Identification of new arylsulfide derivatives as anti-melanogenic agents in a zebrafish model.

A series of aryl sulfide derivatives was synthesized and evaluated for their anti-melanogenic activities. Several compounds, including 3e, 3i and 3q exhibited good anti-melanogenic activities. Among the derivatives, compound 3i showed good inhibitory effects against melanin synthesis and showed no toxicity in reconstituted human eye and skin tissues.

A one-pot synthesis of multifunctional Bi2S3 nanoparticles and the construction of core-shell Bi2S3@Ce6-CeO2 nanocomposites for NIR-triggered phototherapy.

As a direct thin band gap n-type semiconductor, bismuth sulfide (Bi2S3) nanomaterials possess great near-infrared (NIR)-triggered photothermal effects, photoacoustic (PA) and computed tomography (CT) imaging properties. Hence, Bi2S3 nanomaterials have become a research focal point in multiple domains, such as the construction of NIR-triggered nanosystems for cancer therapy. In this study, through a simple one-pot synthesis with the assistance of EDTA-2Na, we first obtained monodispersed spherical Bi2S3 of uniform particle sizes with fascinating photothermal and PA/CT imaging properties. Based on this, we introduced the photosensitizer Ce6 with photodynamic property and CeO2 with the O2-evolving characteristic, and thus designed a core-shell structure of the Bi2S3@Ce6-CeO2 nanocomposites (Bi2S3@Ce6-CeO2 NCs). The as-received Bi2S3@Ce6-CeO2 NCs exhibited a remarkable synergetic photothermal and photodynamic therapeutic effect both in vitro and in vivo, demonstrating its promising potential for cancer treatments. In the long term, the multifunctional PA/CT properties of both Bi2S3 NPs and Bi2S3@Ce6-CeO2 NCs in this study also supply a novel Bi2S3-based platform for constructing integrated diagnosis and treatment platforms.

Facile green synthesis of bismuth sulfide radiosensitizer via biomineralization of albumin natural molecule for chemoradiation therapy aim.

High atomic number Z, nanoparticles are able to enhance the photoelectric and Compton effects under X-Ray irradiation resulting the increase of radiation therapy efficacy. To achieve enhanced radiation therapy, Bi2S3 biocompatible particles coated with bovine serum albumin (BSA) (Bi2S3@BSA HNPs) were prepared through a BSA-mediated biomineralization procedure under green conditions. Then, to achieve improved chemo-radiation therapy against HT-29 cancer cells, curcumin (CUR) as natural anti-cancer therapy agent loaded on the Bi2S3@BSA (Bi2S3@BSA@CUR HNPs). Next, this synthesized nanodrug was evaluated for physical and chemical properties and in vitro cytotoxicity studies. Here, in vitro enhanced chemo-radiation combination therapy power was evaluated against HT-29 cell line under 2 Gy and 6 Gy X-ray irradiation doses. The Bi2S3@BSA HNPs without irradiation rarely affect cell viability which shown the non-toxicity of Bi2S3@BSA HNPs. The result of this study proved that Bi2S3@BSA@CUR HNPs can be used as both proficient vehicles for effective delivery of CUR and radiosensitizer in the treatment of cancer. In addition, the result of this study confirmed that the combination of high Z-element nanoradiosensitizer, Bi2S3@BSA HNPs, with a natural anti-cancer drug, CUR, enhanced therapeutic power against HT-29 cells.

Titanocene Selenide Sulfides Revisited: Formation, Stabilities, and NMR Spectroscopic Properties.

