An unusual thermally sensitive anion–cation interaction, which is characteristic of the anion Eu(FOD)4−, occurs in the complex CHOLEu(FOD)4 (1; CHOL=choline; ...FOD=1,1,1,2,2,3,3‐heptafluoro‐7,7‐dimethyl‐4,6‐octanedionate) and affects both quantum yield and thermochromic behavior. This prompted the design of an Eu3+‐based ratiometric thermometer that functions at temperatures up to 95 °C through a thermally excited state absorption of the Eu3+ ion. The reusable temperature‐sensitive luminescent complex showed a range of relative sensitivity between 0.45 % C−1 at 25 °C, with an increase to 7.0 % C−1 at 95 °C. Confinement of compound 1 in a transparent film of polysulfone resulted in a higher thermal stability of 1 while its luminescence showed a strong temperature dependence.
Heating up: An unusual anion–cation interaction presented by an Eu3+/choline complex prompted the design of a new Eu3+‐based ratiometric thermometer that functions up to temperatures of 110 °C. Its immobilization in a transparent polysulfone film resulted in the loss of the unusual thermochromism while its luminescence showed a strong temperature dependence.
The DABCO-catalyzed 3 + 3 annulation between 3-nitro-2H-chromenes and benzyl 2,3-butadienoate has been developed as a route to 5H-chromeno3,4-bpyridine derivatives. Under optimal reaction conditions, ...5H-chromeno3,4-bpyridines incorporating two allenoate units were obtained in moderate to good yields (30–76%). The same type of transformation could be carried out using butynoates as allene surrogates. Mechanistic studies by mass spectrometry allowed the identification of the key intermediates involved in the reaction mechanism. The reported synthetic methodology represents an entirely new approach for the synthesis of the 5H-chromeno3,4-bpyridine core structure based on allene chemistry.
In hydrological modelling, it is important to consider the uncertainties related to a model’s structures and parameters when different hydrological models are used to represent a system. Therefore, ...an adequate analysis of daily discharge forecasts that takes into account the performance of hydrological models can assist in identifying the best extreme discharge forecasts. In this context, this study aims to evaluate the performance of three hydrological models—Lavras Simulation of Hydrology (LASH), Variable Infiltration Capacity (VIC), and Distributed Hydrological Model (MHD-INPE) in the Verde River basin. The results demonstrate that LASH and MHD can accurately simulate discharges, thereby establishing them as crucial tools for managing water resources in the study region’s basins. Moreover, these findings could serve as a cornerstone for future studies focusing on food and water security, particularly when examining their connection to climate change scenarios.
Pineapple peel still contains an important amount of phenolic compounds and vitamins with valuable antioxidant activity. In this way, the aim of this study was the recovery of the bioactive compounds ...from pineapple peel using environmentally friendly and low-cost techniques, envisaging their application in food products. From the solid-liquid extraction conditions tested, the one delivering an extract with higher total phenolic content and antioxidant capacity was a single extraction step with a solvent-pineapple peel ratio of 1:1 (w/w) for 25 min at ambient temperature, using ethanol-water (80–20%) as a solvent. The resulting extract revealed a total phenolic content value of 11.10 ± 0.01 mg gallic acid equivalent (GAE)/g dry extract, antioxidant activity of 91.79 ± 1.98 µmol Trolox/g dry extract by the DPPH method, and 174.50 ± 9.98 µmol Trolox/g dry extract by the FRAP method. The antioxidant rich extract was subjected to stabilization by the spray drying process at 150 °C of inlet air temperature using maltodextrin (5% w/w) as an encapsulating agent. The results showed that the antioxidant capacity of the encapsulated compounds was maintained after encapsulation. The loaded microparticles obtained, which consist of a bioactive powder, present a great potential to be incorporated in food products or to produce bioactive packaging systems.
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•Photolysis and photocatalysis using Co-TNW of three antidepressants was investigated.•Amitriptyline and venlafaxine showed high degradation rate in photocatalysis.•The structures of ...twenty TPs were elucidated and degradation pathway were proposed.•Trazodone TPs showed mutagenic potential according to in silico toxicity prediction.
This work investigated the catalytic ability of modified cobalt-titanate nanowires (Co-TNW) on photodegradation of three antidepressants: amitriptyline (AMI), trazodone (TRA) and venlafaxine (VEN). The experiments were carried out with spiked tap water under UV–Vis radiation in the presence of Co-TNW as catalyst. The transformation products (TPs) were elucidated by ultra-high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. Degradation pathways were proposed and in silico toxicity assessment (ecotoxicity and mutagenicity) were performed. The results showed an enhancement in the AMI and VEN removal efficiency due to the photocatalyst use. The TRA showed a similar degradation rate in photolysis and photocatalysis. Moreover, it was verified that in the photocatalytic assisted processes, more AMI and VEN TPs were formed. Overall, the structures of twenty TPs were proposed (eight from AMI, seven from TRA and five from VEN) and to the best of found knowledge, fourteen of them have never been described before. Some of these TPs had a higher ecotoxicity than parent compound by the in silico analyses. Regarding of TRA, all TPs resulted in positive mutagenicity in at least one prediction model. Therefore, it is necessary to consider the formation of TPs in photocatalytic degradation of contaminants since they may impose toxicity to aquatic organisms.
