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There is an urgent need to develop safer and more effective modalities for the treatment of numerous pathologies due to the increasing rates of drug resistance, undesired side effects, poor clinical outcomes, etc. Over the past decades, cyclodextrins (CDs) have gathered great attention as potential drug carriers due to their ability to enhance their bioactivities and properties. Likewise, selenium (Se) and tellurium (Te) have been extensively studied during the last decades due to their possible therapeutical applications. Although there is limited research on the relationship between Se and Te and CDs, herein, we highlight different representative examples of the advances related to this topic as well as give our view on the future directions of this emerging area of research. This review encompasses three different aspects of this relationship: (1) modification of the structure of the different CDs; (2) formation of host-guest interaction complexes of naïve CDs with Se and Te derivatives in order to overcome specific limitations of the latter; and (3) the use of CDs as catalysts to achieve novel Se and Te compounds.

There is an urgent need to develop safer and more effective modalities for the treatment of a wide range of pathologies due to the increasing rates of drug resistance, undesired side effects, poor clinical outcomes, etc. Throughout the years, selenium (Se) has attracted a great deal of attention due to its important role in human health. Besides, a growing body of work has unveiled that the inclusion of Se motifs into a great number of molecules is a promising strategy for obtaining novel therapeutic agents. In the current Perspective, we have gathered the most recent literature related to the incorporation of different Se moieties into the scaffolds of a wide range of known drugs and their feasible pharmaceutical applications. In addition, we highlight different representative examples as well as provide our perspective on Se drugs and the possible future directions, promises, opportunities, and challenges of this ground-breaking area of research.

Commercial cyclodextrins (CDs) are commonly used to form inclusion complexes (ICs) with different molecules in order to enhance their water solubility, stability, and bioavailability. Nowadays, there is strong, convincing evidence of the anticancer effect of selenium (Se)-containing compounds. However, pharmaceutical limitations, such as an unpleasant taste or poor aqueous solubility, impede their further evaluation and clinical use. In this work, we study the enhancement of solubility with CD complexes for a set of different nonsteroidal anti-inflammatory drug (NSAID) derivatives with Se as selenoester or diacyl diselenide chemical forms, with demonstrated antitumoral activity. The CD complexes were analyzed via nuclear magnetic resonance (NMR) spectroscopic techniques. In order to obtain additional data that could help explain the experimental results obtained, 3D models of the theoretical CD-compound complexes were constructed using molecular modeling techniques. Among all the compounds, I.3e and II.5 showed a remarkable increase in their water solubility, which could be ascribed to the formation of the most stable interactions with the CDs used, in agreement with the in silico studies performed. Thus, the preliminary results obtained in this work led us to confirm the selection of β and γ-CD as the most suitable for overcoming the pharmaceutical drawbacks of these Se derivatives.

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 uncollected 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. Unfortunately, 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., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

In recent years, both metal-based complexes and selenium-containing compounds have been widely explored for their therapeutic properties due to their roles in biological processes and modulation of diverse molecular targets. However, despite their growing interest, there is no review to date that covers the potential use of the combination of these entities to design new therapeutic derivatives. This review highlights the latest achievements in this particular field, with a focus on compounds with anticancer and/or antimicrobial properties. With this aim, the formation of coordination compounds including several metals bearing selenium either with direct interaction with the metal center or as part of the organic ligand elsewhere is covered. Besides, coordination compounds with a Se(IV) center have been assessed. The biological properties of several selenium-containing organometallic complexes have also been discussed, including metallocenes, half-sandwich complexes, and compounds with N-heterocyclic carbenes, CO, and π-ligands, and other σ-bonded entities. The information compiled in this review may be helpful to design and develop novel, more potent, and safer metal-based compounds for the treatment of several pathologies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

This work reports the synthesis and characterization by Fourier transform infrared spectroscopy (FTIR), 1 H, 13 C, and 79 Se nuclear magnetic resonance (NMR), mass spectrometry, and elemental analysis techniques as well as the in vitro evaluation of the leishmanicidal activity of 13 new selenophosphoramidate derivatives. Among the new compounds, four of them (compounds 1f, 1g, 2f, and 2g), which exhibited the best profiles, were tested against infected macrophages and were selected for further studies related to their leishmanicidal mechanism. In this regard, trypanothione redox system alteration was determined. Compound 1g, under similar conditions, was more effective than the corresponding references. In addition, theoretical calculations showed that this compound also presents most physicochemical and pharmacokinetic properties within the ranges expected for orally available drugs. It is believed that selenophosphoramidate functionalities may represent a scaffold to be explored toward the development of new agents for leishmania treatment.

Chagas disease is a tropical infection caused by the protozoan parasite Trypanosoma cruzi and a global public health concern. It is a paradigmatic example of a chronic disease without an effective treatment. Current treatments targeting T. cruzi are limited to two obsolete nitroheterocyclic drugs, benznidazole and nifurtimox, which lead to serious drawbacks. Hence, new, more effective, safer, and affordable drugs are urgently needed. Selenium and their derivatives have emerged as an interesting strategy for the treatment of different prozotoan diseases, such as African trypanosomiasis, leishmaniasis, and malaria. In the case of Chagas disease, diverse selenium scaffolds have been reported with antichagasic activity in vitro and in vivo . On the basis of these premises, we describe the in vitro and in vivo trypanocidal activity of 41 selenocompounds against the three morphological forms of different T. cruzi strains. For the most active selenocompounds, their effect on the metabolic and mitochondrial levels and superoxide dismutase enzyme inhibition capacity were measured in order to determine the possible mechanism of action. Derivative 26 , with a selenocyanate motif, fulfills the most stringent in vitro requirements for potential antichagasic agents and exhibits a better profile than benznidazole in vivo . This finding provides a step forward for the development of a new antichagasic agent.

