Synthesis and Antiproliferative Activity of Sulfa-Michael Adducts and Thiochromenes Derived from Carbohydrates

The Michael addition reactions of carbohydrate-derived nitroalkenes with ethyl thioglycolate and 2-mercaptobenzyl alcohol were studied. Reactions were conducted under mild, solvent-free conditions with DABCO as a catalyst, affording the corresponding adducts in good yields. Furthermore, compounds resulting from the addition with 2-mercaptobenzyl alcohol were used as starting materials for the synthesis of chiral 3-nitro-2H-thiochromenes. For some of the compounds synthesized herein, the antioxidant and antiproliferative activities against a panel of human solid tumor cell lines were assayed and compared with those of carbohydrate-nitroalkene substrates.Junta de Extremadura GR15022Unión Europea FP7-REGPOT-2012-CT2012-31637-IMBRAI

Whole genome sequencing of Shigella sonnei through PulseNet Latin America and Caribbean: advancing global surveillance of foodborne illnesses

Objectives Shigella sonnei is a globally important diarrhoeal pathogen tracked through the surveillance network PulseNet Latin America and Caribbean (PNLA&C), which participates in PulseNet International. PNLA&C laboratories use common molecular techniques to track pathogens causing foodborne illness. We aimed to demonstrate the possibility and advantages of transitioning to whole genome sequencing (WGS) for surveillance within existing networks across a continent where S. sonnei is endemic. Methods We applied WGS to representative archive isolates of S. sonnei (n = 323) from laboratories in nine PNLA&C countries to generate a regional phylogenomic reference for S. sonnei and put this in the global context. We used this reference to contextualise 16 S. sonnei from three Argentinian outbreaks, using locally generated sequence data. Assembled genome sequences were used to predict antimicrobial resistance (AMR) phenotypes and identify AMR determinants. Results S. sonnei isolates clustered in five Latin American sublineages in the global phylogeny, with many (46%, 149 of 323) belonging to previously undescribed sublineages. Predicted multidrug resistance was common (77%, 249 of 323), and clinically relevant differences in AMR were found among sublineages. The regional overview showed that Argentinian outbreak isolates belonged to distinct sublineages and had different epidemiologic origins. Conclusions Latin America contains novel genetic diversity of S. sonnei that is relevant on a global scale and commonly exhibits multidrug resistance. Retrospective passive surveillance with WGS has utility for informing treatment, identifying regionally epidemic sublineages and providing a framework for interpretation of prospective, locally sequenced outbreaks

Antimicrobial activity on phytopathogenic bacteria and yeast, cytotoxicity and solubilizing capacity of deep eutectic solvents

3 Figuras.-- 4 TablasThe toxicity on oenological yeasts and plant pathogens of eight deep eutectic solvents (DESs) composed of ChCl:Sucrose (1:2), ChCl:1,4-butanediol (1:5), ChCl:Xylitol (2:1), ChCl:1,2-propanediol (1:1), Fructose:Glucose:Sucrose (1:1:1), Betaine:Sucrose (2:1), Betaine:Sucrose (4:1) and Fructose-Glucose-Sucrose (2:3.6:1) was evaluated and compared with the classic solvents dimethylsulfoxide (DMSO), ethanol and glycerol. Most yeast and bacteria were tolerant to DESs consisting of three sugars in a concentration range of 75–600 x 103mg/L for yeasts and 75–1200 x 103mg/L for bacteria. These DESs showed less toxicity than glycerol or DMSO for most microorganisms. The effect of six DESs, ChCl:Sucrose (1:2), ChCl:Xylitol (2:1), Fructose:Glucose:Sucrose (1:1:1), Betaine:Sucrose (2:1), Betaine:Sucrose (4:1) and Fructose-Glucose-Sucrose (2:3.6:1) in different human cancer cell lines (Caco-2, HeLa and HepG2 cells), as well as in peripheral blood mononuclear cells (PBMCs) from healthy volunteers, was studied using flow cytometry. As a result, DESs at concentrations below 1%, affected tumor cells; however, healthy PBMCs were unaffected. In addition, the solubility of poorly-soluble subtances in water (quercetin, phenylmethylsulfonyl fluoride (PFMS), camptothecin (CPT), oleanolic acid, palmitic acid and Red O oil) was evaluated in all DESs previously tested plus two organic acidbased DESs, Betaine:Levulinic acid (1:2) and ChCl:Glycolic acid:Oxalic acid (1:1.6:0.4). All they were compared with conventional solvents (water, DMSO or ethanol) to determine their efficacy as drug solvents. As a result, DESs solubilized quercetin and CPT in the same range as conventional solvents. The antioxidant properties of quercetin solubilized in two DESs and in DMSO were studied in Caco-2 cells. A solution of tert-butyl hydroperoxide (TBH) was used as an inducer of intracellular reactive oxygen species (ROS), resulting in that quercetin's ability to reduce ROS production did not differ when it was solubilized in DESs or DMSO. In this study, we determined the low toxicity of the DESs analyzed on oenological yeasts, phytopathogenic microorganisms and on healthy human cells. The toxicity of DESs on cancer cell lines was also showed. In addition, the ability of DESs to dissolve poorly water-soluble compounds or other substances of interest was also demonstrated, suggesting their use as safe solvents or cryoprotectors useful at an industrial level.This work was supported by the Spanish Government (AGL2016-79088-R and AGL2016-80852-R) and by the Spanish FPI funding program (MEIC) (BES-2017–079648). Sergio Lopez thanks the ‘V Own Research Plan’ of the University of Seville (VPPI‐US) contract (co-founded by the European Social Fund).Peer reviewe

