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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-P Junta de Andalucía. FQM134 Fondo Europeo de Desarrollo Regional (FEDER) y Consejo Nacional de Ciencia y Tecnología de México (CONACYT). CB-2015/257465 Ministerio 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-C22

Every year, more than 500,000 new cases of cervical cancer are reported, making it the fourth leading cause of cancer globally. Although human papillomavirus (HPV) vaccines show promise as a protective measure, HPV-related cancers remain a public health problem since the vaccines, which are only specific to certain viral types, are unavailable for mass distribution. Furthermore, the effects of toxicity following ionizing radiation therapy have reoriented views toward the search for radiosensitizers that can reduce toxicity as a consequence of decreased radiation doses. Here, we isolated ergosterol peroxide (EP) from Pleurotus ostreatus and purified it to test its potential effects in vitro. We thus observed that a gradual increase in EP dose correlates with a loss of viability in HeLa and CaSki cervical cell lines. Dose/response curves were constructed using cervical cancer cell lines, as well as normal human peripheral blood mononuclear cells. The selectivity of EP in human lymphocytes and cervical cancer cell lines was tested, and no toxicity was found in normal cells. A combination of treatments revealed a radiosensitizer effect in HeLa cells, when measuring the exposure to EP followed by irradiation with 137Cs. Our findings suggest that EP may be effective as a radiosensitizer in treating cervical cancer.

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., Graphical Abstract

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 &micro, M) 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.

Background: Fungi from mangrove forests represent a great potential for the bioprospecting of new bioactive metabolites. The rhizosphere of several regions of the world has been widely studied, however, there are no studies on the biodiversity of Mexican mangroves. Objectives: To evaluate the anti-proliferative activity of fungal extracts isolated from accumulated sediments in the rhizosphere of three mangrove species distributed in three zones with different degrees of salinity in Mexico. Methods: The isolated fungi were identified at genus level by taxonomic keys. The anti-proliferative activity was determined by the SRB assay and the strains with values of GI 50

Inspired by diverse marine bioactive compounds, the principle of molecular hybridization was applied to produce a series of new compounds combining diverse heterocyclic systems (oxa/thiazoles and tetrahydropyrans) via a triazole ring, attempting to increase the activity of individual building blocks. These new compounds exhibit a highly interesting antiproliferative activity against different human tumour cells and good selectivity when compared to normal cells. The formation of reactive oxygen species and the interaction with P-gp were also evaluated for the lead compounds., This research was supported by CSIC Grupos No. 654 and No. 983, PEDECIBA Química and the Spanish MINECO. Co-financed by the European Regional Development Fund (ERDF) (CTQ2014-56362-C2-1-P). G. V. would like to thank ANII (Agencia Nacional de Investigación e Innovación) for the award of a doctoral fellowship.

Coumarins are phenolic-type compounds with efficient antioxidant activity due to their ability to scavenge reactive oxygen species. Nevertheless, their ability to behave as photosensitizers capable of generating reactive oxygen species, such as singlet oxygen, has been less studied. In this work, the photosensitizing ability of seven hydroxycoumarins was evaluated through the photooxidation of ergosterol by quantifying the conversion of ergosterol into ergosterol peroxide. In our experimental conditions, we found that almost every tested antioxidant coumarin promotes the peroxidation of ergosterol. The results suggest that the hydroxycoumarins exhibit potential photosensitizing activity by promoting singlet oxygen generation by a Type II photochemical mechanism. Density functional theory (DFT) calculations were also performed to obtain further insight into the chemical reactivity of tested compounds; the observed tendency in the group of antioxidant coumarins to promote the reaction was their hardness due to the principle of maximum hardness. To evaluate our conclusion, we performed the reaction using a highly polarizable coumarin as a photosensitizer, which resulted in an increased photosensitizing capacity supported with DFT calculations, which reinforces our analysis. Finally, we found that hydroxycoumarins can be potentially pro-oxidants since some of them can act as photosensitizers and generate singlet oxygen in the presence of UV–Vis light, a characteristic that must be considered when these compounds are used as antioxidants.