Two new series of 28 selenocyanate and diselenide derivatives containing amide moieties were designed, synthesized, and evaluated for their leishmanicidal activity against Leishmania infantum axenic amastigotes, and selectivity was assessed in human THP-1 cells. Eleven compounds exhibited excellent leishmanicidal activity with EC 50 values lower than the reference drug miltefosine (EC 50 = 2.84 μM). In addition, for six of them the selectivity index ranged from 9 to >1,442, greater than both references used. The most potent and selective compounds were compounds 2h, 2k, and 2m that displayed EC 50 values of 0.52, 1.19, and 0.50 μM, respectively, and a high selectivity index (SI) when tested against THP-1 monocytic cells (SI = >1,442, >672, and >1,100, respectively). These derivatives showed an efficacy similar to that of the reference drugs but much better SI values. They also showed interesting activity values against infected macrophages. Trypanothione reductase (TryR) activity and intracellular thiol level measurement assays were performed for the three best compounds in an attempt to elucidate their mechanism of action. Despite that the new analogs exhibited comparable or better inhibitory activities than the reference TryR inhibitors, more studies are necessary to confirm this result. In summary, our findings suggest that the three compounds described here could constitute leading leishmanicidal drug candidates., (Copyright © 2020 American Society for Microbiology.)

The physicochemical properties of a compound play a crucial role in the cancer development process. In this context, polymorphism can become an important obstacle for the pharmaceutical industry because it frequently leads to the loss of therapeutic effectiveness of some drugs. Stability under manufacturing conditions is also critical to ensure no undesired degradations or transformations occur. In this study, the thermal behaviour of 40 derivatives of a series of sulphur and selenium heteroaryl compounds with potential antitumoural activity were studied. In addition, the most promising cytotoxic derivatives were analysed by a combination of differential scanning calorimetry, X-ray diffraction and thermogravimetric techniques in order to investigate their polymorphism and thermal stability. Moreover, stability under acid, alkaline and oxidative media was tested. Degradation under stress conditions as well as the presence of polymorphism was found for the compounds VA6E and VA7J, which might present a hurdle to carrying on with formulation. On the contrary, these obstacles were not found for derivative VA4J.

Diselenide and sulfonamide derivatives have recently attracted considerable interest as leishmanicidal agents in drug discovery. In this study, a novel series of sixteen hybrid selenosulfonamides has been synthesized and screened for their in vitro activity against Leishmania infantum intracellular amastigotes and THP-1 cells. These assays revealed that most of the compounds exhibited antileishmanial activity in the low micromolar range and led us to identify three lead compounds (derivatives 2, 7 and 14) with IC50 values ranging from 0.83 to 1.47 μM and selectivity indexes (SI) over 17, much higher than those observed for the reference drugs miltefosine and edelfosine. When evaluated against intracellular amastigotes, hybrid compound 7 emerged as the most active compound (IC50 = 2.8 μM), showing higher activity and much less toxicity against THP-1 cells than edelfosine. These compounds could potentially serve as templates for future drug-optimization and drug-development efforts for their use as therapeutic agents in developing countries., (Copyright © 2014 Elsevier Masson SAS. All rights reserved.)

The synthesis, cytotoxic activities and selectivities of 35 derivatives related to quinazoline and pyrido[2,3-d]pyrimidine are described. The synthesized compounds were screened in vitro against four tumoral cell lines - leukemia (CCRF-CEM), colon (HT-29), lung (HTB-54) and breast (MCF-7) - and two cell lines derived from non-malignant cell lines, one mammary (184B5) and one from bronchial epithelium (BEAS-2B). MCF-7 and HTB-54 were the most sensitive cell lines with GI(50) values below 10μM for eleven and ten compounds, respectively. Two compounds (2o and 3a) were identified that evoked a marked cytotoxic effect in all cell lines tested and one compound, 7h, was potent and selective against MCF-7. A preliminary study into the mechanism of the potent derivatives 2o, 3a and 7h indicated that the cytotoxic activities of these compounds might be mediated by inducing cell death without affecting cell cycle phases., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

In the present study, a family of 15 imidothio- and imidoselenocarbamates (1-15) analogs have been synthesized and screened for their in vitro antileishmanial potential against Leishmania infantum promastigotes. The six most active ones (2, 4, 7, 13, 14, and 15) were also tested in an axenic amastigote model. In order to establish their selectivity indexes (SI) the cytotoxic effect of each compound was also assayed against Jurkat and THP-1 cell lines. Compounds 2 and 4, both with a pyridine moiety, showed a moderate antileishmanial activity with an IC(50) value of 4.68 ± 0.46 and 3.03 ± 0.24 μM, respectively, in the amastigote model. The activity was compared with that of standard drugs, edelfosine (IC₅₀ = 0.82 ± 0.13 μM) and miltefosine (IC₅₀ = 2.84 ± 0.10 μM). Related to selectivity, the SI of both compounds are similar to those of the standard drugs when compared against the THP-1 cell line. Moreover, compound 4 was able to reduce the number of amastigote-infected THP-1 cells to 40% of that observed in untreated controls after a 96-h period of treatment. These derivatives thus represent two new leads for further studies aimed at establishing their mechanism of action.

Recent epidemiological studies have demonstrated that selenium may be an effective chemopreventive and anticancer agent with a broad spectrum against several human cancer cells (prostate, colon, bladder, lung, liver, ovarian, leukemia). A wide range of potential mechanisms have been proposed for the antitumorigenic effects of selenium and these include antiandrogen activity, growth inhibitory effects by regulation of p53 and antioxidant function, and through DNA damage. However, apoptosis is one of the most plausible mechanisms for the anticancer activity. The regulating mechanisms of apoptosis are extremely complex and for selenium compounds they mainly involve a mitochondrial pathway, protein kinases, tumor necrosis factor, activation of caspases and reactive oxygen species. The aim of this review is to summarize the current knowledge about more than twenty eight selenium-containing molecules and to discuss the implications for apoptosis and the impact in cancer therapy.