[TiCp2S5] (phase A), [TiCp2Se5] (phase F), and five solid solutions of mixed titanocene selenide sulfides [TiCp2SexS5-x] (Cp = C5H5-) with the initial Se:S ranging from 1:4 to 4:1 (phases B⁻E) were prepared by reduction of elemental sulfur or selenium or their mixtures by lithium triethylhydridoborate in thf followed by the treatment with titanocene dichloride [TiCp2Cl2]. Their 77Se and 13C NMR spectra were recorded from the CS2 solution. The definite assignment of the 77Se NMR spectra was based on the PBE0/def2-TZVPP calculations of the 77Se chemical shifts and is supported by 13C NMR spectra of the samples. The following complexes in varying ratios were identified in the CS2 solutions of the phases B⁻E: [TiCp2Se5] (51), [TiCp2Se4S] (41), [TiCp2Se3S2] (31), [TiCp2SSe3S] (36), [TiCp2SSe2S2] (25), [TiCp2SSeS3] (12), and [TiCp2S5] (01). The disorder scheme in the chalcogen atom positions of the phases B⁻E observed upon crystal structure determinations is consistent with the spectral assignment. The enthalpies of formation calculated for all twenty [TiCp2SexS5-x] (x = 0⁻5) at DLPNO-CCSD(T)/CBS level including corrections for core-valence correlation and scalar relativistic, as well as spin-orbit coupling contributions indicated that within a given chemical composition, the isomers of most favourable enthalpy of formation were those, which were observed by 77Se and 13C NMR spectroscopy.

Synthesis, characterization, crystal structure of novel bis-thiomethylcyclohexanone derivatives and their inhibitory properties against some metabolic enzymes.

In this study, a series of novel bis-thiomethylcyclohexanone compounds (3a-3j) were synthesized by the addition of thio-Michael to the bis-chalcones under mild reaction conditions. The bis-thiomethylcyclohexanone derivatives (bis-sulfides) were characterized by 1H NMR, 13C NMR, FTIR and elemental analysis techniques. Furthermore, the molecular and crystal structures of 3h, 3i and 3j compounds were determined by single crystal X-ray diffraction studies. In this study, X-ray crystallography provided an alternative and often-complementary means for elucidating functional groups at the enzyme inhibitory site. Acetylcholinesterase (AChE) is a member of the hydrolase protein super family and has a significant role in acetylcholine-mediated neurotransmission. Here, we report the synthesis and determining of novel bis-thiomethylcyclohexanone compounds based hybrid scaffold of AChE inhibitors. The newly synthesized bis-thiomethylcyclohexanone compounds showed Ki values of in range of 39.14-183.23 nM against human carbonic anhydrase I isoenzyme (hCA I), 46.03-194.02 nM against human carbonic anhydrase II isoenzyme (hCA II), 4.55-32.64 nM against AChE and 12.77-37.38 nM against butyrylcholinesterase (BChE). As a result, novel bis-thiomethylcyclohexanone compounds can have promising anti Alzheimer drug potential and record novel hCA I, and hCA II enzymes inhibitor.

Light controllable chitosan micelles with ROS generation and essential oil release for the treatment of bacterial biofilm.

Bacterial biofilms are widely associated with persistent infections and food contamination. High resistance to conventional antimicrobial agents resulted in an urgent need for novel formulation to eliminate these bacterial communities. Herein we fabricated light controllable chitosan micelles loading with thymol (T-TCP) for elimination of biofilm. Due to the exterior chitosan, T-TCP micelles easily bind to negative biofilm through electrostatic interaction and efficiently deliver the essential oil payloads. Under irradiation, T-TCP micelles generated ROS, which triggered simultaneous thymol release and also resulted in additional ROS-inducing bactericidal effects, both effectively eradicating biofilms of Listeria monocytogenes and Staphylococcus aureus. This formulation provided a platform for other water-insoluble antimicrobials and might be used as a potent and controllable solution to biofilm fighting.

Fabrication of PEGylated Fe@Bi2S3 nanocomposites for dual-mode imaging and synergistic thermoradiotherapy.

