Switching on prodrugs using radiotherapy.

Chemotherapy is a powerful tool in the armoury against cancer, but it is fraught with problems due to its global systemic toxicity. Here we report the proof of concept of a chemistry-based strategy, whereby gamma/X-ray irradiation mediates the activation of a cancer prodrug, thereby enabling simultaneous chemo-radiotherapy with radiotherapy locally activating a prodrug. In an initial demonstration, we show the activation of a fluorescent probe using this approach. Expanding on this, we show how sulfonyl azide- and phenyl azide-caged prodrugs of pazopanib and doxorubicin can be liberated using clinically relevant doses of ionizing radiation. This strategy is different to conventional chemo-radiotherapy radiation, where chemo-sensitization of the cancer takes place so that subsequent radiotherapy is more effective. This approach could enable site-directed chemotherapy, rather than systemic chemotherapy, with 'real time' drug decaging at the tumour site. As such, it opens up a new era in targeted and directed chemotherapy.

A fast responsive chromogenic and near-infrared fluorescence lighting-up probe for visual detection of toxic thiophenol in environmental water and living cells.

Thiophenols as high toxic environmental pollutants are poisonous for animals and aquatic organisms. Therefore, it is indispensable to monitor thiophenols in the environment. Herein, a novel near-infrared fluorescent probe was developed for the detection of thiophenols, which was easily prepared by one-step coupling of 2,4-dinitrobenzenesulfonyl chloride with Nile blue. The probe showed a significant near infrared (∼675 nm) fluorescence "turn-on" response to thiophenols with some good features including chromogenic reaction, high sensitivity and selectivity, fast response, near-infrared emission along with low detection limit (1.8 nM). The probe was employed to rapidly and visually determine thiophenols in several industrial wastewaters with good recoveries (90-110%). Moreover, this probe has been demonstrated good capability for imaging thiophenol in HeLa cells.

Photodegradation of fluazaindolizine in water under simulated sunlight irradiation: Identification of transformation products and elucidation of transformation mechanism.

The photodegradation of fluazaindolizine in water was investigated under simulated sunlight irradiation. The effects of solution pH, humic acids (HA), nitrates (NO3-) and Fe(III) ions on photolysis of fluazaindolizine were studied. The results indicated that pH did not significantly affect its photodegradation. At low concentration (up to 5 mg/L), HA slightly facilitated the photodegradation of fluazaindolizine, while at high concentration (10-20 mg/L), HA inhibited its photodegradation. The presence of NO3- (0-10 mg/L) and Fe(III) (0-5 mg/L) noticeably accelerated the photodegradation of fluazaindolizine. Moreover, eleven direct transformation products (TPs) were isolated and identified by liquid chromatography quadrupole time-of-flight mass spectrometry. Density functional theory (DFT) calculation was utilized to characterize molecular property of fluazaindolizine and predict the potentiality of the possible photodegradation reaction. Ultimately, a possible transformation mechanism was proposed based on the identified TPs, degradation profiles and DFT calculation. The predominant photoproduct came from ring opening of imidazole-ring and dechlorination. Other TPs resulted from a series of photochemical reactions involving hydroxyl substitution, ring-opening, cleavage, oxidation and decarboxylation. These results were important in elucidating environmental fate of fluazaindolizine in aquatic system and further environmental risk assessment.

Two-photon imaging of the endoplasmic reticulum thiol flux in the brains of mice with depression phenotypes.

Depression is a common mental illness with high morbidity and mortality. Mounting evidence suggests that an imbalance of the oxidant-antioxidant defence system is strongly correlated with depression and the dysfunction of the endoplasmic reticulum (ER) is strongly related to the oxidative stress. Therefore, as vital and abundant antioxidants in the ER, biothiols may contribute to the etiology of depression. However, ideal two-photon (TP) fluorescent probes for in vivo imaging of ER-associated thiols in the brains of mice with depression phenotypes are still lacking. Hence, we describe a fluorescent probe (ER-SH) to visualize thiols in living systems. ER-SH displays high sensitivity, excellent ER-targeting ability, outstanding TP properties and low cytotoxicity. Using this ER-SH probe, we succeeded in revealing an increase in the endogenous thiol levels under ER stress induced by DTT. Significantly, TP in vivo imaging showed for the first time that the thiol levels are reduced in brains of mice with depression phenotypes. Collectively, this work can assist in further understanding the molecular mechanism of depression and offers a crucial dimension for diagnosis and anti-depression treatments.