Currently, cancer remains a global health problem. Despite the existence of several treatments, including chemotherapy, immunotherapy, and radiation therapy, the survival rate for most cancer patients, particularly those with metastasis, remains unsatisfactory. Thus, there is a continuous need to develop novel, effective therapies. In this work, 22 novel molecules containing selenium are reported, including seven Se-acylisoselenoureas synthesized from aliphatic carbodiimides as well as acylselenoureas with the same carbo- and heterocycles and aliphatic amines. After an initial screening at two doses (50 and 10 µM) in MDA-MB-231 (breast), HTB-54 (lung), DU-145 (prostate), and HCT-116 (colon) tumor cell lines, the ten most active compounds were identified. Additionally, these ten hits were also submitted to the DTP program of the NCI to study their cytotoxicity in a panel of 60 cancer cell lines. Compound 4 was identified as the most potent antiproliferative compound. The results obtained showed that compound 4 presented IC50 values lower than 10 µM in the cancer cell lines, although it was not the most selective one. Furthermore, compound 4 was found to inhibit cell growth and cause cell death by inducing apoptosis partially via ROS production. Overall, our results suggest that compound 4 could be a potential chemotherapeutic drug for different types of cancer. [ABSTRACT FROM AUTHOR]

The introduction of selenium (Se) into organic scaffolds has been demonstrated to be a promising framework in the field of medicinal chemistry. A novel design of nonsteroidal anti-inflammatory drug (NSAID) derivatives based on a bioisosteric replacement via the incorporation of Se as diacyl diselenide is reported. The antioxidant activity was assessed using the DPPH radical scavenging assay. The new Se-NSAID derivatives bearing this unique combination showed antioxidant activity in a time- and dose-dependent manner, and also displayed different antiproliferative profiles in a panel of eight cancer cell lines as determined by the MTT assay. Ibuprofen derivative 5 was not only the most antioxidant agent, but also selectively induced toxicity in all the cancer cell lines tested (IC50 < 10 µM) while sparing nonmalignant cells, and induced apoptosis partially without enhancing the caspase 3/7 activity. Furthermore, NSAID derivative 5 significantly suppressed tumor growth in a subcutaneous colon cancer xenograft mouse model (10 mg/kg, TGI = 72%, and T/C = 38%) without exhibiting any apparent toxicity. To our knowledge, this work constitutes the first report on in vitro and in vivo anticancer activity of an unprecedented Se-NSAID hybrid derivative and its rational use for developing precursors for bioisosteric selenocompounds with appealing therapeutic applications. [ABSTRACT FROM AUTHOR]

Oxidative stress surrounding cancer cells provides them with certain growth and survival advantages necessary for disease progression. In this context, Se-containing molecules have gained attention due to their anticancer and antioxidant activity. In our previous work, we synthesized a library of 39 selenoesters containing functional groups commonly present in natural products (NP), which showed potent anticancer activity, but did not demonstrate high radical scavenger activity. Thus, 20 novel Se derivatives resembling NP have been synthesized presenting acylselenourea functionality in their structures. Radical scavenger activity was tested using DPPH assay and in vitro protective effects against ROS-induced cell death caused by H2O2. Additionally, antiproliferative activity was evaluated in prostate, colon, lung, and breast cancer cell lines, along with their ability to induce apoptosis. Compounds 1.I and 5.I showed potent cytotoxicity against the tested cancer cell lines, along with high selectivity indexes and induction of caspase-mediated apoptosis. These compounds exhibited potent and concentration-dependent radical scavenging activity achieving DPPH inhibition similar to ascorbic acid and trolox. To conclude, we have demonstrated that the introduction of Se in the form of acylselenourea into small molecules provides strong radical scavengers in vitro and antiproliferative activity, which may lead to the development of promising dual compounds. [ABSTRACT FROM AUTHOR]

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 µM. 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 × 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. [ABSTRACT FROM AUTHOR]

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 µM, 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 µM. They also exhibited antibacterial activity in six bacterial strains, notably in S. epidermidis with MIC and MBC values of 12.5 µg/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. [ABSTRACT FROM AUTHOR]

Selenium (Se) is an essential element for human health as it is involved in different physiological functions. Moreover, a great number of Se compounds can be considered potential agents in the prevention and treatment of some diseases. It is widely recognized that Se activity is related to multiple factors, such as its chemical form, dose, and its metabolism. The understanding of its complex biochemistry is necessary as it has been demonstrated that the metabolites of the Se molecules used to be the ones that exert the biological activity. Therefore, the aim of this review is to summarize the recent information about its most remarkable metabolites of acknowledged biological effects: hydrogen selenide (HSe−/H2Se) and methylselenol (CH3SeH). In addition, special attention is paid to the main seleno-containing precursors of these derivatives and their role in different pathologies. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Tetronic micelles were used as nanocarriers for a new family of selenodiazoles. • The micelles enhance the water-solubility and cytotoxicity of the Se-derivatives. • The new Se constructs are selective towards cancer prostate and breast cancer cells. • Increasing the length of the constructs’ hydrocarbon chain increases their activity. • SE12 (side chain with 12 methylenes) shows a activity 100-fold higher than ebselen. Abstract Selenium (Se) incorporated into organic frameworks has demonstrated anticancer activity against several cancer types. One of the drawbacks of most of these constructs is their poor solubility and bioavailability, which can be overcome with the use of suitable nanocarriers. We have synthesized a series of 5-substituted amide selenodiazoles, based on the parent structure of ebselen, an organoselenium drug with proven cytoprotective activity, and solubilized them in polymeric micelles of poloxamines, poly(ethylene oxide)-poly(propylene oxide) X-shaped tetrablock-copolymers. Scattering methods (SANS and DLS) were employed to characterize the micellar nanocarriers. MTT biological evaluation highlights the selectivity of the Se-compounds towards cancer cells, with MCF-7 standing as the most responsive line. The alkylation of the heterocycle with a 12-carbon hydrophobic tail displays the highest activity, showing a 100-fold increase with respect to ebselen. This compound also exhibits the greatest increase in solubility in poloxamine micelles, overall resulting in a one-fold increase in activity with respect to the non-formulated form, making it a hit compound for further optimization. [ABSTRACT FROM AUTHOR]

