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Small Molecules Containing Sulfur, Selenium, or Tellurium as Bioactive Compounds

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 April 2021) | Viewed by 30338

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Dr. Daniel Plano Amatriain

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Department of Pharmaceutical Sciences, School of Pharmacy and Nutrition, University of Navarra, Irunlarrea 1, E-31008 Pamplona, Spain
Interests: selenium; cancer; trypanosome; NSAIDs; organic synthesis; molecular biology; chemical sciences
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Carmen Sanmartín

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Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Irunlarrea 1, E-31008 Pamplona, Spain
Interests: selenium; cancer; leishmania; medicinal chemistry
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Dr. Carlos Aydillo

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Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Irunlarrea 1, E-31008 Pamplona, Spain
Interests: organic synthesis; amino acids; selenium

Special Issue Information

Dear Colleagues,

Substantial evidence suggests that small organic molecules decorated with sulfur, selenium, or tellurium (organochalcogens) have a plethora of effects on different diseases, including cancer, Alzheimer’s, and infectious and parasitic diseases. This Special Issue will gather the latest advances in the preclinical development of these organochalcogen derivatives. Thus, this Special Issue will collect strong in vitro and in vivo data regarding the molecular biology of these organochalcogens. Additionally, research articles could contain synthesis and characterization of new organochalcogen derivatives and the development of new carriers, although it is not the main aim of this Special Issue. To sum up, this Special Issue will contribute to the preclinical development of organochalcogens, which have demonstrated to date unique and unexpected features compared with the related non-organochalcogen analogs.

Dr. Daniel Plano
Prof. Carmen Sanmartín
Dr. Carlos Aydillo
Guest Editors

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Keywords

Sulfur
Selenium
Tellurium
Organochalcogen
Cancer
Alzheimer’s
Parasitic diseases
Infectious diseases

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Published Papers (9 papers)

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Research

38 pages, 5651 KiB

Open AccessArticle

Comprehensive Evaluation of Biological Effects of Pentathiepins on Various Human Cancer Cell Lines and Insights into Their Mode of Action

by Lisa Wolff, Siva Sankar Murthy Bandaru, Elias Eger, Hoai-Nhi Lam, Martin Napierkowski, Daniel Baecker, Carola Schulzke and Patrick J. Bednarski

Int. J. Mol. Sci. 2021, 22(14), 7631; https://doi.org/10.3390/ijms22147631 - 16 Jul 2021

Cited by 8 | Viewed by 3125

Abstract

Pentathiepins are polysulfur-containing compounds that exert antiproliferative and cytotoxic activity in cancer cells, induce oxidative stress and apoptosis, and inhibit glutathione peroxidase (GPx1). This renders them promising candidates for anticancer drug development. However, the biological effects and how they intertwine have not yet been systematically assessed in diverse cancer cell lines. In this study, six novel pentathiepins were synthesized to suit particular requirements such as fluorescent properties or improved water solubility. Structural elucidation by X-ray crystallography was successful for three derivatives. All six underwent extensive biological evaluation in 14 human cancer cell lines. These studies included investigating the inhibition of GPx1 and cell proliferation, cytotoxicity, and the induction of ROS and DNA strand breaks. Furthermore, selected hallmarks of apoptosis and the impact on cell cycle progression were studied. All six pentathiepins exerted high cytotoxic and antiproliferative activity, while five also strongly inhibited GPx1. There is a clear connection between the potential to provoke oxidative stress and damage to DNA in the form of single- and double-strand breaks. Additionally, these studies support apoptosis but not ferroptosis as the mechanism of cell death in some of the cell lines. As the various pentathiepins give rise to different biological responses, modulation of the biological effects depends on the distinct chemical structures fused to the sulfur ring. This may allow for an optimization of the anticancer activity of pentathiepins in the future. Full article

(This article belongs to the Special Issue Small Molecules Containing Sulfur, Selenium, or Tellurium as Bioactive Compounds)

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22 pages, 5608 KiB

Open AccessArticle

Novel Seleno-Aspirinyl Compound AS-10 Induces Apoptosis, G1 Arrest of Pancreatic Ductal Adenocarcinoma Cells, Inhibits Their NF-κB Signaling, and Synergizes with Gemcitabine Cytotoxicity

by Deepkamal N. Karelia, Sangyub Kim, Manoj K. Pandey, Daniel Plano, Shantu Amin, Junxuan Lu and Arun K. Sharma

Int. J. Mol. Sci. 2021, 22(9), 4966; https://doi.org/10.3390/ijms22094966 - 7 May 2021