The synthesis of stable and potentially bioactive xylofuranosyl nucleoside analogues and potential sugar diphosphate or nucleotide mimetics comprising a 1,2,3‐triazole moiety is reported. ...3′‐O‐Methyl‐branched N‐benzyltriazole isonucleosides were accessed in 5–7 steps and 42–54 % overall yields using a Cu(I)‐catalyzed cycloaddition of 3‐O‐propargyl‐1,2‐O‐isopropylidene‐α‐D‐xylofuranose with benzyl azide as key step. Related isonucleotides were obtained by 5‐O‐phosphorylation of acetonide‐protected 3‐O‐propargyl xylofuranose and further “click” cycloaddition or by Staudinger‐phosphite reaction of a 5‐azido N‐benzyltriazole isonucleoside. Hydroxy‐, amino‐ or bromomethyl triazole 5′‐isonucleosides were synthesized by thermal cycloaddition of 5‐azido 3‐O‐benzyl/dodecyl xylofuranoses with propargyl alcohol, propargylamine or propargyl bromide. Better yields (82–85 %) were obtained when using propargyl alcohol and a high 1,4‐regioselectivity was attained with propargyl bromide. Further O/N‐phosphorylation or Arbuzov reaction led to (triazolyl)methyl phosphates, phosphoramidates or phosphonates. The latter were converted into uracil nucleoside 5′‐(triazolyl)methyl phosphonates as prospective nucleoside diphosphate mimetics.
Sweet nucleos(t)ides: The synthesis of novel 3′/5′‐isonucleosides and related prospective nucleotide or sugar diphosphate mimetics containg a triazole unit as a nucleobase surrogate or as a potential phosphate group bioisostere is described. The synthetic methodologies employed 3‐O‐propargyl or 5‐azido xylofuranoses as precursors and included the azide‐alkyne cycloaddition, N/O‐phosphorylation, the Staudinger reaction, the Arbuzov reaction or N‐glycosylation as key steps.
Nevirapine (NVP) is a non-nucleoside reverse transcriptase inhibitor used against human immunodeficiency virus type-1 (HIV-1), mostly to prevent mother-to-child HIV-1 transmission in developing ...countries. Despite its clinical efficacy, NVP administration is associated with a variety of toxic responses that include hepatotoxicity and skin rash. Although the reasons for the adverse effects of NVP administration are still unclear, increasing evidence supports the involvement of metabolic activation to reactive electrophiles. In particular, Phase II activation of the NVP metabolite 12-hydroxy-NVP is thought to mediate NVP binding to bionucleophiles, which may be at the onset of toxicity. In the present study, we investigated the nature and specific locations of the covalent adducts produced in human serum albumin and human hemoglobin by reaction in vitro with the synthetic model electrophile 12-mesyloxy-NVP, used as a surrogate for the Phase II metabolite 12-sulfoxy-NVP. Multiple sites of modification were identified by two different mass spectrometry-based methodologies, liquid chromatography−electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS) and matrix-assisted laser desorption ionization tandem mass spectrometry (MALDI-TOF-TOF-MS). These two distinct methodologies, which in some instances afforded complementary information, allowed the identification of multiple adducts involving cysteine, lysine, tryptophan, histidine, serine, and the N-terminal valine of hemoglobin. Tryptophan, which is not a common site of covalent protein modification, was the NVP-modified amino acid residue detected in the two proteins and consistently identified by both LC-ESI-MS/MS and MALDI-TOF-TOF-MS. The propensity of tryptophan to react with the NVP-derived electrophile is further emphasized by the fact that human serum albumin possesses a single tryptophan residue, which suggests a remarkable selectivity that may be useful for biomonitoring purposes. Likewise, the NVP adduct with the terminal valine of hemoglobin, detected by LC-ESI-MS/MS after N-alkyl Edman degradation, appears as an easily assessed marker of NVP binding to proteins. Our results demonstrate the merits and complementarity of the two MS-based methodologies for the characterization of protein binding by NVP and suggest a series of plausible biomarkers of NVP toxicity that should be useful in the monitoring of toxicity effects in patients administered NVP.
Polyhydroxyalkanoate (PHA) production using halophilic bacteria has been revisited because less severe operational conditions with respect to sterility can be applied, also alleviating production ...costs.