Nanocomposites for integrating imaging and therapy have attracted tremendous attention for biomedical applications. Herein, Fe@Bi2S3 nanocomposites modified with polyethylene glycol (PEG) molecules are fabricated for synergistic thermoradiotherapy. For such nanocomposites, Bi2S3 exhibits a strong absorbance in the near-infrared (NIR) region, which allows Bi2S3 to convert energy from light into heat for effective photothermal therapy (PTT), whereas Bi can also significantly enhance radio-mediated cell death induction as a radiotherapy sensitizer due to its high atomic number (high-Z). Most importantly, it is found that the combination of PTT and radiation therapy (RT), using PEGylated Fe@Bi2S3 nanocomposites, can bring a strong synergistic effect for the tumor treatment in in vitro and in vivo experiments. Besides, the magnetic Fe core and the Bi2S3 shell components endow this nanocomposite with an ability to serve as both a magnetic resonance imaging (MRI) and computed tomography (CT) contrast agent. Therefore, our work presents a new type of multifunctional nanocomposite with the potential for synergistic thermoradiotherapy and simultaneously MRI/CT imaging.

Colloidal synthesis of biocompatible iron disulphide nanocrystals.

The aim of this research was to synthesis biocompatible iron disulphide nanocrystals at different reaction temperatures using the colloidal synthesis methodology. Synthesis was conducted at the 220-240 °C range of reaction temperatures at intervals of 5 °C in an inert argon atmosphere. The toxicity of iron disulphide nanocrystals was evaluated in vitro using mouse fibroblast cell line. Two complementary assays were conducted: the first to evaluate cell viability of the fibroblast via an MTT assay and the second to determine the preservation of fibroblast nuclei integrity through DAPI staining, which labels nuclear DNA in fluorescence microscopes. Through TEM and HRTEM, we observed a cubic morphology of pyrite iron disulphide nanocrystals ranging in sizes 25-50 nm (225 °C), 50-70 nm (230 °C) and >70 nm (235 °C). Through X-ray diffraction, we observed a mixture of pyrite and pyrrohotite in the samples synthesized at 225 °C and 240 °C, showing the best photocatalytic activity at 80% and 65%, respectively, for the degradation of methylene blue after 120 minutes. In all experimental groups, iron disulphide nanocrystals were biocompatible, i.e. no statistically significant differences were observed between experimental groups as shown in a one-way ANOVA and Tukey's test. Based on all of these results, we recommend non-cytotoxic semiconductor iron sulphide nanocrystals for biomedical applications.

Facile Preparation of 4-Substituted Quinazoline Derivatives.

Reported in this paper is a very simple method for direct preparation of 4-substituted quinazoline derivatives from a reaction between substituted 2-aminobenzophenones and thiourea in the presence of dimethyl sulfoxide (DMSO). This is a unique complementary reaction system in which thiourea undergoes thermal decomposition to form carbodiimide and hydrogen sulfide, where the former reacts with 2-aminobenzophenone to form 4-phenylquinazolin-2(1H)-imine intermediate, whilst hydrogen sulfide reacts with DMSO to give methanethiol or other sulfur-containing molecule which then functions as a complementary reducing agent to reduce 4-phenylquinazolin-2(1H)-imine intermediate into 4-phenyl-1,2-dihydroquinazolin-2-amine. Subsequently, the elimination of ammonia from 4-phenyl-1,2-dihydroquinazolin-2-amine affords substituted quinazoline derivative. This reaction usually gives quinazoline derivative as a single product arising from 2-aminobenzophenone as monitored by GC/MS analysis, along with small amount of sulfur-containing molecules such as dimethyl disulfide, dimethyl trisulfide, etc. The reaction usually completes in 4-6 hr at 160 ºC in small scale but may last over 24 hr when carried out in large scale. The reaction product can be easily purified by means of washing off DMSO with water followed by column chromatography or thin layer chromatography.

Facile synthesis of CdTe@GdS fluorescent-magnetic nanoparticles for tumor-targeted dual-modal imaging.

