Nowadays, oxidative cell damage is one of the common features of cancer and Alzheimer's disease (AD), and Se-containing molecules, such as ebselen, which has demonstrated strong antioxidant activity, have demonstrated well-established preventive effects against both diseases. In this study, a total of 39 Se-derivatives were synthesized, purified, and spectroscopically characterized by NMR. Antioxidant ability was tested using the DPPH assay, while antiproliferative activity was screened in breast, lung, prostate, and colorectal cancer cell lines. In addition, as a first approach to evaluate their potential anti-Alzheimer activity, the in vitro acetylcholinesterase inhibition (AChEI) was tested. Regarding antioxidant properties, compound 13a showed concentration- and time-dependent radical scavenging activity. Additionally, compounds 14a and 17a showed high activity in the melanoma and ovarian cancer cell lines, with LD50 values below 9.2 mu M. Interestingly, in the AChEI test, compound 14a showed almost identical inhibitory activity to galantamine along with a 3-fold higher in vitro BBB permeation (Pe = 36.92 x 10(-6) cm/s). Molecular dynamics simulations of the aspirin derivatives (14a and 14b) confirm the importance of the allylic group instead of the propargyl one. Altogether, it is concluded that some of these newly synthesized Se-derivatives, such as 14a, might become very promising candidates to treat both cancer and AD.

Background The novel selenium-aspirin compound AS-10 was recently reported by us with a cancer cell killing potency three orders of magnitude greater than aspirin in pancreatic cancer cell lines with caspase-mediated apoptosis and a reasonable selectivity against malignant cells. Although we also observed its cytocidal activity against PC-3 and DU145 androgen receptor (AR)-negative and P53-null/mutant aggressive human prostate cancer (PCa) cell lines in NCI-60 screen, the potential involvement and targeting of AR and P53 pathways that are intact in early-stage prostate carcinogenesis has not been examined, nor its primary molecular signaling after exposure. Methods Human LNCaP PCa cells with functional AR and intact P53 were used to examine their cell cycle and cell fate responses to AS-10 exposure and upstream molecular signaling events including histone acetylation as a known aspirin effect. The AR-positive 22Rv1 human PCa cells were used to validate key findings. Results In addition to confirming AS-10's superior cytocidal potency than aspirin against all four PCa cell lines, we report a rapid (within 5 min) promotion of histone acetylation several hours ahead of the suppression of AR and prostate-specific antigen (PSA, coded by KLK3 gene) in LNCaP and 22Rv1 cells. AS-10 decreased AR and KLK3 mRNA levels without impacting pre-existing AR protein degradation or nuclear translocation in LNCaP cells. Sustained exposure to AS-10 arrested cells predominantly in G(1), and induced caspase-mediated apoptosis without necrosis. The death induced by AS-10 in LNCaP cells was attenuated by nontranscriptional activation of P53 protein or Jun N-terminal Kinase cellular stress signaling and was mitigated modestly by glutathione-boosting antioxidant N-acetylcysteine. AS-10 synergized with histone deacetylase inhibitor SAHA to suppress AR/PSA abundance and kill LNCaP cells. RNA-seq confirmed AR suppression at the transcriptional level and suggested multiple oncogene, cyclin, and CDK/CKI transcriptional actions to contribute to the cellular consequences. Conclusions AS-10 promotes histone acetylation as its probable primary mechanism of action to induce PCa cell-cycle arrest and apoptosis, regardless of AR and P53 status. Nevertheless, the inhibition of AR signaling through mechanisms distinct from canonical AR antagonists may hold promise for combinatorial use with androgen deprivation therapy regimens or AR-axis targeting drugs.