Cited by 15 | Viewed by 3418

Abstract

Current available therapies for pancreatic ductal adenocarcinoma (PDAC) provide minimal overall survival benefits and cause severe adverse effects. We have identified a novel molecule AS-10, a selenazolidine-bis-aspirinyl derivative, that was two to three orders of magnitude more potent than aspirin and at least one to two orders of magnitude more potent than gemcitabine in inhibiting PDAC cancer cell growth/viability against three PDAC cell lines while sparing mouse embryonic fibroblasts in the same exposure range. In Panc-1 cells, AS-10 induced apoptosis without necrosis, principally through caspase-3/7 cascade and reactive oxygen species, in addition to an induction of G₁ cell cycle block. Transcriptomic profiling with RNA-seq indicated the top responses to AS-10 exposure as CDKN1A (P21Cip1), CCND1, and nuclear transcription factor-kappa B (NF-κB) complex and the top functions as cell cycle, cell death, and survival without inducing the DNA damage gene signature. AS-10 pretreatment (6 h) decreased cytokine tumor necrosis factor-alpha (TNF-α)-stimulated NF-κB nuclear translocation, DNA binding activity, and degradation of cytosolic inhibitor of κB (IκB) protein. As NF-κB activation in PDAC cells confers resistance to gemcitabine, the AS-10 combination with gemcitabine increased the in vitro cytotoxicity more than the additivity of both compounds. Overall, our results suggest AS-10 may be a promising drug lead for PDAC, both as a single agent and in combination therapy. Full article

(This article belongs to the Special Issue Small Molecules Containing Sulfur, Selenium, or Tellurium as Bioactive Compounds)

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14 pages, 7529 KiB

Open AccessArticle

In Vitro Cytotoxicity of Trastuzumab (Tz) and Se-Trastuzumab (Se-Tz) against the Her/2 Breast Cancer Cell Lines JIMT-1 and BT-474

by Priyanka Bapat, Debalina Goswami Sewell, Mallory Boylan, Arun K. Sharma and Julian E. Spallholz

Int. J. Mol. Sci. 2021, 22(9), 4655; https://doi.org/10.3390/ijms22094655 - 28 Apr 2021

Cited by 4 | Viewed by 3550

Abstract

Her/2+ breast cancer accounts for ~25% mortality in women and overexpression of Her/2 leads to cell growth and tumor progression. Trastuzumab (Tz) with Taxane is the preferred treatment for Her/2+ patients. However, Tz responsive patients often develop resistance to Tz treatment. Herein, redox selenides (RSe-) were covalently linked to Tz using a selenium (Se)-modified Bolton–Hunter Reagent forming Seleno-Trastuzumab (Se-Tz; ~25 µgSe/mg). Se-Tz was compared to Tz and sodium selenite to assess the viability of JIMT-1 and BT-474 cells. Comparative cell viability was examined by microscopy and assessed by fluorometric/enzymatic assays. Se-Tz and selenite redox cycle producing superoxide (O₂^•−) are more cytotoxic to Tz resistant JIMT-1 and Tz sensitive BT-474 cells than Tz. The results of conjugating redox selenides to Tz suggest a wider application of this technology to other antibodies and targeting molecules. Full article

(This article belongs to the Special Issue Small Molecules Containing Sulfur, Selenium, or Tellurium as Bioactive Compounds)

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19 pages, 3594 KiB

Open AccessArticle

The Pharmacology and Therapeutic Utility of Sodium Hydroselenide

by Kavitej Samra, Mathun Kuganesan, William Smith, Anna Kleyman, Robert Tidswell, Nishkantha Arulkumaran, Mervyn Singer and Alex Dyson

Int. J. Mol. Sci. 2021, 22(6), 3258; https://doi.org/10.3390/ijms22063258 - 23 Mar 2021

Cited by 9 | Viewed by 3482

Abstract

Metabolically active gasotransmitters (nitric oxide, carbon monoxide and hydrogen sulfide) are important signalling molecules that show therapeutic utility in oxidative pathologies. The reduced form of selenium, hydrogen selenide (HSe⁻/H₂Se), shares some characteristics with these molecules. The simple selenide salt, sodium hydroselenide (NaHSe) showed significant metabolic activity, dose-dependently decreasing ex vivo O₂ consumption (rat soleus muscle, liver) and transiently inhibiting mitochondrial cytochrome C oxidase (liver, heart). Pharmacological manipulation of selenoprotein expression in HepG2 human hepatocytes revealed that the oxidation status of selenium impacts on protein expression; reduced selenide (NaHSe) increased, whereas (oxidized) sodium selenite decreased the abundance of two ubiquitous selenoproteins. An inhibitor of endogenous sulfide production (DL-propargylglycine; PAG) also reduced selenoprotein expression; this was reversed by exogenous NaHSe, but not sodium hydrosulfide (NaHS). NaHSe also conferred cytoprotection against an oxidative challenge (H₂O₂), and this was associated with an increase in mitochondrial membrane potential. Anesthetized Wistar rats receiving intravenous NaHSe exhibited significant bradycardia, metabolic acidosis and hyperlactataemia. In summary, NaHSe modulates metabolism by inhibition of cytochrome C oxidase. Modification of selenoprotein expression revealed the importance of oxidation status of selenium therapies, with implications for current clinical practice. The utility of NaHSe as a research tool and putative therapeutic is discussed. Full article