Trace element selenium and its metabolites have received a great deal of attention with regard to the development of new therapies for both cancer prevention and treatment. Following this approach, our research group has synthesized a series of novel selenocarbamates derivatives. We present thermal analysis of the novel compounds, performed with differential scanning calorimetry and thermogravimetric analysis. Relationship is found among thermal analytical data and structure of the different series of compounds. These data allow establishing criteria for the selection of substituents that improve the stability. The most thermally unstable compounds are those with higher cytotoxic activities, suggesting that the release of methylselenol could be implicated in the biological activity. [ABSTRACT FROM AUTHOR]

Mycorrhizal inoculation can enhance the nutritional value of lettuces. However, the role of arbuscular mycorrhizal fungi (AMF) in biofortification of selenium (Se) in lettuce is unknown. We tested the capacity of two cultivars of lettuces, inoculated or not with AMF, for accumulating Se in shoots after applying sodium selenite or new synthesized organic selenocompounds. Sodium selenite was the most effective for increasing Se in shoots, but it decreased levels of macronutrients, micronutrients and proteins in one cultivar. Mycorrhizal inoculation reduced the accumulation of Se in leaves, but inoculated plants had higher contents of minerals, proteins and/or sugars than the non-inoculated controls supplied with Se. Mycorrhizal inoculation may impair the biofortification of lettuces with Se, but could be adequate for cultivating lettuces on soils rich in Se. The organic imidoselenocarbamate improved the effectiveness of AMF for enhancing growth, and proteins and sugars in leaves of one greenhouse-grown cultivar of lettuce. [ABSTRACT FROM AUTHOR]

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 GI50 value of 1.98 µM in the DTP (NCI-60) cell panel, resulting in being especially active in renal cancer cells. [ABSTRACT FROM AUTHOR]

Differential scanning calorimetry (DSC) and thermogravimetry (TG) are analytical and quantitative methods capable of providing reliable, fast and reproducible results. These data allow establishing the thermal stability, purity degree and the polymorphic behavior of organic compounds. Thermal analysis of fusion and degradation processes was carried out on organonitrogen, organosulfur and organoselenium phthalazine derivatives to establish thermal stability criteria. Decomposition and fusion temperatures of 27 biological active compounds, synthesized by our research group were determined using TG and DSC. Analysis of the thermal data indicated that: (a) in general, nitrogen compounds are more stable than sulfur and selenium compounds; (b) thioderivatives possess degradation temperatures higher than selenium compounds; (c) the presence of selenium atoms in molecular structure has associated a minor thermal stability; (d) sulfide derivatives decomposition process have higher T values than disulfide compounds; (e) there are differences in the stability due to groups selenol, methylseleno, and cyanoseleno; (f) the nature of the substituent located on the benzyl ring has no effects on selenophthalazines thermal stability. [ABSTRACT FROM AUTHOR]

Selenium (Se) is an essential trace element involved in different physiological functions of the human body and plays a role in cancer prevention and treatment. Induction of apoptosis is considered an important cellular event that can account for the cancer preventive effects of Se. The mechanisms of Se-induced apoptosis are associated with the chemical forms of Se and their metabolism as well as the type of cancer studied. So, some selenocompounds, such as SeO2 involve the activation of caspase-3 while sodium selenite induces apoptosis in the absence of the activation of caspases. Modulation of mitochondrial functions has been reported to play a key role in the regulation of apoptosis and also to be one of the targets of Se compounds. Other mechanisms for apoptosis induction are the modulation of glutathione and reactive oxygen species levels, which may function as intracellular messengers to regulate signaling pathways, or the regulation of kinase, among others. Emerging evidence indicates the overlaps between the apoptosis and other types of cell death such as autophagy. In this review we report different processes of cell death induced by Se compounds in cancer treatment and prevention. [ABSTRACT FROM AUTHOR]

Although the causes of cancer lie in mutations or epigenic changes at the genetic level, their molecular manifestation is the dysfunction of biochemical pathways at the protein level. The 518 protein kinases encoded by the human genome play a central role in various diseases, a fact that has encouraged extensive investigations on their biological function and three dimensional structures. Selenium (Se) is an important nutritional trace element involved in different physiological functions with antioxidative, antitumoral and chemopreventive properties. The mechanisms of action for selenocompounds as anticancer agents are not fully understood, but kinase modulation seems to be a possible pathway. Various organosulfur compounds have shown antitumoral and kinase inhibition effects but, in many cases, the replacement of sulfur by selenium improves the antitumoral effect of compounds. Although Se atom possesses a larger atomic volume and nucleophilic character than sulfur, Se can also formed interactions with aminoacids of the catalytic centers of proteins. So, we propose a novel chemical library that includes organoselenium compounds as kinase modulators. In this study thirteen selenocompounds have been evaluated at a concentration of 3 or 10 μM in a 24 kinase panel using a Caliper LabChip 3000 Drug Discover Platform. Several receptor (EGFR, IGFR1, FGFR1…) and non-receptor (Abl) kinases have been selected, as well as serine/threonine/lipid kinases (AurA, Akt, CDKs, MAPKs…) implicated in main cancer pathways: cell cycle regulation, signal transduction, angiogenesis regulation among them. The obtained results showed that two compounds presented inhibition values higher than 50% in at least four kinases and seven derivatives selectively inhibited one or two kinases. Furthermore, three compounds selectively activated IGF-1R kinase with values ranging from -98% to -211%. In conclusion, we propose that the replacement of sulfur by selenium seems to be a potential and useful strategy in the search of novel chemical compound libraries against cancer as kinase modulators. [ABSTRACT FROM AUTHOR]

The present study describes the biological evaluation of a library of 59 organoselenium compounds as superoxide (O2-) generators and cytotoxic agents in human prostate cancer cells (PC-3) and in breast adenocarcinoma (MCF-7). In order to corroborate that the biological activity for selenium compounds depends on the chemical form, a broad structural variety is presented. These structures include selenocyanates, diselenides, selenoalkyl functional moieties and eight newly synthesized symmetrically substituted dithioselenites and selenylureas. Eleven of the derivatives tested showed high levels of superoxide generation in vitro via oxidation of reduced glutathione (GSH) and nine of them were more catalytic than the reference compound, diselenodipropionic acid. Eighteen of the library compounds inhibited cell growth more than or similar to reference chemotherapeutic drugs in PC-3 and eleven were more potent cytotoxic agents than etoposide in the MCF-7 cell line. Considering both parameters (superoxide generation and cell cytotoxicity) compounds B1, C6 and C9 displayed the best therapeutic profiles. Considering that many diselenide compounds can generate superoxide (O2-) in vitro via oxidation of GSH and other thiols, the analogue B1, that contains a diselenide moiety, was selected for a preliminary mechanistic investigation, which . revealed that B1 has apoptogenic effects similar to camptothecin mediated by reactive oxygen species (ROS) in lymphocytic leukemia cells (CCRF-CEM) and affected the MCF-7 cell-cycle in G2/M and S-phases. [ABSTRACT FROM AUTHOR]