Multimodal imaging has made great contribution for diagnosis and therapy of disease since it can provide more effective and complementary information in comparison to any single imaging modality. The design and fabrication of fluorescent-magnetic nanoparticles for multimodal imaging has rapidly developed over the years. Herein, we demonstrate the facile synthesis of GdS coated CdTe nanoparticles (CdTe@GdS NPs) as multimodal agents for fluorescence (FL) and T1-weighted magnetic resonance (MR) imaging. These nanoparticles obtain both prominent fluorescent and paramagnetic properties by coating the GdS shell on the surface of CdTe core via a simple room-temperature route in aqueous solution directly. It is shown that the as-prepared CdTe@GdS NPs have high quantum yield (QY) value of 12% and outstanding longitudinal relaxation rate (r1) of 11.25 mM s(-1), which allow them to be employed as FL/MR dual-modal imaging contrast agents. They also exhibit small particle size of 5 nm, excellent colloidal stability and low cellular toxicity for concentrations up to 750 µg mL(-1). In addition, with the conjugation of folic acid, the nanoparticles were successfully used for tumor-targeted FL/MR dual-modal imaging in vitro and in vivo.

Medicinal Chemistry: Insights into the Development of Novel H2S Donors.

Hydrogen sulfide (H2S) was traditionally considered as a toxic gas. However, recent studies have demonstrated H2S is an endogenously generated gaseous signaling molecule (gasotransmitter) with importance on par with that of two other well-known endogenous gasotransmitters, nitric oxide (NO) and carbon monoxide (CO). Although H2S's exact mechanisms of action are still under investigation, the production of endogenous H2S and the exogenous administration of H2S have been demonstrated to elicit a wide range of physiological responses including modulation of blood pressure and protection of ischemia reperfusion injury, exertion of anti-inflammatory effects, and reduction of metabolic rate. These results strongly suggest that modulation of H2S levels could have potential therapeutic values. In this regard, synthetic H2S-releasing agents (i.e., H2S donors) are not only important research tools, but also potential therapeutic agents. This chapter summarizes the knowledge of currently available H2S donors. Their preparation, H2S releasing mechanisms, and biological applications are discussed.

Design of a selenylsulfide-bridged EGFR dimerization arm mimic.

The epidermal growth factor receptor (EGFR) dimerization arm is a key feature that stabilizes dimerization of the extracellular receptor, thereby mediating activation of the tyrosine kinase domain. Peptides mimicking this ß-loop feature can disrupt dimer formation and kinase activation, yet these peptides lack structural constraints or contain redox sensitive disulfide bonds which may limit their stability in physiological environments. Selenylsulfide bonds are a promising alternative to disulfide bonds as they maintain much of the same structural and chemical behavior, yet they are inherently less prone to reduction. Herein, we describe the synthesis, stability and activity of selenylsulfide-bridged dimerization arm mimics. The synthesis was accomplished using an Fmoc-based strategy along with C-terminal labeling for improved overall yield. This selenylsulfide-bridged peptide displayed both proteolytic stability and structural stability even under reducing conditions, demonstrating the potential application of the selenylsulfide bond to generate redox stable ß-loop peptides for disruption of protein-protein interactions.

ROS-responsive microspheres for on demand antioxidant therapy in a model of diabetic peripheral arterial disease.

A new microparticle-based delivery system was synthesized from reactive oxygen species (ROS)-responsive poly(propylene sulfide) (PPS) and tested for "on demand" antioxidant therapy. PPS is hydrophobic but undergoes a phase change to become hydrophilic upon oxidation and thus provides a useful platform for ROS-demanded drug release. This platform was tested for delivery of the promising anti-inflammatory and antioxidant therapeutic molecule curcumin, which is currently limited in use in its free form due to poor pharmacokinetic properties. PPS microspheres efficiently encapsulated curcumin through oil-in-water emulsion and provided sustained, on demand release that was modulated in vitro by hydrogen peroxide concentration. The cytocompatible, curcumin-loaded microspheres preferentially targeted and scavenged intracellular ROS in activated macrophages, reduced in vitro cell death in the presence of cytotoxic levels of ROS, and decreased tissue-level ROS in vivo in the diabetic mouse hind limb ischemia model of peripheral arterial disease. Interestingly, due to the ROS scavenging behavior of PPS, the blank microparticles also showed inherent therapeutic properties that were synergistic with the effects of curcumin in these assays. Functionally, local delivery of curcumin-PPS microspheres accelerated recovery from hind limb ischemia in diabetic mice, as demonstrated using non-invasive imaging techniques. This work demonstrates the potential for PPS microspheres as a generalizable vehicle for ROS-demanded drug release and establishes the utility of this platform for improving local curcumin bioavailability for treatment of chronic inflammatory diseases.

