Inés Maya

Effects of dietary virgin olive oil polyphenols: hydroxytyrosyl acetate and 3, 4-dihydroxyphenylglycol on DSS-induced acute colitis in mice

Hydroxytyrosol, a polyphenolic compound from extra virgin olive oil (EVOO) has exhibited an improvement in a model of DSS-induced colitis. However, other phenolic compounds present such as hydroxytyrosyl acetate (HTy-Ac) and 3,4-dihydroxyphenylglycol (DHPG) need to be explored to complete the understanding of the overall effects of EVOO on inflammatory colon mucosa. This study was designed to evaluate the effect of both HTy-Ac and DHPG dietary supplementation in the inflammatory response associated to colitis model. Six-week-old mice were randomized in four dietary groups: sham and control groups received standard diet, and other two groups were fed with HTy-Ac and DHPG, respectively, at 0.1%. After 30 days, all groups except sham received 3% DSS in drinking water for 5 days followed by a regime of 5 days of water. Acute inflammation was evaluated by Disease Activity Index (DAI), histology and myeloperoxidase (MPO) activity. Colonic expression of iNOS, COX-2, MAPKs, NF-kB and FOXP3 were determined by western blotting. Only HTy-Ac-supplemented group showed a significant DAI reduction as well as an improvement of histological damage and MPO. COX-2 and iNOS protein expression were also significantly reduced. In addition, this dietary group down-regulated JNK phosphorylation and prevented the DSS-induced nuclear translocation level of p65. However, no significant differences were observed in the FOXP3 expression. These results demonstrated, for the first time, that HTy-Ac exerts an antiinflammatory effect on acute ulcerative colitis. We concluded that HTy-Ac supplement might provide a basis for developing a new dietary strategy for the prevention of ulcerative colitis.

Naturally Occurring Hydroxytyrosol Derivatives: Hydroxytyrosyl Acetate and 3,4-Dihydroxyphenylglycol Modulate Inflammatory Response in Murine Peritoneal Macrophages. Potential Utility as New Dietary Supplements

This work evaluated the effects of extra virgin olive oil (EVOO) phenols, hydroxytyrosyl acetate (2) and 3,4-dihydroxyphenylglycol (3), as well as two new acyl derivatives of 3, 4-(1,2-di(butanoyloxy)ethyl)benzene-1,2-diol (7) and 4-(1,2-di(lauroyloxy)ethyl)benzene-1,2-diol (8), on LPS-stimulated murine peritoneal macrophages in comparison with hydroxytyrosol (HTy, 1). Compounds 2, 3, 7, and 8 showed a strong reactive oxygen species (ROS)-scavenging activity, reducing significantly nitrite levels with a significant decrease on iNOS expression [2 (50 μM, 0.44 ± 0.03; 100 μM, 0.44 ± 0.01; p < 0.01); 3 (50 μM, 0.37 ± 0.03; 100 μM, 0.37 ± 0.01; p < 0.001); 7 (50 μM, 0.45 ± 0.06; p < 0.01)] . However, only 2 and 3 down-regulated COX-2 expression [2 (50 μM, 0.72 ± 0.04, p < 0.05; 100 μM, 0.54 ± 0.06, p < 0.01); 3 (50 μM, 0.56 ± 0.05, p < 0.05; 100 μM, 0.37 ± 0.04; p < 0.001)] and prevented IKBα degradation [2 (100 μM, 1.63 ± 0.14, p < 0.01); 3 (100 μM, 1.82 ± 0.09; p < 0.01)] ; the diacylated compounds 7 and 8 showed worse anti-inflammatory activity than the parent 3. In conclusion, 2 and 3 phenolic derivatives could play an important role in the anti-inflammatory effect of EVOO. The implication of this study for the nutrition and general health of the population rests in the possible use of natural HTy derivatives with better hydrophilic/lipophilic balance, thus improving its pharmacodynamic and pharmacokinetic profiles, as new dietary supplements in foods.