Several new (5-aryloxy-pyrazolyl)- and (5-aryl/olefin-sulfanyl-pyrazolyl)-dibenzo[b,e] [1,4] diazepinone scaffolds have been synthesized, by assembling 5-substituted 3-methyl-1-phenyl-pyrazole-4-carbaldehydes of varied nature with different cyclic diketones and aromatic diamines successfully in the presence of indium chloride in acetonitrile, at room temperature. Desired products are excellent in the purity and isolated without chromatography. All new structures are confirmed, on the basis of single-crystal X-ray diffraction data of representative 29e. Compounds reported in the present work revealed good antioxidant, antimicrobial and antiproliferative activities with promising FRAP (ferric reducing antioxidant power), bacterial resistance and human solid tumor cell growth inhibitory values, respectively. Compounds 25c and 29e, overall, registered good to moderate activity against A549 (lung), HeLa (cervix), SW1573 (lung) T-47D (breast) and WiDr (colon) cell lines, with GI50 values in the 2.6–5.1 μM and 1.8–7.5 μM ranges, respectively. Molecular docking was carried out to elucidate the binding modes of the compounds (25c, 29e) to topoisomerase I and II.

Concerned by the devastating effects of Alzheimer's disease, and the lack of effective drugs, we have carried out the design of a series of tacrine-phenolic heterodimers in order to tackle the multifactorial nature of the disease. Hybridization of both pharmacophores involved the modification of the nature (imino, amino, ether) and the length of the tether, together with the type (hydroxy, methoxy, benzyloxy), number and position of the substituents on the aromatic residue. Title compounds were found to be strong and selective inhibitors of human BuChE (from low nanomolar to subnanomolar range), an enzyme that becomes crucial in the more advanced stages of the disease. The lead compound, bearing an ether-type tether, had an IC50 value of 0.52 nM against human BuChE, and a selectivity index of 323, with an 85-fold increase of activity compared to parent tacrine; key interactions were analysed using molecular modelling. Moreover, it also inhibited the self-aggregation of Aβ42, lacking neurotoxicity up to 5 μM concentration, and showed neuroprotective activity in primary rat neurons in a serum and K+ deprivation model, widely employed for reproducing neuronal injury and senescence. Moreover, low hepatoxicity effects and complete stability under physiological conditions were found for that compound. So, overall, our lead compound can be considered as a promising multitarget-directed ligand against Alzheimer's disease, and a good candidate for developing new drugs.

A multicomponent reaction has been developed by incorporating quinoline-3-carbaldehyde, 1,3-cyclohexanedione and 2,3-diaminopyridine into some new quinolylpyrido[2,3-b][1,4]benzodiazepinone assemblies under catalyst- and solvent-free conditions at 120 °C. Further reaction of the resulting intermediates with allyl bromide led to the formation of the corresponding N5-allylated products, in situ, with higher yields in the same pot. Many candidates of this new class revealed noticeable activities against the representative human solid tumour cell lines A549 (lung), HBL-100 (breast), HeLa (cervix), SW1573 (lung), T-47D (breast) and WiDr (colon). The most active compounds resemble the standard drug etoposide in antiproliferative activity against HeLa, T-47D and WiDr cell lines. Docking studies in the active site of MDM2 led us to consider this protein a plausible target for the antiproliferative effects of the compounds.

Photodynamic therapy (PDT) is a potentially non-invasive therapeutic strategy that involves the use of a photosensitizing agent molecule capable to absorb light at a specific wavelength and to transfer the absorbed energy to generate singlet oxygen. This oxidizing agent reacts with double bonds of membrane phospholipids and sterols present in biological membranes causing damages and/or cell permeability. With the aim to analyze and to determine the effectiveness of possible photosensitizing agents, in this work we evaluate the in vitro amoebicidal effect of nine cosmetic dyes, 1–9, belonging to the xanthene, chlorophyll, aminoanthraquinone, and pyrene group of chromophores, against Acanthamoeba castellanii Neff. Red 22 (2, eosin Y) and red 28 (4) were the most effective photosensitizers to inhibit cell growth, with 2 showing the highest growth inhibition when it is activated by white light. The study of their mechanisms of action reveals that red 22 (2) increases membrane permeability and induces chromatin condensation of parasites, and could be used in combined therapies with currently used drugs.