Neglected tropical diseases (NTDs) encompass a group of infectious diseases with a protozoan etiology, high incidence, and prevalence in developing countries. As a result, economic factors constitute one of the main obstacles to their management. Endemic countries have high levels of poverty, deprivation and marginalization which affect patients and limit their access to proper medical care. As a matter of fact, statistics remain un-collected in some affected areas due to non-reporting cases. World Health Organization and other organizations proposed a plan for the eradication and control of the vector, although many of these plans were halted by the COVID-19 pandemic. Despite of the available drugs to treat these pathologies, it exists a lack of effectiveness against several parasite strains. Treatment protocols for diseases such as American trypanosomiasis (Chagas disease), leishmaniasis, and human African trypanosomiasis (HAT) have not achieved the desired results. Un-fortunately, these drugs present limitations such as side effects, toxicity, teratogenicity, renal, and hepatic impairment, as well as high costs that have hindered the control and eradication of these diseases. This review focuses on the analysis of a collection of scientific shreds of evidence with the aim of identifying novel chalcogen-derived molecules with biological activity against Chagas disease, leishmaniasis and HAT. Compounds illustrated in each figure share the distinction of containing at least one chalcogen element. Sulfur (S), selenium (Se), and tellurium (Te) have been grouped and analyzed in accordance with their design strategy, chemical synthesis process and biological activity. After an exhaustive revision of the related literature on S, Se, and Te compounds, 183 compounds presenting excellent biological performance were gathered against the different causative agents of CD, leishmaniasis and HAT.

A total of twenty-five novel carboxylic acid, methylester, methylamide or cyano nonsteroidal anti-inflammatory drug (NSAID) derivatives incorporating Se in the chemical form of selenoester were reported. Twenty Se-NSAID analogs exhibited an increase in cytotoxic potency compared with parent NSAID scaffolds (aspirin, salicylic acid, naproxen, indomethacin and ketoprofen). Top five analogs were selected to further study their cytotoxicity in a larger panel of cancer cells and were also submitted to the DTP program of the NCI's panel of 60 cancer cell lines. Compounds 4a and 4d stood out with IC50 values below 10 mu M in several cancer cells along with a selectivity index higher than 5 in breast cancer cells. Remarkably, analog 4d was found to inhibit cell growth notably in two breast cancer cell lines by inducing apoptosis, and to be metabolized to release the parent NSAID along with the Se fragment. Taken together, our results show that Se-NSAID analog 4d could be a potential chemotherapeutic drug for breast cancer.

The co-administration of glial cell line-derived neurotrophic factor (GDNF) and mesenchymal stem cells (MSCs) in hydrogels (HGs) has emerged as a powerful strategy to enhance the efficient integration of transplanted cells in Parkinson's disease (PD). This strategy could be improved by controlling the cellular microenvironment and biomolecule release and better mimicking the complex properties of the brain tissue. Here, we develop and characterize a drug delivery system for brain repair where MSCs and GDNF are included in a nanoparticle-modified supramolecular guest-host HA HG. In this system, the nanoparticles act as both carriers for the GDNF and active physical crosslinkers of the HG. The multifunctional HG is mechanically compatible with brain tissue and easily injectable. It also protects GDNF from degradation and achieves its controlled release over time. The cytocompatibility studies show that the developed biomaterial provides a friendly environment for MSCs and presents good compatibility with PC12 cells. Finally, using RNA-sequencing (RNA-seq), we investigated how the three-dimensional (3D) environment, provided by the nanostructured HG, impacted the encapsulated cells. The transcriptome analysis supports the beneficial effect of including MSCs in the nanoreinforced HG. An enhancement in the anti-inflammatory effect of MSCs was observed, as well as a differentiation of the MSCs toward a neuron-like cell type. In summary, the suitable strength, excellent self healing properties, good biocompatibility, and ability to boost MSC regenerative potential make this nanoreinforced HG a good candidate for drug and cell administration to the brain.