Fabrication, characterization, and application of greigite nanoparticles for cancer hyperthermia.

Greigite is a Fe-S-containing complex having magnetic properties mainly synthesized in the solution. In the present study, greigite was synthesized by a coprecipitation method at different pH's and reaction times. The greigite phase was analyzed by the X-ray diffraction (XRD) method at an optimum pH of 3.0 and reaction time of 10 min, respectively. The magnetization characterization by superconducting quantum interference device (SQUID) revealed that the magnetic saturation was obtained at 16.1538 (emu/g). The inductive heating property of the greigite nanoparticles was carried out by induction heater power cube (IHPC) in an alternating current magnetic field and the results indicated that the heating effect was significant. Transmission electron microscopy (TEM) revealed that the size of the greigite was around 50-100 nm and the edges of nanoparticles have no clear boundary or distinctive morphology. Studies on LDH and WST-I assay revealed low cytotoxicity at greigite concentrations of 1 mg/ml. In vitro experiments suggested that cancerous cells, human lung adenocarcinoma epithelial cell line (A549), had the ability to become more damaged under AC magnetic field than the normal human lung cells (HFL-1).

Enzymatic- and temperature-sensitive controlled release of ultrasmall superparamagnetic iron oxides (USPIOs).

BACKGROUND: Drug and contrast agent delivery systems that achieve controlled release in the presence of enzymatic activity are becoming increasingly important, as enzymatic activity is a hallmark of a wide array of diseases, including cancer and atherosclerosis. Here, we have synthesized clusters of ultrasmall superparamagnetic iron oxides (USPIOs) that sense enzymatic activity for applications in magnetic resonance imaging (MRI). To achieve this goal, we utilize amphiphilic poly(propylene sulfide)-bl-poly(ethylene glycol) (PPS-b-PEG) copolymers, which are known to have excellent properties for smart delivery of drug and siRNA. RESULTS: Monodisperse PPS polymers were synthesized by anionic ring opening polymerization of propylene sulfide, and were sequentially reacted with commercially available heterobifunctional PEG reagents and then ssDNA sequences to fashion biofunctional PPS-bl-PEG copolymers. They were then combined with hydrophobic 12 nm USPIO cores in the thin-film hydration method to produce ssDNA-displaying USPIO micelles. Micelle populations displaying complementary ssDNA sequences were mixed to induce crosslinking of the USPIO micelles. By design, these crosslinking sequences contained an EcoRV cleavage site. Treatment of the clusters with EcoRV results in a loss of R2 negative contrast in the system. Further, the USPIO clusters demonstrate temperature sensitivity as evidenced by their reversible dispersion at ~75°C and re-clustering following return to room temperature. CONCLUSIONS: This work demonstrates proof of concept of an enzymatically-actuatable and thermoresponsive system for dynamic biosensing applications. The platform exhibits controlled release of nanoparticles leading to changes in magnetic relaxation, enabling detection of enzymatic activity. Further, the presented functionalization scheme extends the scope of potential applications for PPS-b-PEG. Combined with previous findings using this polymer platform that demonstrate controlled drug release in oxidative environments, smart theranostic applications combining drug delivery with imaging of platform localization are within reach. The modular design of these USPIO nanoclusters enables future development of platforms for imaging and drug delivery targeted towards proteolytic activity in tumors and in advanced atherosclerotic plaques.

Antiproliferative effect of natural tetrasulfides in human breast cancer cells is mediated through the inhibition of the cell division cycle 25 phosphatases.