Photosensitizer molecules capable of absorbing UV radiation and visible light through photochemical reactions can generate singlet oxygen (1O2). 1O2 is an oxidizing agent that can react with biomolecules causing oxidative damage. Cosmetic dyes possess chromophore groups capable of performing the absorption process of electromagnetic radiation thereby they could act as photosensitizers. The aim of this research was to evaluate the photosensitizing ability of 25 dyes used as cosmetic ingredients through photo-oxidation of ergosterol as an indirect detection method of 1O2. The presence of 1O2 was indirectly detected by ergosterol conversion into ergosterol peroxide through 1H-NMR mixture analysis. Our results showed that 9 cosmetic dyes belonging to pyrene, chlorophyll, xanthene and aminoanthraquinone groups were able to act as photosensitizers in the generation of 1O2. The photosensitizing ability of these dyes could be contradictory if they are used as cosmetic ingredients because of pro-oxidants effects caused by 1O2 and its implications in skin photoaging. On the other hand, in regard to the photosensitizing ability of the remaining dyes tested belonging to the azo, triarylmethane, hydroxyanthraquinone, quinoline and indigoid groups, these were found not capable of photosensitizing 1O2 generation, consequently their use as cosmetic ingredients wouldn't suppose an oxidation risk caused by 1O2.

Herein we report a straightforward preparation of new antiproliferative agents based on the hybridization of a coumarin skeleton and an organoselenium motif. Three families were obtained: isoselenocyanate, selenocarbamates and selenoureas. The main purpose of these hybrid structures is the development of new antiproliferative agents with a multitarget mode of action. A strong correlation between the nature of the organosenium scaffold and the antiproliferative activity was observed. Thus, whereas selenocarbamates proved to be inactive, or moderate antiproliferative agents, isoselenocyanate and most of the selenoureas behaved as strong antiproliferative agents, with GI50 values within the low micromolar range. Interestingly, a good selectivity toward tumor cell lines was found for some of the compounds. Moreover, an increase in the ROS level was observed for tumor cells, and accordingly, these pro-oxidant species might be involved in their mode of action. Overall, title compounds were found not to be substrates for P-glycoprotein, which is overexpressed in many cancer cells as a way of detoxification, and thus, to develop drug resistance. In silico calculations revealed that the selenoderivatives prepared herein might undergo a strong interaction with the active site of HDAC8, and therefore, be potential inhibitors of histone deacetylase 8. In vitro assessment against HDAC8 revealed a strong inhibition of such enzyme exerted by selenoureas, particularly by symmetrical coumarin-containing selenourea. Two compounds showed good antiproliferative data and appear as plausible leads for further testings. The symmetrical coumarin 6 displays the best in vitro inhibition of HDAC8, but is affected by P-gp. In contrast, the N-butyl selenourea coumarin derivative 5a escapes P-gp resistance but has lower HDAC8 inhibition activity.

Herein our team explored a promising synthetic trail to Functionalized pyrazolodihydropyridine core using hydroxyl alkyl ammonium ionic liquid via one-pot fusion of 3-methyl-1-phenyl-1H-pyrazole-5-amine, different heterocyclic aldehydes and 1, 3-Cyclic diones. The aimed compounds were obtained by Domino-Knoevenagel condensation and Michael addition followed by cyclization. The reaction transformation involves the formation of two CC and one CN bond formation. The perspective of the present work is selectively approached to Functionalized pyrazolodihydropyridine core excluding other potential parallel reactions under environmentally benign reaction condition. The present protocol show features such as the low E-factor, ambiphilic behavior of ionic liquid during reaction transformation, scale-up to a multigram scale, reusability of the ionic liquid, mild reaction condition, and produce water as a byproduct. All newly derived compounds were evaluated for their in vitro biological activities. In preliminary biological studies compound, 4c showed better potency than the standard drug ampicillin against Gram-negative bacteria (E. coli); the compound 4i exhibited outstanding activity against S. aeruginosa which is far better than ampicillin, chloramphenicol, and ciprofloxacin. The compound 4m was found more potent against C. albicans, than that of griseofulvin and show equipotency to nystatin whereas, in preliminary antitubercular screening, compound 4o was exhibited more potency than rifampicin. Noteworthy compounds 4f and 4i were found most active in antiproliferative screening.