Halomonas boliviensis
was selected because it is a moderate halophile able to grow and attain high poly-3-hydroxybutyrate (P3HB) contents under 5–45 g/L NaCl concentrations, conditions that discourage microbial contamination. Industrial residues of the red alga
Gelidium corneum
after agar extraction were used as sugar platform to reduce costs associated with the carbon source. These residues still comprise a high carbohydrate content (30–40% w/w) of mainly cellulose, and their hydrolysates can be used as substrates for the bioproduction of value-added products. Preliminary assays using glucose were carried out to determine the best conditions for growth and P3HB production by
H. boliviensis
in bioreactor fed-batch cultivations. Two strategies were addressed, namely nitrogen or phosphorus limitation, to promote polymer accumulation. Similar P3HB cell contents of 50% (g
polymer
/g
CDW
) and yields
Y
P3HB/glucose
of 0.11–0.15 g
polymer
/g
glucose
were attained under both conditions. However, higher specific productivities were reached under P-limitation, and thus, this strategy was adopted in the subsequent study. Two organic acids, resulting from glucose metabolism, were identified to be gluconic and 2-oxoglutaric acid. Reducing the oxygen concentration in the cultivation medium to 5% sat was found to minimize organic acid production and enhance the yield of polymer on sugar to 0.20 g
P3HB
/g
glucose
. Finally, fed-batch cultivations using
G. corneum
hydrolysates as the only C-source achieved an overall volumetric productivity of 0.47 g/(L.h), 40% polymer accumulation, and negligible gluconic acid production.
Abstract Despite its efficacy, including in the prevention of vertical transmission, the antiretroviral nevirapine is associated with severe idiosyncratic hepatotoxicity and skin rash. The mechanisms ...underlying nevirapine toxicity are not fully understood, but drug bioactivation to reactive metabolites capable of forming stable protein adducts is thought to be involved. This hypothesis is based on the paradigm that drug reactive metabolites have the potential to bind to self-proteins, which results in drug-modified proteins being perceived as foreign by the immune system. The aim of the present work was to identify hemoglobin adducts in HIV patients as biomarkers of nevirapine haptenation upon bioactivation. The ultimate goal is to develop diagnostic methods for predicting the onset of nevirapine-induced toxic reactions. All included subjects were adults on nevirapine-containing antiretroviral therapy for at least 1 month. The protocol received prior approval from the Hospital Ethics Committees and patients gave their written informed consent. Nevirapine-derived adducts with the N -terminal valine of hemoglobin were analyzed by an established liquid chromatography–electrospray ionization-tandem mass spectrometry method and characterized on the basis of retention time and mass spectrometric fragmentation pattern by comparison with adduct standards prepared synthetically. The nevirapine adducts were detected in 12/13 patient samples, and quantified in 11/12 samples (2.58 ± 0.8 fmol/g of hemoglobin). This work represents the first evidence of nevirapine-protein adduct formation in man and confirms the ability of nevirapine to modify self-proteins, thus providing clues to the molecular mechanisms underlying nevirapine toxicity. Moreover, the possibility of assessing nevirapine-protein adduct levels has the potential to become useful for predicting the onset of nevirapine-induced adverse reactions.
The synthesis and anticancer evaluation of novel N-glycosyl derivatives containing N-substituted glucuronamide moieties, as nucleoside analogs or as prospective mimetics of glycosyl phosphates or of ...nucleotides, is reported. These compounds comprise N-anomerically-linked nucleobases or motifs that are surrogates of a phosphate group, such as sulfonamide or phosphoramidate moieties. 1-Sulfonamido glucuronamides containing N-benzyl, N-propargyl or N-dodecyl carboxamide units were synthesized through glycosylation of methanesulfonamide with tetra-O-acetyl glucuronamides. 1-Azido glucuronamides were accessed by microwave-assisted reactions of tetra-O-acetyl glucuronamides with TMSN
and were further converted into N-glycosylphosphoramidates by treatment with trimethyl phosphite. Potential glucuronamide-based nucleotide mimetics comprising both an anomeric sulfonamide/phosphoramidate group and a benzyltriazolylmethyl amide system at C-5, as nucleobase mimetics, were synthesized via 'click' cycloaddition of N-propargyl glucuronamide derivatives with benzyl azide. N-Dodecyl tetra-O-acetyl glucuronamides were converted into uracil and purine nucleosides via N-glycosylation of the corresponding silylated nucleobases. Biological screening revealed significant antiproliferative activities of the N-dodecyl glucuronamide-containing sulfonamide, phosphoramidate and nucleosides in K562 and MCF-7 cells. The highest effect was exhibited by the N
-linked purine nucleoside in the breast cancer cell MCF-7 with a GI
value similar to that of clinically used 5-fluorouracil. Immunoblotting and cell cycle analysis of K562 cells treated with the most active compound as well as evaluation of the effect of this nucleoside on the activities of caspases 3 and 7 showed induction of apoptosis as the mechanism of cell death.
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