A series of 30 novel N,N disubstituted selenoureas were synthesized, characterized, and their antioxidant ability was tested using 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid (ABTS) assays. Additionally, their cytotoxic activity was tested in vitro in a panel of three different cancer (breast, lung and colon) and two normal cell lines. Each selenourea entity contains a para-substituted phenyl ring with different electron-withdrawing and electron-donating groups, and different aliphatic and aromatic nuclei. All of the synthesized selenoureas present antioxidant capacity at high concentrations in the DPPH assay, and three of them (2b, 2c and 2d) showed greater radical scavenging capacity than ascorbic acid at lower concentrations. These results were confirmed by the ABTS assay, where these novel selenoureas present even higher antioxidant capacity than the reference compound Trolox. On the other hand, 10 selenoureas present IC50 values below 10 µM in at least one cancer cell line, resulting in the adamantyl nucleus (6a–6e), the most interesting in terms of activity and selectivity. Outstanding results were found for selenourea 6c, tested in the NCI60 cell line panel and showing an average GI50 of 1.49 µM for the 60 cell lines, and LC50 values ranging from 9.33 µM to 4.27 µM against 10 of these cancer cell lines. To gain insight into its anticancer activity mechanism, we investigated the cell cycle progression of the promising compound 6c, as well as the type of programmed-cell death in a colon cancer cell line it provokes (HT-29). Compound 6c provoked S phase cell cycle arrest and the induction of cell death was independent of caspase activation, suggesting autophagy, though this assertion requires additional studies. Overall, we envision that this compound can be further developed for the potential treatment of colon cancer. [ABSTRACT FROM AUTHOR]

Breast cancer is a multifactor disease, and many drug combination therapies are applied for its treatment. Selenium derivatives represent a promising potential anti-breast cancer treatment. This study reports the cytotoxic activity of forty-one amides and phosphoramidates containing selenium against five cancer cell lines (MCF-7, CCRF-CEM, HT-29, HTB-54 and PC-3) and two nonmalignant cell lines (184B5 and BEAS-2B). MCF-7 cells were the most sensitive and the selenoamides I.1f and I.2f and the selenium phosphoramidate II.2d, with GI50 values ranging from 0.08 to 0.93 µM, were chosen for further studies. Additionally, radical scavenging activity for all the compounds was determined using DPPH and ABTS colorimetric assays. Phosphoramidates turned out to be inactive as radical scavengers. No correlation was observed for the antioxidant activity and the cytotoxic effect, except for compounds I.1e and I.2f, which showed dual antioxidant and antitumor activity. The type of programmed cell death and cell cycle arrest were determined, and the results provided evidence that I.1f and I.2f induced cell death via autophagy, while the derivative II.2d provoked apoptosis. In addition, Western blot analysis corroborated these mechanisms with an increase in Beclin1 and LC3-IIB and reduced SQSTM1/p62 levels for I.1f and I.2f, as well as an increase in BAX, p21 and p53 accompanied by a decrease in BCL-2 levels for derivative II.2d. [ABSTRACT FROM AUTHOR]

Selenium is an essential micronutrient with a wide range of biological effects in mammals. The inorganic form of selenium, selenite, is supplemented to relieve individuals with selenium deficiency and to alleviate associated symptoms. Additionally, physiological and supranutritional selenite have shown selectively higher affinity and toxicity towards cancer cells, highlighting their potential to serve as chemotherapeutic agents or adjuvants. At varying doses, selenite extensively regulates cellular signaling and modulates many cellular processes. In this study, we report the identification of Delta–Notch signaling as a previously uncharacterized selenite inhibited target. Our transcriptomic results in selenite treated primary mouse hepatocytes revealed that the transcription of Notch1, Notch2, Hes1, Maml1, Furin and c-Myc were all decreased following selenite treatment. We further showed that selenite can inhibit Notch1 expression in cultured MCF7 breast adenocarcinoma cells and HEPG2 liver carcinoma cells. In mice acutely treated with 2.5 mg/kg selenite via intraperitoneal injection, we found that Notch1 expression was drastically lowered in liver and kidney tissues by 90% and 70%, respectively. Combined, these results support selenite as a novel inhibitor of Notch signaling, and a plausible mechanism of inhibition has been proposed. This discovery highlights the potential value of selenite applied in a pathological context where Notch is a key drug target in diseases such as cancer, fibrosis, and neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Aspirin (ASA) has attracted wide interest of numerous scientists worldwide thanks to its chemopreventive and chemotherapeutic effects, particularly in colorectal cancer (CRC). Incorporation of selenium (Se) atom into ASA has greatly increased their anti-tumoral efficacy in CRC compared with the organic counterparts without the Se functionality, such as the promising antitumoral methylseleno-ASA analog (1a). Nevertheless, the efficacy of compound 1a in cancer cells is compromised due to its poor solubility and volatile nature. Thus, 1a has been formulated with native α-, β- and γ-cyclodextrin (CD), a modified β-CD (hydroxypropyl β-CD, HP-β-CD) and Pluronic F127, all of them non-toxic, biodegradable and FDA approved. Water solubility of 1a is enhanced with β- and HP- β-CDs and Pluronic F127. Compound 1a forms inclusion complexes with the CDs and was incorporated in the hydrophobic core of the F127 micelles. Herein, we evaluated the cytotoxic potential of 1a, alone or formulated with β- and HP- β-CDs or Pluronic F127, against CRC cells. Remarkably, 1a formulations demonstrated more sustained antitumoral activity toward CRC cells. Hence, β-CD, HP-β-CD and Pluronic F127 might be excellent vehicles to improve pharmacological properties of organoselenium compounds with solubility issues and volatile nature. [ABSTRACT FROM AUTHOR]

Selenium compounds are pivotal in medicinal chemistry for their antitumoral and antioxidant properties. Forty seven acylselenoureas have been designed and synthesized following a fragment-based approach. Different scaffolds, including carbo- and hetero-cycles, along with mono- and bi-cyclic moieties, have been linked to the selenium containing skeleton. The dose- and time-dependent radical scavenging activity for all of the compounds were assessed using the in vitro 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) assays. Some of them showed a greater radical scavenging capacity at low doses and shorter times than ascorbic acid. Therefore, four compounds were evaluated to test their protective effects against H2O2-induced oxidative stress. One derivative protected cells against H2O2-induced damage, increasing cell survival by up to 3.6-fold. Additionally, in vitro cytotoxic activity of all compounds was screened against several cancer cells. Eight compounds were selected to determine their half maximal inhibitory concentration (IC50) values towards breast and lung cancer cells, along with their selectivity indexes. The breast cancer cells turned out to be much more sensitive than the lung. Two compounds (5d and 10a) stood out with IC50 values between 4.2 μM and 8.0 μM towards MCF-7 and T47D cells, with selectivity indexes greater than 22.9. In addition, compound 10b exhibited dual antioxidant and cytotoxic activities. Although further evidence is needed, the acylselenourea scaffold could be a feasible frame to develop new dual agents. [ABSTRACT FROM AUTHOR]

The prognosis for patients with metastatic melanoma remains very poor. Constitutive signal transducer and activator of transcription 3 (STAT3) activation has been correlated to metastasis, poor patient survival, larger tumor size, and acquired resistance against vemurafenib (PLX-4032), suggesting its potential as a molecular target. We recently designed a series of isoseleno- and isothio-urea derivatives of several biologically active heterocyclic scaffolds. The cytotoxic effects of lead isoseleno- and isothio-urea derivatives (compounds 1 and 3) were studied in a panel of five melanoma cell lines, including B-RAFV600E-mutant and wild-type (WT) cells. Compound 1 (IC50 range 0.8–3.8 µM) showed lower IC50 values than compound 3 (IC50 range 8.1–38.7 µM) and the mutant B-RAF specific inhibitor PLX-4032 (IC50 ranging from 0.4 to >50 µM), especially at a short treatment time (24 h). These effects were long-lasting, since melanoma cells did not recover their proliferative potential after 14 days of treatment. In addition, we confirmed that compound 1 induced cell death by apoptosis using Live-and-Dead, Annexin V, and Caspase3/7 apoptosis assays. Furthermore, compound 1 reduced the protein levels of STAT3 and its phosphorylation, as well as decreased the expression of STAT3-regulated genes involved in metastasis and survival, such as survivin and c-myc. Compound 1 also upregulated the cell cycle inhibitor p21. Docking studies further revealed the favorable binding of compound 1 with the SH2 domain of STAT3, suggesting it acts through STAT3 inhibition. Taken together, our results suggest that compound 1 induces apoptosis by means of the inhibition of the STAT3 pathway, non-specifically targeting both B-RAF-mutant and WT melanoma cells, with much higher cytotoxicity than the current therapeutic drug PLX-4032. [ABSTRACT FROM AUTHOR]

Malignant diseases present a serious public health burden and their treatment with traditional chemotherapy cannot be considered an all-round solution, due to toxic side effects. Selenium compounds (Se-compounds) have received substantial attention in medicinal chemistry, especially in experimental chemotherapy, both as cytotoxic agents and adjuvants in chemotherapy. A checkerboard microplate method was applied to study the drug interactions of Se-compounds and clinically relevant chemotherapeutic drugs against the multidrug-resistant (MDR) subtype of mouse t-lymphoma cells overexpressing the ABCB1 transporter. Se-compounds showed synergistic interactions with chemotherapeutic agents targeting the topoisomerase enzymes or the microtubule apparatus. The ketone-containing selenoesters showed synergism at lower concentrations (1.25 µM). Most of the tested compounds interacted antagonistically with alkylating agents and verapamil. A thiophene-containing Se-compound showed synergism with all tested drugs, except cisplatin. While the exact mechanism of drug interactions is yet unknown, the potency of the selenocompounds as efflux pump inhibitors or the potentiation of their efficacy as reactive oxygen species modulators may play a role in their complementary activity against the tested MDR lymphoma cell line. [ABSTRACT FROM AUTHOR]

Redox active selenium (Se) compounds have gained substantial attention in the last decade as potential cancer therapeutic agents. Several Se compounds have shown high selectivity and sensitivity against malignant cells. The cytotoxic effects are exerted by their biologically active metabolites, with methylselenol (CH3SeH) being one of the key executors. In search of novel CH3SeH precursors, we previously synthesized a series of methylselenoesters that were active (GI50 < 10 µM at 72 h) against a panel of cancer cell lines. Herein, we refined the mechanism of action of the two lead compounds with the additional synthesis of new analogs (ethyl, pentyl, and benzyl derivatives). A novel mechanism for the programmed cell death mechanism for Se-compounds was identified. Both methylseleninic acid and the novel CH3SeH precursors induced entosis by cell detachment through downregulation of cell division control protein 42 homolog (CDC42) and its downstream effector β1-integrin (CD29). To our knowledge, this is the first time that Se compounds have been reported to induce this type of cell death and is of importance in the characterization of the anticancerogenic properties of these compounds. [ABSTRACT FROM AUTHOR]