A green procedure for the regio- and chemoselective hydrophosphonylation of unsaturated systems using CaO under solventless conditions

Diethyl phosphite and diphenylphosphine add to a series of unsaturated derivatives using environmentally-friendly calcium oxide as a basic promoter under solventless conditions at room temperature. The corresponding adducts are obtained in a totally regioselective fashion, via a 1,4-addition on α,β-unsaturated esters and sulfone, and a 1,2-addition on cyclic and acyclic α,β-unsaturated aldehydes and ketones.

A practical one-pot synthesis of O-unprotected glycosyl thioureas

Abstract An expeditious and high-yielding one-pot procedure to prepare different types of O -unprotected N -β- d -glycopyranosyl, N ′-substituted thioureas and di-β- d -glucopyranosyl thioureido bolaamphiphiles from β- d -glycopyranosylamines via O -unprotected glycopyranosyl isothiocyanates has been developed.

Synthesis and antioxidant activity of O-alkyl selenocarbamates, selenoureas and selenohydantoins.

The preparation of three different families of lipophilic organoselenium compounds (aryl- and sugar-derived selenoureas, O-alkyl selenocarbamates and selenohydantoins) has been carried out in order to evaluate their in vitro antioxidant profile, analyzing the influence of the selenium-containing functional group, and the substituents on the activity. Title compounds have therefore been studied for the first time as free radical, hydrogen peroxide, alkyl peroxides and nitric oxide scavengers using colorimetric methods; furthermore, their glutathione peroxidase-like activity has also been analyzed by NMR spectroscopy. Free radical scavenging activity has been evaluated using the DPPH method; the strongest free radical scavengers were found to be both, aryl- and sugar-derived selenoureas, with EC₅₀ values ranging 19-46 μM. Concerning anti-H₂O₂ activity, measured by the horseradish peroxidase-mediated oxidation of phenol red, the best results were achieved for aryl selenohydantoins, showing a 61-76% inhibition at 0.5 mM concentration. Organoselenium compounds were also found to be capable of inhibiting the chain reaction involving lipid peroxidation (ferric thiocyanate method); thus, when tested at 0.74 mM, sugar selenocarbamates exhibited 49-71% inhibition of alkyl peroxides-mediated degradation of linoleic acid. Nitric oxide scavenging was studied by transforming sodium nitroprusside into nitrite ion, which in turn was transformed into an easily UV-detectable azocompound; aryl selenocarbamates exhibited 64-80% inhibition at 0.71 mM concentration. It has also been demonstrated that selenoxo compounds can behave as excellent glutathione peroxidase mimics; thus a 0.05 molar equiv. of the title compounds catalyzed efficiently the H₂O₂-mediated oxidation of dithiothreitol into the corresponding cyclic disulfide, mimicking removal of H₂O₂ exerted by glutathione peroxidase; t(1/2) values were found to be quite low for aryl- and sugar-derived selenoureas (2.0-12.7 min).

New N-alkylsulfonamides and alkyl sulfonates derived from 6-C-sulfosugars

Protected 6-C-sulfosugars have been transformed into alkyl sulfonates and N-alkylsulfonamides, including a pseudo-disaccharide with a 6 to 6′-sulfonamide linkage. The method involves the oxidation of 6-thioacetate sugar derivatives to 6-C-sulfosugars, and their transformation into sulfonyl chlorides using SO2Cl2 in anhydrous CH2Cl2 followed by in situ coupling with nucleophiles in the presence of an excess of base. Sulfonylation through phase-transfer conditions has proved to be suitable for the synthesis of the pseudo-disaccharide.