Photodynamic therapy with redaporfin targets the endoplasmic reticulum and Golgi apparatus.

Preclinical evidence depicts the capacity of redaporfin (Redp) to act as potent photosensitizer, causing direct antineoplastic effects as well as indirect immune-dependent destruction of malignant lesions. Here, we investigated the mechanisms through which photodynamic therapy (PDT) with redaporfin kills cancer cells. Subcellular localization and fractionation studies based on the physicochemical properties of redaporfin revealed its selective tropism for the endoplasmic reticulum (ER) and the Golgi apparatus (GA). When activated, redaporfin caused rapid reactive oxygen species-dependent perturbation of ER/GA compartments, coupled to ER stress and an inhibition of the GA-dependent secretory pathway. This led to a general inhibition of protein secretion by PDT-treated cancer cells. The ER/GA play a role upstream of mitochondria in the lethal signaling pathway triggered by redaporfin-based PDT Pharmacological perturbation of GA function or homeostasis reduces mitochondrial permeabilization. In contrast, removal of the pro-apoptotic multidomain proteins BAX and BAK or pretreatment with protease inhibitors reduced cell killing, yet left the GA perturbation unaffected. Altogether, these results point to the capacity of redaporfin to kill tumor cells via destroying ER/GA function.

Optimization of nimesulide oxidation via a UV-ABC/H2O2 treatment process: Degradation products, ecotoxicological effects, and their dependence on the water matrix.

Nimesulide (Nim) degradation in ultrapure water (UW) and municipal sewage (MS) via UV-ABC/H2O2 was investigated. The variables included in the experimental design were time, initial Nim, and initial H2O2 concentrations. Resulting decreases in Nim concentration (monitored by high performance liquid chromatography (HPLC) using a photodiode array detector operating at a maximum UV absorbance of 300 nm), mineralization (from total organic carbon (TOC) measurements), and ecotoxicity (assays employing the bioindicators Daphnia similis, Artemia salina, and Allium cepa) were also studied. Degradation rates of 90% or higher were found for 15-20 min reaction times, employing combinations of [H2O2] = 50-150 mg L-1 and [Nim] = 8.5-15 mg L-1 prepared with MS. Mineralization rates of 70% and higher were attained within 60 min of reaction for [Nim] = 15 mg L-1 prepared in MS with [H2O2] = 100 mg L-1. Nim by-products were detected and possible degradation pathways proposed. Ecotoxicity evaluation using A. salina, D. similis, and A. cepa revealed that the treated samples had significantly lower toxicity. Exposure to treated samples resulted in survival rates of 79% for A. salina and over 90% for D. similis. No root growth inhibition was observed in A. cepa exposed to treated samples, whereas exposure to untreated samples inhibited root growth by 60%. Statistical analysis revealed elimination of cytotoxicity and reduction of genotoxicity against A. cepa. The results showed that the UV-ABC/H2O2 process can be employed as a pre- or post-treatment method to remove Nim from contaminated wastewater.

Unexpected Photo-instability of 2,6-Sulfonamide-Substituted BODIPYs and Its Application to Caged GABA.

Investigation of the unexpected photo-instability of 2,6-sulfonamide-substituted derivatives of the boron dipyrromethene (BODIPY) fluorophore led to the discovery of a photoreaction accompanied by multiple bond scissions. We characterized the photoproducts and utilized the photoreaction to design a caged γ-aminobutyric acid (GABA) derivative that can release GABA upon irradiation in the visible range (>450 nm). This allowed us to stimulate neural cells in mouse brain slices.

Enhanced Photocatalytic Activity of as-Prepared Sodium Titanates for m-Dinitrobenzene Reduction and Sulfosulfuron Oxidation.

This paper demonstrates the preparation and photocatalytic activity of sodium titanate nanorods and nanotubes prepared by hydrothermal method using P25-TiO2 as the precursor. XRD results confirmed the monoclinic structure of sodium titanate nanorods obtained after calcinations of orthorhombic sodium titanate nanotubes at 800 °C for 2 h. The BET surface area of sodium titanate nanotubes (176 m2 g-1) was significantly reduced for sodium titanate nanorods (21 m2 g-1) formation because of the collapsing of the hollow interior of the former during its high temperature sintering. The selective formation of m-diaminobenzene by the photoreduction of the m-dinitrobenzene was found to be comparable by sodium titanate nanorods (89.5 ± 0.5%) and P25-TiO2 (98.2 ± 0.8%), whereas Au-deposition (0.5 and 2 wt%) onto sodium titanate nanorods notably altered the products (m-nitroaniline and m-diaminobenzene) distribution after 8 h of UV-light irradiation and which was confirmed later by GC-MS analysis. This high photoactivity of as-prepared nanorods could be credited to better delocalization and longer relaxation lifetime (68 µs) of photoexcited e-/h+ pairs along the length of crystalline sodium titanate nanorods than P25-TiO2 (45 µs) as measured from Time-resolved spectroscopy. The photooxidation of sulfosulfuron herbicide (1000 ppm) and corresponding CO2 formation was found to be highest with sodium titanate nanotubes due to the presence of more hydroxyl groups over the largest surface area that dominates over its least relaxation lifetime (41 µs).

Mechanistic QSAR models for interpreting degradation rates of sulfonamides in UV-photocatalysis systems.

Photocatalysis is one of the most effective methods for treating antibiotic wastewater. Thus, it is of great significance to determine the relationship between degradation rates and structural characteristics of antibiotics in photocatalysis processes. In the present study, the photocatalytic degradation characteristics of 10 sulfonamides (SAs) were studied using two photocatalytic systems composed of nanophase titanium dioxide (nTiO2) plus ultraviolet (UV) and nTiO2/activated carbon fiber (ACF) plus UV. The results indicated that the largest apparent SA degradation rate constant (Kapp) is approximately 5 times as large as that of the smallest one. Based on the degradation mechanism and the partial least squares regression (PLS) method, optimum Quantitative Structure Activity Relationship (QSAR) models were developed for the two systems. Mechanistic models indicated that the degradation rule of SAs in the TiO2 systems strongly relates to their highest occupied molecular orbital (Ehomo), the maximum values of nucleophilic attack (f(+)x), and the minimum values of the most negative partial charge on a main-chain atom (q(C)min), whereas the maximum values of OH radical attack (f(0)x) and the apparent adsorption rate constant values (kad) are key factors affecting the degradation rule of SAs in the TiO2/ACF system.

Simultaneous determination of sulfonamides and metabolites in manure samples by one-step ultrasound/microwave-assisted solid-liquid-solid dispersive extraction and liquid chromatography-mass spectrometry.

An in-line matrix cleanup method was used for the simultaneous extraction of 15 sulfonamides and two metabolites from manure samples. The ultrasound/microwave-assisted extraction (UMAE) combined with solid-liquid-solid dispersive extraction (SLSDE) procedure provides a simple sample preparation approach for the processing of manure samples, in which the extraction and cleanup are integrated into one step. Ultrasonic irradiation power, extraction temperature, extraction time, and extraction solvent, which could influence the UMAE efficiency, were investigated. C18 was used as the adsorbent to reduce the effects of interfering components during the extraction procedure. The extracts were concentrated, and the analytes were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) without any further cleanup. The isotopically labeled compounds sulfamethoxazole-d 4, sulfamethazine-d 4, sulfamonomethoxine-d 4, and sulfadimethoxine-d 6 were selected as internal standards to minimize the matrix effect in this method. The recoveries of the antibiotics tested ranged from 71 to 118 % at the three spiking levels examined (20, 200, and 500 µg · kg(-1)). The limits of detections were 1.2-3.6 µg · kg(-1) and the limits of quantification were 4.0-12.3 µg · kg(-1) for the sulfonamides and their metabolites. The applicability of the method was demonstrated by analyzing 30 commercial manure samples. The results indicated that UMAE-SLSDE combined with LC-MS/MS is a simple, rapid, and environmentally friendly method for the analysis of sulfonamides and their metabolites in manure, and it could provide the basis for a risk assessment of the antibiotics in agricultural environments.

Characterization of vemurafenib phototoxicity in a mouse model.