• Novel selenoderivatives CAIs of the β-CA from L. donovani chagasi are reported. • In vitro studies reported potent inhibition of the β-CA from L. donovani chagasi. • Leishmanicidal evaluation on L. infantum amastigotes and cytotoxicity in THP-1 cells. We report new organoselenium compounds bearing the sulfonamide moiety as effective inhibitors of the β-isoform of Carbonic Anhydrase from the unicellular parasitic protozoan L. donovani chagasi. All derivatives were evaluated in vitro for their leishmanicidal activities against Leishmania infantum amastigotes along with their cytotoxicities in human THP-1 cells. Compounds 3e-g showed their activity in the low micromolar range with IC 50 values spanning from 0.72 to 0.81 µM and selectivity indexes (SI) > 8 (for 3g SI > 30), thus much higher than those observed for the reference drugs miltefosine and edelfosine. This is the first study which reports new selenoderivatives with promising leishmanicidal properties and acting as Carbonic Anhydrase inhibitors too thus paving the way to the development of innovative agents for the treatment of neglected diseases such as leishmaniasis. [ABSTRACT FROM AUTHOR]

Taking into account that multidrug resistance (MDR) is the main cause for chemotherapeutic failure in cancer treatment and as a continuation of our efforts to overcome this problem we report the evaluation of one cyclic selenoanhydride ( 1 ) and ten selenoesters ( 2 – 11 ) in MDR human colon adenocarcinoma Colo 320 cell line. The most potent derivatives ( 1 , 9 – 11 ) inhibited the ABCB1 efflux pump much stronger than the reference compound verapamil. Particularly, the best one ( 9 ) was 4-fold more potent than verapamil at a 10-fold lower concentration. Furthermore, the evaluated derivatives exerted a potent and selective cytotoxic activity. In addition, they were strong apoptosis inducers as the four derivatives triggered apoptotic events in a 64–72% of the examined MDR Colo 320 human adenocarcinoma cells. [ABSTRACT FROM AUTHOR]

Abstract Twenty-seven novel benzo[ c ][1,2,5]selenadiazole-5-carboxylic acid (BSCA) derivatives were designed and synthesized. Anti-proliferative activity of these structures was tested in vitro against a panel of five human cancer cell lines, including prostate (PC-3), colon (HT-29), leukemia (CCRF-CEM), lung (HTB-54) and breast (MCF-7). Four compounds (5 , 6 , 7 and 19) showed potent inhibitory activity with GI 50 values below 10 μM in at least one of the cancer cell lines. The selectivity of these compounds was further examined in two non-malignant cell lines derived from breast (184B5) and lung (BEAS-2B). Compound 7 exhibited promising anti-proliferative activity (GI 50 = 3.7 μM) in MCF-7 cells, together with high selectivity index (SI > 27.1). The induction of cell death by compound 7 was independent of the apoptotic process and it did not affect cell cycle progression either. Likewise, radical scavenging properties of the new selenadiazole derivatives were confirmed by testing their ability to scavenge DPPH radicals. Four compounds (1 , 2 , 8 and 9) showed potent radical scavenging activity, compound 9 being the most effective. Overall, while compound 7 was identified as the most cell growth inhibitory agent and selectively toxic to cancer cells, compound 9 proved to be the most potent antioxidant among the selenadiazole derivatives synthesized. This series of compounds can serve as an excellent scaffold to achieve new and potent antioxidant compounds useful for several diseases, i.e. cancer, neurodegenerative, heart diseases and leishmaniasis, considering the high radical scavenging activity and low toxicity showed by most of the compounds. Graphical abstract Image 1 Highlights • 27 novel BSCA derivatives were designed and synthesized. • Compound 7 potently inhibited cancer cell viability and showed high selectivity. • Compound 7 neither induced apoptosis nor had effect on cell cycle progression. • Compound 9 showed significant high radical scavenging activity. [ABSTRACT FROM AUTHOR]

In this work, 27 novel hybrid derivatives containing diverse substituents with chalcogen atoms (selenium or sulfur) and several active heterocyclic scaffolds have been synthesized. Compounds were tested against two human cancer cells lines (MCF7 and PC-3) and a normal human mammary epithelial cell line (184B5) in order to determine their activity and selectivity against malignant cells. Ten compounds showed GI 50 values below 10 μM in at least one of the cancer cell lines and six of them exhibited a selectivity index higher than 9. In general, selenium-containing compounds were more active than their corresponding sulfur analogs but we found some thiocyanate derivatives with comparable or higher activity and selectivity. Among the different substituents, the seleno- and thio-cyanate groups showed the most promising results. On the basis of their potent activity and high selectivity index, compounds 7e and 8f (containing a thiocyanate and a selenocyanate group, respectively) were selected for further biological evaluation. Both the compounds induced caspase-dependent cell death and cell cycle arrest in G 2 /M phase. In addition, these compounds do not violate any of the Lipinski's Rule of Five and thus possess good potential to become drugs, compound 7e being particularly promising. [ABSTRACT FROM AUTHOR]

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 IC 50 values below 10 μM 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. [Display omitted] • Twenty-five compounds containing a selenoester group were synthesized from NSAIDs. • The Se-NSAID derivatives were evaluated for their antiproliferative activities. • Compounds 4a & 4d showed potent cytotoxicity and selectivity in breast cancer cells. • Compounds 4d effectively induced apoptosis in two breast cancer cell lines. • Indomethacin-derived compound 4d presented an appealing therapeutic profile. [ABSTRACT FROM AUTHOR]

In previous studies, 56 novel selenoesters and one cyclic selenoanhydride with chemopreventive, antiproliferative and cytotoxic activity were described. Herein, the selenoanhydride and selected selenoesters were evaluated for their ability to reverse the cancer multidrug resistance (MDR) using the ABCB1 efflux pump inhibition assay in mouse MDR T-lymphoma cells. Results showed that the selenoanhydride ( 1 ) and the selenoesters with ketone terminal fragments ( 9 – 11 ) exerted (1.7–3.6)-fold stronger efflux pump inhibitory action than the reference verapamil. In addition, those four derivatives triggered apoptotic events in more than 80% of the examined MDR mouse cells. [ABSTRACT FROM AUTHOR]