For many years, in vitro and in vivo studies have reported that organosulfur compounds (OSCs), naturally found in Allium vegetables, are able to suppress the proliferation of various tumor cells. In spite of recent advances, the specific molecular mechanisms involved in OSC activity are still unclear. Considering the antiproliferative effects observed in cancer cells, we postulated that OSCs might target the cell division cycle (Cdc) 25 phosphatases which are crucial enzymes of the cell cycle. Our findings suggest phosphatases Cdc25 as possible targets of naturally occuring polysulfides contributing to their anticancer properties. We report on the inhibitory activity of tetrasulfides occurring naturally in garlic and onion towards the human Cdc25 phosphatases. Diallyl- and dipropyltetrasulfides have emerged as interesting irreversible inhibitors of the Cdc25 isoforms A and C in vitro. Furthermore, growth of both sensitive (MCF-7) and resistant (Vcr-R) human breast carcinoma cells was significantly decreased by these tetrasulfides. The observed antiproliferative effect appeared to be associated with a G2-M cell cycle arrest.

Coactivity of sulfide ingredients: a new perspective of the larvicidal activity of garlic essential oil against mosquitoes.

BACKGROUND: The activity of several garlic oil ingredients against Culex pipiens L. larvae was studied. In addition to diallyl sulfide (DS) and diallyl disulfide (DDS), the garlic oils used included one essential oil (EO) and two semi-synthetic garlic essential oils (SSGEO1 and SSGEO2), which resulted from the enrichment of EO with DS and DDS standards respectively. The oils were compared with respect to their toxicity. RESULTS: The chemical composition of the tested oils was evaluated by means of gas chromatography-mass spectrometry. Experimental data from the tested samples revealed high toxicity. In detail, DDS (6.09 mg L(-1)) was the most active, followed by SSGEO2 (7.05 mg L(-1)) and EO (8.01 mg L(-1)), while SSGEO1 and DS were relatively inactive. CONCLUSION: The addition of DDS to EO did not change the toxic effect of the essential oil, whereas the presence of DS in excess produced an enriched essential oil with low toxicity. Furthermore, the antagonistic effect of DS and DDS against the other components of EO was shown by the application of two equations obtained from the literature. Their larvicidal performances were correlated, for the first time, with their detailed chemical composition. Data analysis strongly indicated the toxicity of the other EO sulfur ingredients.

Novel synthesis and pharmacological evaluation as alpha2-adrenoceptor ligands of O-phenylisouronium salts.

The synthesis of nine new mono- and bis-O-phenylisouronium compounds (2, 6b-10b and 12b-14b) and their Boc-protected isourea precursors (2a, 6a-10a and 12a-14a) is described. The carbodiimide 4, which was formed, had been suggested as the reactive intermediate species and driving force of the reaction. All final substrates were tested as potential alpha(2)-ARs ligands in human brain tissue by means of radioligand binding experiments and were compared to the potential antidepressant 1, as well as other related guanidine containing derivatives.

Synthesis and biological activity of a novel inhibitor of dihydroceramide desaturase.

A novel mechanism-based dihydroceramide desaturase inhibitor (XM462) in which the substrate C5 methylene group is replaced by a sulfur atom is reported. Dihydroceramide desaturase inhibition occurred both in vitro and in cultured cells with IC(50) values of 8.2 and 0.78 microM, respectively, at a substrate concentration of 10 microM. In vitro experiments showed that XM462 produced a mixed-type inhibition (K(i)=2 microM, alpha=0.83). LC-MS analyses showed that accumulation of endogenous dihydroceramides occurred in cells upon treatment with XM462 in serum-free medium, whereas ceramides built up in controls. In addition, XM462 was found to be metabolised to its 1-glucosyl and 1-phosphocholine derivatives, and to the products of N-deacylation and reacylation with palmitoyl and stearoyl groups. In Jurkat A3 cells cultured in serum-free medium, viability, as the percentage of trypan blue unstained cells in total cells, was reduced upon XM462 treatment (5 microM, 24 h), but not in controls. The interest of this compound is discussed.