N-Substituted 3-Aminooxindoles and N-Propargyl Derivatives: Potential Biological Activities against Alzheimer's Disease

The oxindole core is an important structural motif in many natural and synthetic substances with various biological activities including anticancer, antineurodegenerative, and antimicrobial properties. This report focuses on the synthesis and biological activity of a series of novel N-substituted 3-aminooxindoles and their assessment in cholinesterase (ChE) and monoamine oxidase (MAO) inhibition. With regard to MAO inhibition, a series of Npropargyl containing derivatives was synthesized and screened. Despite being weak inhibitors of MAO-A and MAO-B, the compounds were selective for butyrylcholinesterase (BuChE) over acetylcholinesterase (AChE). Most of them were strong inhibitors of BuChE with IC50 ’ s of less than 1 µM, and one compound showed an IC50 = 27 nM. The mechanism of action of the inhibition was pin-pointed through molecular modeling, and was validated using saturation-transfer-difference (STD) NMR. Some of the compounds were screened for anti-oxidant properties, but showed no activity. The same compounds were screened in the neurodegenerative disease model cellline SH-SY5Y and although some were found to be non-cytotoxic, others were moderately cytotoxic. Continuous live cell imaging experiments showed that the compounds do not induce relevant cell damage and thus, the compounds might be interesting drug candidates for Alzheimer’s disease. Furthermore, the most active compounds showed excellent drug-likeness and pharmacological properties predicted using Swiss-ADME, and the pharmacokinetic simulations indicated that all these compounds cross the blood-brain-barrier.Fundação para a Ciência e a Tecnologia (FCT) LAQV-REQUIMTE (FCT/ MCTES; UIDB/50006/2020|UIDP/50006/2020)Ministerio de Ciencia e Innovación PID2020-116460RB-100Junta de Andalucía FQM-134Estonian Research Council PRG1509Gobierno de España PID2021-123059OB-I00Fondo Social Europeo, Islas Canarias ACIISI TESIS2020010055Asociación Española Contra el Cáncer (AECC)COST Action 15135Universidad de Hadrec Králové (Facultad de Ciencias), Erasmus+ (2019-1-CZ01-KA103-06005

Alperujo extract, hydroxytyrosol, and 3,4-dihydroxyphenylglycol are bioavailable and have antioxidant properties in vitamin E-deficient rats-a proteomics and network analysis approach

Scope: Olive products are rich in phenolic compounds, which are natural antioxidants in vitro. We tested the in vivo effects of alperujo, an olive production by-product, as well as hydroxytyrosol and 3,4-dihydroxyphenylglycol (DHPG) isolated from alperujo, on indices and pathways of oxidative and metabolic stress in a vitamin E-deficient rat model. Methods and results: Rats were fed a vitamin E-deficient diet for 10 weeks, followed by this diet supplemented with either 100 mg/kg diet dα-tocopherol, alperujo extract, hydroxytyrosol, or 10 mg/kg diet DHPG, for a further 2 weeks. We detected alperujo phenolics in tissues and blood, indicating they are bioavailable. Alperujo extract partially ameliorated elevated plasma levels of thiobarbituric acid reactive substances and also lowered plasma cholesterol levels, whereas hydroxytyrosol increased plasma triglyceride levels. Proteomics and subsequent network analysis revealed that hepatic mitochondrial aldehyde dehydrogenase (ALDH2), of which protein and activity levels were regulated by dα-tocopherol and olive phenolics, represents a novel central regulatory protein hub affected by the dietary interventions. Conclusion: The in vivo free radical scavenging properties of olive phenolics appear relatively modest in our model. But alternative mechanisms, including regulation of ALDH2, may represent relevant antioxidant mechanisms by which dietary olive phenolics could have beneficial impact on cardiovascular health. © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim