Chemoselective Preparation of New Families of Phenolic-Organoselenium Hybrids—A Biological Assessment

Being aware of the enormous biological potential of organoselenium and polyphenolic compounds, we have accomplished the preparation of novel hybrids, combining both pharma-cophores in order to obtain new antioxidant and antiproliferative agents. Three different families have been accessed in a straightforward and chemoselective fashion: carbohydrate-containing N-acylisoselenoureas, N-arylisoselenocarbamates and N-arylselenocarbamates. The nature of the organoselenium framework, number and position of phenolic hydroxyl groups and substituents on the aromatic scaffolds afforded valuable structure–activity relationships for the biological as-says accomplished: antioxidant properties (antiradical activity, DNA-protective effects, Glutathione peroxidase (GPx) mimicry) and antiproliferative activity. Regarding the antioxidant activity, selenocar-bamates 24–27 behaved as excellent mimetics of GPx in the substoichiometric elimination of H2O2 as a Reactive Oxygen Species (ROS) model. Isoselenocarbamates and particularly their selenocarbamate isomers exhibited potent antiproliferative activity against non-small lung cell lines (A549, SW1573) in the low micromolar range, with similar potency to that shown by the chemotherapeutic agent cisplatin (cis-diaminodichloroplatin, CDDP) and occasionally with more potency than etoposide (VP-16).Ministerio de Ciencia e Innovación PID2020-116460RB-I00Junta de Andalucía FQM134Gobierno de las Islas Canarias ProID202001010

Masked Phenolic-Selenium Conjugates: Potent and Selective Antiproliferative Agents Overcoming P-gp Resistance

Cancer accounts for one of the most complex diseases nowadays due to its multifactorial nature. Despite the vast number of cytotoxic agents developed so far, good therapeutic approaches are not always reached. In recent years, multitarget drugs are gaining great attention against multifactorial diseases in contraposition to polypharmacy. Herein we have accomplished the conjugation of phenolic derivatives with an ample number of organochalcogen motifs with the aim of developing novel antiproliferative agents. Their antioxidant, and antiproliferative properties (against six tumour and one non-tumour cell lines) were analysed. Moreover, in order to predict P-gp-mediated chemoresistance, the P-glycoprotein assay was also conducted in order to determine whether compounds prepared herein could behave as substrates of that glycoprotein. Selenium derivatives were found to be significantly stronger antiproliferative agents than their sulfur isosters. Moreover, the length and the nature of the tether, together with the nature of the organoselenium scaffold were also found to be crucial features in the observed bioactivities. The lead compound, bearing a methylenedioxyphenyl moiety, and a diselenide functionality, showed a good activity (GI50 = 0.88-2.0 µM) and selectivity towards tumour cell lines (selectivity index: 14-32); moreover, compounds considered herein were not substrates for the P-gp efflux pump, thus avoiding the development of chemoresistance coming from such mechanism, commonly found for widely-used chemotherapeutic agents

Tuning the activity of iminosugars: novel N-alkylated deoxynojirimycin derivatives as strong BuChE inhibitors

We have designed unprecedented cholinesterase inhibitors based on 1-deoxynojirimycin as potential anti-Alzheimer’s agents. Compounds are comprised of three key structural motifs: the iminosugar, for interaction with cholinesterase catalytic anionic site (CAS); a hydrocarbon tether with variable lengths, and a fragment derived from 2-phenylethanol for promoting interactions with peripheral anionic site (PAS). Title compounds exhibited good selectivity towards BuChE, strongly depending on the substitution pattern and the length of the tether. The lead compounds were found to be strong mixed inhibitors of BuChE (IC50 = 1.8 and 1.9 µM). The presumptive binding mode of the lead compound was analysed using molecular docking simulations, revealing H-bond interactions with the catalytic subsite (His438) and CAS (Trp82 and Glu197) and van der Waals interactions with PAS (Thr284, Pro285, Asn289). They also lacked significant antiproliferative activity against tumour and non-tumour cells at 100 µM, making them promising new agents for tackling Alzheimer’s disease through the cholinergic approach.Dirección General de Investigación de España. CTQ2016-78703-PJunta de Andalucía. FQM134Fondo Europeo de Desarrollo Regional (FEDER) y Consejo Nacional de Ciencia y Tecnología de México (CONACYT). CB-2015/257465Ministerio de Ciencia, Innovación y Universidades y Agencia Estatal de Investigación de España y Fondos FEDER de la Unión Europea (MCIU/AEI/FEDER). PGC2018-094503-B-C2

A Straightforward Access to New Families of Lipophilic Polyphenols by Using Lipolytic Bacteria

The chemical synthesis of new lipophilic polyphenols with improved properties presents technical difficulties. Here we describe the selection, isolation and identification of lipolytic bacteria from food-processing industrial wastes, and their use for tailoring a new set of com- pounds with great interest in the food industry. These bacteria were employed to produce lipolytic supernatants, which were applied without further purification as biocatalysts in the chemoselective and regioselective synthesis of lipophilic partially acetylated phenolic com- pounds derived from olive polyphenols. The chemoselectivity of polyphenols acylation/dea- cylation was analyzed, revealing the preference of the lipases for phenolic hydroxyl groups and phenolic esters. In addition, the alcoholysis of peracetylated 3,4-dihydroxyphenylglycol resulted in a series of lipophilic 2-alkoxy-2-(3,4-dihydroxyphenyl)ethyl acetate through an unexpected lipase-mediated etherification at the benzylic position. These new compounds are more lipophilic and retained their antioxidant properties. This approach can provide access to unprecedented derivatives of 3,4-dihydroxyphenylglycol with improved propertiesJunta de Andalucía P08-NMR-3515, P11-CVI-7427 MO, FQM134 y BIO-213European Regional Development Fund (FEDER

Procedimiento para la obtención de secoiridoides dialdehídicos

Procedimiento para la obtención de secoiridoides dialdehídicos.Esta invención se refiere un procedimiento para la obtención de secoiridoides dialdehídicos, tales como la oleaceína y oleocantal mediante el uso de DMSO. Este procedimiento permite doblar e

Procedimiento para la obtención de secoiridoides dialdehídicos

Procedimiento para la obtención de secoiridoides dialdehídicos.Esta invención se refiere un procedimiento para la obtención de secoiridoides dialdehídicos, tales como la oleaceína y oleocantal mediante el uso de DMSO. Este procedimiento permite doblar e

Selenium and Sulphur Derivatives of Hydroxytyrosol: Inhibition of Lipid Peroxidation in Liver Microsomes of Vitamin E-deficient Rats

Purpose: The objective of this study was to evaluate the capacity of modified phenols synthesized from hydroxytyrosol, a natural olive oil phenol, specifically those containing a selenium or sulphur group, to inhibit lipid peroxidation. Methods: The compounds’ abilities to inhibit lipid peroxidation in liver microsomes obtained from vitamin E-deficient rats were compared to hydroxytyrosol. Results: All synthetic compounds had a significant higher ability to inhibit lipid peroxidation than hydroxytyrosol. Selenium derivates displayed a higher antioxidant activity than sulphur derivatives. In addition, the antioxidant activity increased with a higher number of heteroatoms in the hydroxytyrosol molecular structure. Conclusion: The study shows, for the first time, the ability of synthetic compounds, derived from the most active phenol present in olives in free form (hydroxytyrosol), and containing one or two atoms of sulphur or selenium, to inhibit the lipid peroxidation of vitamin E-deficient microsomes. The antioxidant activity of five thioureas, a disulfide, a thiol, three selenoureas, a diselenide, and a selenonium were evaluated and the results showed a higher inhibition of lipid peroxidation than the natural phenol. Selenium and sulphur derivatives of hydroxytyrosol are novel antioxidants with the potential to supplement the lack of vitamin E in the diet as natural alternatives for the prevention of diseases related to oxidative damage.Ministerio de Economía y Competitividad AGL2016-79088RPrograma Ramón y Cajal RYC-2012-1045

New tacrine dimers with antioxidant linkers as dual drugs: Anti-Alzheimer's and antiproliferative agents

open11siWe have designed a series of tacrine-based homo- and heterodimers that incorporate an antioxidant tether (selenoureido, chalcogenide) as new dual compounds: for the treatment of Alzheimer's disease and as antiproliferative agents. Symmetrical homodimers bearing a dichalcogenide or selenide-based tether, the best compounds in the series, were found to be strong and highly selective electric eel AChE inhibitors, with inhibition constants within the low nanomolar range. This high inhibitory activity was confirmed on recombinant human AChE for the most interesting derivatives. The three most promising homodimers also showed a good inhibitory activity towards amyloid-β self aggregation. The symmetric disulfide derivative bis[5-(1â²,2â²,3â²,4â-tetrahydroacridin-9â²-ylamino)pentyl]disulfide (19) showed the best multipotent profile and was not neurotoxic on immortalized mouse cortical neurons even at 50 μM concentration. These results represent an improvement in activity and selectivity compared to parent tacrine, the first marketed drug against Alzheimer's disease. Title compounds also exhibited excellent in vitro antiproliferative activities against a panel of 6 human tumor cell lines, with GI50values within the submicromolar range for the most potent derivatives (0.12â0.95 μM); such values represent a spectacular increase compared to currently-used chemotherapeutic agents, such as 5-FU (up to 306âfold) and cisplatin (up to 162âfold). Cell cycle experiments indicated the accumulation of cells in the G1phase of the cycle, a different mechanism than the reported for cisplatin. The breast cancer cell lines turned out to be the most sensitive one of the panel tested.embargoed_20190929Roldán-Peña, Jesús M.; Alejandre-Ramos, Daniel; López, Oscar; Maya, Inés; Lagunes, Irene; Padrón, José M.; Peña-Altamira, Luis Emiliano; Bartolini, Manuela; Monti, Barbara; Bolognesi, Maria L.; Fernández-Bolaños, José G.Roldán-Peña, Jesús M.; Alejandre-Ramos, Daniel; López, O scar; Maya, Inés; Lagunes, Irene; Padrón, José M.; Peña-Altamira, Luis Emiliano; Bartolini, Manuela; Monti, Barbara; Bolognesi, Maria L.; Fernández-Bolaños, José G

Inhibitory effect of olive phenolic compounds isolated from olive oil by-product on melanosis of shrimps

Melanosis is an unsolved problem of the crustacean industry and the cause of great loss of value. This study investigates the effect of two potent, natural antioxidants isolated from olive waste (hydroxytyrosol, HT and 3,4-dihydroxyphenylglycol, DHPG) and three novel HT-derivatives containing selenium and sulfur (dihydroxytyrosyl diselenide, N-hydroxytyrosyl selenourea, and N- hydroxytyrosyl thiourea) on the prevention of melanosis in Atlantic ditch shrimp (Palaemonetes varians) during refrigerated storage. These results clearly demonstrate the positive inhibitory effect of DHPG and dihydroxytyrosyl diselenide on delaying melanosis in vivo, although this effect was not dose dependent. The effect was associated with a concomitant-inhibitory effect on tyrosinase activity in vitro. To our knowledge, so far no studies on the prevention of melanosis have been conducted on this small specie of shrimp which is available in large quantities at any time of the year at low cost. Studies with these promising compounds could then be extended to other more economically important species with a greater guarantee of success.Ministerio de Economía y Competitividad AGL2013‐R, CTQ2016‐78703‐