally new chemical structures., (Copyright © 2017 Elsevier Masson SAS. All rights reserved.)

Naturally occurring, multiple cysteine-containing peptides are a structurally unique class of compounds with a wide range of therapeutic and diagnostic applications. The development of reliable, precise chemical methods for their preparation is of paramount importance to facilitate exploration of their utility. We report here a straightforward and effective approach based on stepwise, sequentially directed disulfide bond formation, exemplified by the synthesis of four-disulfide bond-containing insulin analogs. Cysteine protection consisted of tert-butylthiol (StBu), thiol-trimethoxyphenyl (STmp), trityl (Trt), 4-methoxytrityl (Mmt), S-acetamidomethyl (Acm), and tert-butyl (tBu). This report describes chemistry that is broadly applicable to cysteine-rich peptides and the influence of a fourth disulfide bond on insulin bioactivity.

The d-/l-peptide gramicidin A (gA) is well known as a pivotal ion channel model and shows a broad spectrum of bioactivities such as antibiosis, antimalarial activity, as well as hemolysis. We applied inter-chain disulfide bonds to constrain the conformational freedom of gA into parallel and antiparallel dimeric topologies. Albeit the constructs were not found to be monoconformational, CD- and IR-spectroscopic studies suggested that this strategy indeed restricted the conformational space of the d-/l-peptide construct, and that β-helical secondary structures prevail. Correlative testing of gA dimers in antimicrobial, antimalarial, and ion conduction assays suggested that the tail-to-tail antiparallel single stranded β 6.3 helix dominantly mediates the bioactivity of gA. Other conformers are unlikely to contribute to these activities. From these investigations, only weakly ion conducting gA dimers were identified that retained nM antimalarial activity., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Organic compounds possessing the -S-S- bond, often called disulfide or disulfane, are extremely important and useful in various fields. They often exhibit unique and diverse chemistry in synthetic, biochemical, pharmacological areas as well as are vastly used as vulcanizing agents for rubbers and elastomers. In peptide and protein chemistry, the disulfide bridges impart stability in folding and their synthesis is a pivotal transformation in modern medicinal chemistry research. On the other hand, microwave (MW) provides heat energy source, an alternative to conventional heating, and is used for diverse chemical reactions. This review has presented the progress towards the synthesis of small organic disulfanes and acyclic/cyclic peptides bearing the -S-S- bond specifically under microwave irradiation, which often facilitated the formation of disulfides over conventional heating both in terms of reaction time and efficiency., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

The ability to reversibly cross-link proteins and peptides grants the amino acid cysteine its unique role in nature as well as in peptide chemistry. We report a novel class of S-alkylsulfonyl-l-cysteines and N-carboxy anhydrides (NCA) thereof for peptide synthesis. The S-alkylsulfonyl group is stable against amines and thus enables its use under Fmoc chemistry conditions and the controlled polymerization of the corresponding NCAs yielding well-defined homo- as well as block co-polymers. Yet, thiols react immediately with the S-alkylsulfonyl group forming asymmetric disulfides. Therefore, we introduce the first reactive cysteine derivative for efficient and chemoselective disulfide formation in synthetic polypeptides, thus bypassing additional protective group cleavage steps., (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

A new synthetic route to human relaxin-2 has been established through a sequential disulfide bond formation process in the absence of iodine. It is enabled by a combination of cysteine protection with penicillin G acylase-labile Phacm and a newly identified thiol activator bis(5-(2-methoxyethoxy)-2-pyrimidinyl disulfide. The long-standing challenges in relaxin B-chain assembly and its poor solubility have been solved by the insertion of two isoacyl dipeptide segments. The overall yield was 25% from the B chain and 5.8% from the B-chain starting resin.