Vemurafenib is a first-in-class, small molecule B-Raf kinase inhibitor for the treatment of patients with unresectable or metastatic melanoma carrying the BRAFV600E mutation, commercially available since 2011. A general phototoxic potential was identified early during development; however, based on results of an animal study in hairless rats, it was concluded that there would exist no relevant risk for humans. Surprisingly, signs of clinical photosensitivity were reported in many patients during clinical development. Therefore, it became a fundamental question to understand this discrepancy. An established mouse model (oral UV-Local Lymph Node Assay, UV-LLNA) for the assessment of in vivo photosafety was used to investigate the impact of formulations, dose levels, duration of treatment, and timing of irradiation. Moreover, a basic pharmacokinetic profile was established within the same mouse strain. We were able to demonstrate dose- and time-dependent phototoxicity of vemurafenib using commercially available tablets (stabilized amorphous material). The lowest phototoxic dose was 350 mg/kg administrated for 3 consecutive days followed by exposure to UV-visible irradiation at a UVA-normalized dose of 10 J/cm². In comparison, pure vemurafenib, which easily forms crystalline variants and is known to have poor bioavailability, was tested at 350 mg/kg, and no signs of phototoxicity could be seen. The most apparent difference between the early study in hairless rats and this study in mice was the spectral range of the irradiation light source (350-400 nm vs 320-700 nm). Because vemurafenib does not absorb sufficiently light above 350 nm, this difference can easily explain the negative earlier study result in hairless rats.

Acoustic-like dynamics of amorphous drugs in the THz regime.

The high frequency dynamics of Indomethacin and Celecoxib glasses has been investigated by inelastic x-ray scattering, accessing a momentum-energy region still unexplored in amorphous pharmaceuticals. We find evidence of phonon-like acoustic dynamics, and determine the THz behavior of sound velocity and acoustic attenuation. Connections with ordinary sound propagation are discussed, along with the relation between fast and slow degrees of freedom as represented by non-ergodicity factor and kinetic fragility, respectively.

Potential phototoxicity of rosuvastatin mediated by its dihydrophenanthrene-like photoproduct.

In this work, rosuvastatin has been used to gain insight into the molecular basis of statin photosensitization. This lipid-lowering drug, also known as "superstatin", contains a 2-vinylbiphenyl-like moiety and has been previously described to decompose under solar irradiation, yielding stable dihydrophenanthrene analogues. During photophysical characterization of rosuvastatin, only a long-lived transient at ca. 550 nm was observed and assigned to the primary photocyclization intermediate. Thus, the absence of detectable triplet-triplet absorption and the low yield of fluorescence rules out the role of the parent drug as an efficient sensitizer. In this context, the attention has been placed on the rosuvastatin main photoproduct (ppRSV). Indeed, the photobehavior of this dihydrophenanthrene-like compound presents the essential components needed for an efficient biomolecule photosensitizer i.e. (i) a high intersystem crossing quantum yield (Φ(ISC) = 0.8), (ii) a triplet excited state energy of ca. 67 kcal mol(-1), and (iii) a quantum yield of singlet oxygen formation (Φ(Δ)) of 0.3. Furthermore, laser flash photolysis studies revealed a triplet-triplet energy transfer from the triplet excited state of ppRSV to thymidine, leading to the formation of cyclobutane thymidine dimers, an important type of DNA lesion. Finally, tryptophan has been used as a probe to investigate the type I and/or type II character of ppRSV-mediated oxidation. In this way, both an electron transfer process giving rise to the tryptophanyl radical and a singlet oxygen mediated oxidation were observed. On the basis of the obtained results, rosuvastatin, through its major photoproduct ppRSV, should be considered as a potential sensitizer.

Photodegradation of the herbicide azimsulfuron using nanocrystalline titania films as photocatalyst and low intensity Black Light radiation or simulated solar radiation as excitation source.

Aqueous solutions of the herbicide azimsulfuron have been treated by a photocatalytic process employing titania nanocrystalline films as photocatalyst. Results showed that solutions of this herbicide at maximum possible concentration can be photodegraded in a time of a few hours by using low intensity UVA radiation comparable with that of the UVA of solar noon. Similar results have also been obtained with simulated solar radiation. Thus heterogeneous photocatalysis can be employed for the treatment of waters polluted by this herbicide.

An easy microwave-assisted synthesis of sulfonamides directly from sulfonic acids.

An easy and handy synthesis of sulfonamides directly from sulfonic acids or its sodium salts is reported. The reaction is performed under microwave irradiation, has shown a good functional group tolerance, and is high yielding.