The reactivity of thiophene in Diels-Alder reactions is investigated with different maleimide derivatives. In this paper, we have synthesized for the first time the Diels-Alder adducts of thiophene at room temperature and atmospheric pressure. Maleimido-thiophene adducts were promoted by AlCl3. The effects of solvent, time, temperature and the use of different Lewis acids were studied, showing dramatic effects for solvent and Lewis acid. Furthermore, the catalysis with AlCl3 is highly stereoselective, preferably providing the exo form of the adduct. Additionally, we also discovered the ability of AlCl3 to catalyze the arylation of maleimides to yield 3-aryl succinimides in a straightforward manner following a Friedel-Crafts-type addition. The inclusion of a selenocyanate group contributes to the cytotoxic activity of the adduct. This derivatization (from compound 7 to compound 15) results in an average GI(50) value of 1.98 mu M in the DTP (NCI-60) cell panel, resulting in being especially active in renal cancer cells.

Gold nanopArtículos (AuNPs) modified with four organoselenium compounds, i.e., 4-selenocyanatoaniline (compound 1), 4,4'-diselanediyldianiline (compound 2), N-(4-selenocyanatophenyl)cinnamamide (compound 3), and N-(3-selenocyanatopropyl)cinnamamide (compound 4), were synthesized following two different approaches: direct conjugation and non-covalent immobilization onto hydrophilic and non-cytotoxic AuNPs functionalized with 3-mercapto-1-propanesulfonate (3MPS). Both free compounds and AuNPs-based systems were characterized via UV-Vis, FTIR NMR, mass spectrometry, and SR-XPS to assess their optical and structural properties. Size and colloidal stability were evaluated by DLS and zeta-potential measurements, whereas morphology at solid-state was evaluated by atomic force (AFM) and scanning electron (FESEM) microscopies. AuNPs synthesized through chemical reduction method in presence of Se-based compounds as functionalizing agents allowed the formation of aggregated NPs with little to no solubility in aqueous media. To improve their hydrophilicity and stability mixed AuNPs-3MPS-1 were synthesized. Besides, Se-loaded AuNPs-3MPS revealed to be the most suitable systems for biological studies in terms of size and colloidal stability. Selenium derivatives and AuNPs were tested in vitro via MTT assay against PC-3 (prostatic adenocarcinoma) and HCT-116 (colorectal carcinoma) cell lines. Compared to free compounds, direct functionalization onto AuNPs with formation of Au-Se covalent bond led to non-cytotoxic systems in the concentration range explored (0-100 mu g/mL), whereas immobilization on AuNPs-3MPS improved the cytotoxicity of compounds 1, 3, and 4. Selective anticancer response against HCT-116 cells was obtained by AuNPs-3MPS-1. These results demonstrated that AuNPs can be used as a platform to tune the in vitro biological activity of organoselenium compounds.

Gold nanoparticles (AuNPs) modified with four organoselenium compounds, i.e., 4-selenocyanatoaniline (compound 1), 4,4'-diselanediyldianiline (compound 2), N-(4-selenocyanatophenyl)cinnamamide (compound 3), and N-(3-selenocyanatopropyl)cinnamamide (compound 4), were synthesized following two different approaches: direct conjugation and non-covalent immobilization onto hydrophilic and non-cytotoxic AuNPs functionalized with 3-mercapto-1-propanesulfonate (3MPS). Both free compounds and AuNPs-based systems were characterized via UV-Vis, FTIR NMR, mass spectrometry, and SR-XPS to assess their optical and structural properties. Size and colloidal stability were evaluated by DLS and ¿-potential measurements, whereas morphology at solid-state was evaluated by atomic force (AFM) and scanning electron (FESEM) microscopies. AuNPs synthesized through chemical reduction method in presence of Se-based compounds as functionalizing agents allowed the formation of aggregated NPs with little to no solubility in aqueous media. To improve their hydrophilicity and stability mixed AuNPs-3MPS-1 were synthesized. Besides, Se-loaded AuNPs-3MPS revealed to be the most suitable systems for biological studies in terms of size and colloidal stability. Selenium derivatives and AuNPs were tested in vitro via MTT assay against PC-3 (prostatic adenocarcinoma) and HCT-116 (colorectal carcinoma) cell lines. Compared to free compounds, direct functionalization onto AuNPs with formation of Au-Se covalent bond led to non-cytotoxic systems in the concentration range explored (0-100 ¿g/mL), whereas immobilization on AuNPs-3MPS improved the cytotoxicity of compounds 1, 3, and 4. Selective anticancer response against HCT-116 cells was obtained by AuNPs-3MPS-1. These results demonstrated that AuNPs can be used as a platform to tune the in vitro biological activity of organoselenium compounds.