A series of novel selenourea derivatives and corresponding thiourea analogs were synthesized and tested against a panel of six human cancer cell lines: melanoma (1205Lu), lung carcinoma (A549), prostatic carcinoma (DU145), colorectal carcinoma (HCT116), pancreatic epithelioid carcinoma (PANC-1) and pancreatic adenocarcinoma (BxPC3). In general, we found that the selenium-containing derivatives were more potent than their isosteric sulfur analogs. Four selenourea derivatives ( 1e , 1f , 1g and 1i ) showed IC 50 values below 10 μM in all of tested cell lines at 72 h. On the basis of its potent activity, compound 1g was selected for further biological evaluation in different colon cancer cell lines. Our results indicated that compound 1g induced apoptosis by caspase activation, along with inhibition of anti-apoptotic proteins. [ABSTRACT FROM AUTHOR]

Arbuscular mycorrhizal fungi (AMF) favored the accumulation of secondary metabolites in leaves of lettuces in previous studies. When fertilized with selenium (Se), mycorrhizal lettuces had more proteins, sugars and minerals than non-mycorrhizal ones. However, Se contents were lower in mycorrhizal plants suggesting a negative correlation between Se and AMF applications. The aim of the present study was to test if Se fertilization interfered with AMF technology for enhancing secondary metabolites in lettuces. Green and red-leaf lettuces were or not inoculated with AMF and received or not different selenocompounds. Flavonols and anthocyanins were non-destructively measured. At harvest, growth, water status, chlorophylls, carotenoids, phenolics and antioxidant capacity were determined. In green-leaf lettuces Se application counteracted benefits of AMF on chlorophylls and carotenoids and decreased phenolics. In red-leaf lettuces, sodium selenite positively interacted with AMF in enhancing flavonols, but imidoselenocarbamate reduced flavonols in mycorrhizal plants. No significant interaction between AMF and Se was detected for the total antioxidant capacity in leaves of both types of lettuces. The efficiency of mycorrhizal technology for improving antioxidant compounds in the edible tissues of lettuces can be modified under Se fertilization, being the interaction positive or negative depending on lettuce cultivar, antioxidant compound and chemical form of selenocompound. [ABSTRACT FROM AUTHOR]

Novel selenocyanate and diselenide derivatives containing a carbamate moiety were synthesised and evaluated in vitro to determine their cytotoxic and radical scavenging properties. Cytotoxic activity was tested against a panel of human cell lines including CCRF-CEM (lymphoblastic leukaemia), HT-29 (colon carcinoma), HTB-54 (lung carcinoma), PC-3 (prostate carcinoma), MCF-7 (breast adenocarcinoma), 184B5 (non-malignant, mammary gland derived) and BEAS-2B (non-malignant, derived from bronchial epithelium). Most of the compounds displayed high antiproliferative activity with GI 50 values below 10 μM in MCF-7, CCRF-CEM and PC-3 cells. Radical scavenging properties of the new selenocompounds were confirmed testing their ability to scavenge DPPH and ABTS radicals. Based on the activity of selenium-based glutathione peroxidases (GPxs), compounds 1a , 2e and 2h were further screened for their capacity to reduce hydrogen peroxide under thiol presence. Results suggest that compound 1a mimics GPxs activity. Cytotoxic parameters, radical scavenging activity and ADME profile point to 1a as promising drug candidate. [ABSTRACT FROM AUTHOR]

The PI3K/Akt/mTOR/S6 ribosomal protein signalling pathway is a key potential target in breast cancer therapy, playing a central role in proliferation and cell survival. In this study, we found that the seleno-compound 2,4-dihydroselenoquinazoline ( 3a ) generally inhibited this signalling axis in MCF-7 breast cancer cells and caused downregulation of S6 ribosomal protein phosphorylation in a dose- and time-dependent manner. Furthermore, 3a caused a dose- and time-dependent decrease in MCF-7 cell viability as well as cell cycle arrest in G 2 /M. Interestingly 3a also induced apoptosis, as evidenced by cleavage of PARP and caspase-7, and inhibited autophagy, as demonstrated by accumulation of LC3-II and p62/SQSTM1. Given that induction of autophagy has been previously described as a mechanism by which some breast cancer cells counteract proapoptotic signalling and develop resistance to anti-hormone therapy, this suggests that this derivative, which both triggers apoptosis and inhibits autophagy, may be beneficial in preventing and overcoming resistance in breast cancer cells. The data also show the complexity of this signalling axis which is far from being understood. [ABSTRACT FROM AUTHOR]

Abstract: A series of 31 new selenoesters were synthesized and their cytotoxic activity was evaluated against a prostate cancer cell line (PC-3). The most active compounds were also tested against three tumoural cell lines (MCF-7, A-549 and HT-29) and one non-tumour prostate cell line (RWPE-1). Thirteen compounds showed significant activity towards all tumour cells investigated, and some of them were even more potent than etoposide and cisplatin, which were used as reference drugs. Because of their pronounced potency and/or selectivity, four analogues (5, 21, 28 and 30), were selected in order to assess their redox properties related to a possible redox modulating activity. The glutathione peroxidase (GPx) assay showed slight activity for compound 30 and the 2,2-diphenyl-1-picrylhydrazyl-(DPPH) assay showed a weak activity for compounds 5 and 28. The present results revealed that analogues 5, 21, 28 and 30 might serve as a useful starting point for the design of improved anti-tumour agents. [Copyright &y& Elsevier]

Abstract: In the search for molecules with potential antiangiogenic activity we found that several imidoselenocarbamate derivatives, which have pro-apoptotic and antiproliferative activities, under hypoxic conditions release methylselenol, a volatile and highly reactive gas that was considered to be responsible for the observed biological activity. The kinetic for the liberation of methylselenol is highly dependent on the nature of the overall structure and correlate with their proven pro-apoptotic activity in lung cancer cell line H157. The preliminary structure–activity relationships allow us to select as the basic structural element a scaffold constructed with an imidoselenocarbamate fragment decorated with a methyl residue on the Se central atom and two heteroaromatic lateral rings. These imidoselenocarbamate derivatives may be of interest both for their antitumoral activities and because they have a structure that can be considered as a template for the design of new derivatives with apoptotic activity. This activity is related to the controlled delivery of methylselenol and makes this an interesting approach to develop new antitumoral agents. [Copyright &y& Elsevier]