Novel 3-sulphonamido-quinazolin-4(3H)-one derivatives: microwave-assisted synthesis and evaluation of antiviral activities against respiratory and biodefense viruses.

We designed and synthesized novel 2,3-disubstituted quinazolin-4(3H)-ones by microwave technique and characterized them by spectral analysis. Synthesized compounds were screened for cytotoxicity and for antiviral activity against influenza A (H1N1, H3N2 and H5N1), severe acute respiratory syndrome corona, dengue, yellow fever, Venezuelan equine encephalitis (VEE), Rift Valley fever, and Tacaribe viruses in cell culture. A neutral red uptake assay was used to determine 50% virus-inhibitory concentrations (EC50) of test compounds and their 50% cytotoxicity concentration (CC50) in uninfected Madin-Darby canine kidney, Vero, and Vero 76 cells; selectivity indices (ratio of CC50 to EC50) were derived from the data. The compound 4-(6,8-dibromo-4-oxo-2-phenyl quinazolin-3(4H)-yl)-N-(4,5-dimethyloxazol-2yl) benzenesulphonamide 15 inhibited the replication of avian influenza (H5N1) virus (EC50 = 8.4 microg/ml, CC50 > 100 microg/ml, SI > 11.9) as did 4-(6-bromo-4oxo-2phenylquinazolin-3(4H)-yl) benzene]sulphonamide 5 (EC50 = 3 microg/ml, CC50 = 32 microg/ml, SI = 11). Compound 5 was also moderately active against VEE and Tacaribe viruses. The methodology described in this report is applicable for rapid synthesis of many compounds with potential antiviral properties.

Oxidation of sulfamethoxazole and related antimicrobial agents by TiO2 photocatalysis.

The widespread detection of pharmaceutically active compounds, including many synthetic antimicrobial agents, in aquatic environments is raising public health concerns. As a result, there is growing interest in the development of innovative technologies to efficiently transform these compounds to non-toxic and pharmaceutically inactive byproducts. This work examines the photocatalytic degradation of sulfamethoxazole (SMX) and related sulfonamide antimicrobial agents in aqueous suspensions of nanophase titanium dioxide (TiO(2)). Experimental results demonstrate that SMX is mineralized by TiO(2) irradiated with ultraviolet-A light (UVA: 324<

Photodegradation of penoxsulam.

This study was carried out to characterize the photodegradation of penoxsulam and to evaluate the significance of photolysis for its fate and dissipation. Degradation studies of (14)C-labeled isotopes of penoxsulam in a "merry-go-round" reactor suggest that aqueous photodegradation proceeds via three possible pathways: cleavage of the sulfonamide bridge, stepwise degradation of the triazolopyrimidine system and its substituents, and photooxidation of the sulfonyl group. Seven major photoproducts were found, and six were identified. Two of the identified photodegradation products seem to be either rapidly biodegraded when formed or not formed in significant amounts in environmental conditions.

Development of HPLC/ESI-MS and HPLC/1H NMR methods for the identification of photocatalytic degradation products of iodosulfuron.

In the present study, HPLC/ESI-MS and stopped-flow HPLC/1H NMR methods were developed and applied to separate and characterize the byproducts arising from TiO2-catalyzed photodegradation of the herbicide iodosulfuron methyl ester (IOME) in aqueous solution under UV irradiation. Prior to identification, irradiated solutions of IOME (200 and 1000 mg.L(-1)) were concentrated by solid-phase extraction using two cartridges: Isolute C18 and Isolute ENV+. Analytical separation was achieved on a C18 reversed-phase column with ACN/H2O (HPLC/MS) or ACN/D2O (HPLC/NMR) as mobile phase and a linear gradient with a chromatographic run time of 35 min. The combination of UV and MS data allowed the structural elucidation of more than 20 degradation products, whereas 1H NMR data permitted an unequivocal confirmation of the identities of major products and the differentiation of several positional isomers, in particular, the hydroxylation isomers. The obtained results permitted us to propose a possible degradation scheme and to put in evidence the presence of privileged sites for the attack of OH radicals. This work shows, for the first time, the application of combined HPLC with UV, MS, and NMR detection for complete structural elucidation of photocatalytic degradation products, and it will be of particular value in studies on the elimination of pollutants in aqueous solutions by photocatalysis.