In this study, the thermal behavior of a series of leishmanicidal selenocyanate and diselenide biological active compounds has been studied by means of differential scanning calorimetry, X-ray diffraction and thermogravimetry in order to establish thermal stability criteria and investigate their polymorphism. Moreover, stability under acid, alkaline and oxidative media was tested using high-performance liquid chromatography with fluorescence detection. The results of the experiments show that there are five types of polymorphic behaviors for the studied compounds. In addition, relationship is found among stability and a series of structural effects and stress conditions of compounds.

Currently, cancer, leishmaniasis and bacterial infections represent a serious public health burden worldwide. Six cinnamyl and benzodioxyl derivatives incorporating selenium (Se) as selenocyanate, diselenide, or selenide were designed and synthesized through a nucleophilic substitution and/or a reduction using hydrides. Ferrocene was also incorporated by a Friedel-Crafts acylation. All the compounds were screened in vitro for their antiproliferative, antileishmanial, and antibacterial properties. Their capacity to scavenge free radicals was also assessed as a first approach to test their antioxidant activity. Benzodioxyl derivatives 2a-b showed cytotoxicity against colon (HT-29) and lung (H1299) cancer cell lines, with IC50 values below 12 mu M, and were also fairly selective when tested in nonmalignant cells. Selenocyanate compounds 1-2a displayed potent antileishmanial activity in L. major and L. infantum, with IC50 values below 5 mu M. They also exhibited antibacterial activity in six bacterial strains, notably in S. epidermidis with MIC and MBC values of 12.5 mu g/mL. Ferrocene-containing selenide 2c was also identified as a potent antileishmanial agent with radical scavenging activity. Remarkably, derivative 2a with a selenocyanate moiety was found to act as a multitarget compound with antiproliferative, leishmanicidal, and antibacterial activities. Thus, the current work showed that 2a could be an appealing scaffold to design potential therapeutic drugs for multiple pathologies.

According to World Health Organization, neglected tropical diseases encompass all diseases that occur solely, or principally, in the tropics. In practice, the term is often taken to refer to infectious diseases that thrive in hot, humid conditions. Clinical and epidemiological studies suggest that selenium (Se) play an important role in tropical diseases, such as tuberculosis, leishmaniasis, filariasis and chagas, acting as preventive agent or in diagnosis and prognosis. Recent studies have evinced the importance of selenium in oxidative status and antioxidant defense capabilities during the course of infection and progression of the illness in human patients and experimental models. For this reason, one of the most relevant mechanism of action proposed involve selenoproteins, i.e. glutathione peroxidase (GPx), an enzyme that protects against oxidative stress and modulates the redox processes. In addition, it was observed that low Se levels were positively correlated with an increased susceptibility to infections. Besides, Se supplementation is proposed as an adjuvant therapy for treatment of these chronic diseases. However, there is a lack in the literature references related to synthesis and biological evaluation of novel derivatives containing selenium moiety against these diseases. During the last years our research group is interested in the design and synthesis of organoselenium compounds as new class of agents for treatment of neglected tropical diseases. In the present year we have reported two general structures with leishmanicidal activity, corresponding both of them to symmetrical compounds. The firsts are alkyl imidoselenocarbamates (alkyl isoselenourea) which possessed a moderate effect in vitro and the second ones are selenocyanates and diselenides. It is remarkable that some of them showed stronger in vitro antileishmanial activity than edelfosine and miltefosine, used as reference drugs, and combined high potency and low cytotoxicity against Jurkat and THP-1 cells. Selenium and Tropical Diseases (PDF Download Available). Available from: https://www.researchgate.net/publication/235745925_Selenium_and_Tropical_Diseases [accessed Jun 21, 2017].