Expeditious synthesis of cyclic isourea derivatives of β-D-glucopyranosylamine

2-(Alkylamino, dialkylamino, arylamino)tetrahydropyrano[2,3-d]oxazoles are prepared in good yield by a one-pot three-step synthesis from O-unprotected β-d-glucopyranosylamine, by its transformation into glucopyranosyl isothiocyanate in dioxane–water, coupling with amines, and reaction of the corresponding thioureas with yellow mercury(II) oxide in the same reaction medium. In the case of diethylamine prolonged reaction time during the last step, with an extra portion of yellow HgO, led to N,N-diethyl-N′-(β-d-glucopyranosyl)urea in a one-pot four-step synthesis. 2-(β-d-Glucopyranosylamino)tetrahydropyrano[2,3-d]oxazole, an analogue of trehazolin, is obtained in good yield by cyclocondensation of 1,3-bis(β-d-glucopyranosyl)thiourea.

Synthesis of new C-sulfosugars and C-sulfoalditols: Amadori rearrangement of 6-C-sulfo-d-fucose

Abstract The novel 6-deoxy-6-C-sulfo- d -galactose (6-sulfofucose) potassium salt was prepared by oxidation of 1,2,3-tri-O-acetyl-6-S-acetyl-4-O-benzoyl-6-deoxy-α- d -galactopyranose with hydrogen peroxide and potassium acetate in acetic acid. Its cyclohexylammonium salt underwent a spontaneous conversion into 1-cyclohexylamino-1,6-dideoxy- d -tagatofuranose-6-C-sulfonic acid 4 through an Amadori rearrangement. 6-Deoxy-6-C-sulfo- d -glucose (sulfoquinovose) and 6-deoxy-6-C-sulfo- d -galactose were transformed into the corresponding 6-deoxy-6-C-sulfoalditols and 1-amino-1,6-dideoxy-6-C-sulfoalditols by reduction and reductive amination, respectively. The α anomeric configuration of 4, crystallised as the monohydrate, was assigned by X-ray crystallographic analysis. A conformation between E5 and 4T5 for the sugar ring, stabilised by a strong intramolecular hydrogen bond between NH and O-4, was observed.

Synthesis of furan 4′-thio-C-nucleosides, their methylsulfonium and sulfoxide derivatives. Evaluation as glycosidase inhibitors

Abstract A series of furan C -nucleosides having a sulfur atom in the sugar ring were synthesised. The α and β anomers of 3-ethoxycarbonyl-2-methyl-5-(4′-thio- d -erythrofuranosyl)furans 10 and 11 were obtained by acid treatment of (4′- S -acetyl-4′-thio- d - arabino -tetritol-1-yl)furan 9 . Oxidation of 10 with m -chloroperbenzoic acid gave sulfoxide 12 as one epimer at the sulfur atom whereas 11 was transformed into sulfoxide 13 as an epimeric mixture. S -Methylation of 10 and 11 with methyl triflate led to sulfonium salts 14 and 15 . The prepared compounds were found to be moderate inhibitors of α- l -fucosidase.

Enhanced chemopreventive activity of hydroxytyrosol on HL60 and HL60R cells by chemical conversion into thio derivatives.

Thio derivatives of hydroxytyrosol containing thiol, thioacetate and disulfide functionalities were synthesized from natural hydroxytyrosol (3,4-DHPEA) via 3,4-dihydroxyphenethyl halides. These compounds, containing the combination of catechol moiety and divalent sulfur functions, were tested for the pro-apoptotic and anti-proliferative activities on both parental HL60 and multi-drug resistant HL60R cells. It was found that all synthesized compounds were more effective than 3,4-DHPEA in inducing apoptosis on HL60R cells, and that the hydroxytyrosol disulfide was the most active pro-apoptotic and anti-proliferative compound on both HL60 and HL60R cells. Different from 3,4-DHPEA, all thio derivatives of hydroxytyrosol induced apoptosis by a mechanism not involving the release of H(2)O(2) in the culture medium. The data on HL60R cells suggest that these compounds could be able to reverse the resistance toward the most common drugs in cancer therapy.