In the current study, we explored for the first time, the mechanism of action of the new Casein kinase 1e(CK1e) selective inhibitorGSD0054. Although GSD0054 behaved as a selective CK1einhibitor in enzymatic assays, we studied whether this inhibitoryactivity also occurred inside the cells. The effects of GSD0054 onβ-catenin expression and disruption of cell cycle progressionwere studied in the human breast cancer cell lines MDA-MB-453 (β-catenin negative) and T-47D (β-catenin positive). We alsoperformed molecular modeling studies using computational docking against CK1eto explain and predict the mechanism ofaction of this compound. Moreover, the commercially available CK1einhibitor PF-4800567 and the CK1δ/einhibitors PF-670462and IC261 were also studied for comparison purposes. GSD0054 showed anti-proliferative activity against MDA-MB-453 andT-47D cells despite the fact that MDA-MB-453 cells do not possess activeβ-catenin. However, selective cell killing occurred inthe more resistant,β-catenin active, T-47D cells. CK1ewas confirmed as a cellular target, although other targets or alternativemechanisms of action could possibly explain the anti-proliferative activity in MDA-MB-453 cells

Consumption of antioxidant supplements is associated to prevention of several diseases. However, recent studies suggest that antioxidants, besides scavenge free radicals could lead development of tumors. Due to conflicting reports on the antioxidant benefits, the capacity to photosensitize the generation of singlet oxygen of seven natural antioxidants was evaluated through photo-oxidation of ergosterol which proved to be an efficient method of indirect detection of singlet oxygen. Our results showed that curcumin, resveratrol and quercetin have pro-oxidant activity due they act as photosensitizers in generation of singlet oxygen. In addition, we observed that genistein, naringenin, β-carotene and gallic acid besides their antioxidant activity against ROS radicals, are capable of quenching ROS non-radicals as singlet oxygen. Finally, our results allow us to propose a new approach in classification of natural antioxidants scavengers of free radicals, based on their activity as quenchers of singlet oxygen or as photosensitizers in singlet oxygen generation.

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 GR15022 Unión Europea FP7-REGPOT-2012-CT2012-31637-IMBRAIN

We 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-(1′,2′,3′,4’-tetrahydroacridin-9′-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 GI50 values within the submicromolar range for the most potent derivatives (0.12–0.95 μM); such values represent a spectacular increase compared to currently-used chemotherapeutic agents, such as 5-FU (up to 306−fold) and cisplatin (up to 162−fold). Cell cycle experiments indicated the accumulation of cells in the G1 phase 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. Dirección General de Investigación CTQ2016-78703-P, CTQ2011-28417-C02-01, CEI10/00018 Junta de Andalucía FQM134 Fondo Europeo de Desarrollo Regional 501100008530 EU Research Potential FP7-REGPOT-2012-CT2012-31637-IMBRAIN

Moderate consumption of red wine provides beneficial effects to health. This is attributed to polyphenol compounds present in wine such as resveratrol, quercetin, gallic acid, rutin, and vanillic acid. The amount of these antioxidants is variable; nevertheless, the main beneficial effects of red wine are attributed to resveratrol. However, it has been found that resveratrol and quercetin are able to photosensitize singlet oxygen generation and conversely, gallic acid acts as quencher. Therefore, and since resveratrol and quercetin are some of the most important antioxidants reported in red wines, the aim of this research was to evaluate the photosensitizing ability of 12 red wine extracts through photo-oxidation of ergosterol. The presence of

Michael additions between carbohydrate derived nitroalkenes and several aliphatic and aromatic amines proceeded in a stereoselective way, leading to peracetylated 2-amino-1,2-dideoxy-1-nitro-heptitols. In addition, the antiproliferative activity of some of the new adducts has been studied. The results allowed to identify lead compounds which show GI50 values in the range 1.7–19 μM.