(This article belongs to the Special Issue Small Molecules Containing Sulfur, Selenium, or Tellurium as Bioactive Compounds)

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26 pages, 2112 KiB

Open AccessArticle

Dispirooxindoles Based on 2-Selenoxo-Imidazolidin-4-Ones: Synthesis, Cytotoxicity and ROS Generation Ability

by Vladimir K. Novotortsev, Maxim E. Kukushkin, Viktor A. Tafeenko, Dmitry A. Skvortsov, Marina A. Kalinina, Roman V. Timoshenko, Nelly S. Chmelyuk, Liliya A. Vasilyeva, Boris N. Tarasevich, Petr V. Gorelkin, Alexander S. Erofeev, Alexander G. Majouga, Nikolai V. Zyk and Elena K. Beloglazkina

Int. J. Mol. Sci. 2021, 22(5), 2613; https://doi.org/10.3390/ijms22052613 - 5 Mar 2021

Cited by 13 | Viewed by 3119

Abstract

A regio- and diastereoselective synthesis of two types of dispiro derivatives of 2-selenoxoimidazolidin-4-ones, differing in the position of the nitrogen atom in the central pyrrolidine ring of the spiro-fused system—namely, 2-selenoxodispiro[imidazolidine-4,3′-pyrrolidine-2′,3″-indoline]-2″,5-diones (5a-h) and 2-senenoxodispiro[imidazolidine-4,3′-pyrrolidine-4′,3″-indoline]-2″,5-diones (6a-m)—were developed based on a 1,3-dipolar cycloaddition of azomethine ylides generated from isatin and sarcosine or formaldehyde and sarcosine to 5-arylidene or 5-indolidene-2-selenoxo-tetrahydro-4H-imidazole-4-ones. Selenium-containing dispiro indolinones generally exhibit cytotoxic activity near to the activity of the corresponding oxygen and sulfur-containing derivatives. Compounds 5b, 5c, and 5e demonstrated considerable in vitro cytotoxicity in the 3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl tetrazolium bromide (MTT) test (concentration of compounds that caused 50% death of cells (CC₅₀) 7.6–8.7 μM) against the A549 cancer cell line with the VA13/A549 selectivity index 5.2–6.9; some compounds (5 and 6) increased the level of intracellular reactive oxygen species (ROS) in the experiment on A549 and PC3 cells using platinized carbon nanoelectrode. The tests for p53 activation for compounds 5 and 6 on the transcriptional reporter suggest that the investigated compounds can only have an indirect p53-dependent mechanism of action. For the compounds 5b, 6b, and 6l, the ROS generation may be one of the significant mechanisms of their cytotoxic action. Full article

(This article belongs to the Special Issue Small Molecules Containing Sulfur, Selenium, or Tellurium as Bioactive Compounds)

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12 pages, 1427 KiB

Open AccessArticle

Selenite Inhibits Notch Signaling in Cells and Mice

by Michael Powers, Liu Liu, Dane Deemer, Selina Chen, Aaron Scholl, Masafumi Yoshinaga and Zijuan Liu

Int. J. Mol. Sci. 2021, 22(5), 2518; https://doi.org/10.3390/ijms22052518 - 3 Mar 2021

Cited by 6 | Viewed by 2735

Abstract

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. Full article

(This article belongs to the Special Issue Small Molecules Containing Sulfur, Selenium, or Tellurium as Bioactive Compounds)

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17 pages, 6012 KiB

Open AccessArticle

New Formulation of a Methylseleno-Aspirin Analog with Anticancer Activity Towards Colon Cancer

by Ana Carolina Ruberte, Gustavo González-Gaitano, Arun K. Sharma, Carlos Aydillo, Ignacio Encío, Carmen Sanmartín and Daniel Plano

Int. J. Mol. Sci. 2020, 21(23), 9017; https://doi.org/10.3390/ijms21239017 - 27 Nov 2020

Cited by 8 | Viewed by 2798

Abstract

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. Full article

(This article belongs to the Special Issue Small Molecules Containing Sulfur, Selenium, or Tellurium as Bioactive Compounds)

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18 pages, 3598 KiB

Open AccessArticle

Metabolic Response of the Yeast Candida utilis During Enrichment in Selenium

by Marek Kieliszek, Katarzyna Bierla, Javier Jiménez-Lamana, Anna Maria Kot, Jaime Alcántara-Durán, Kamil Piwowarek, Stanisław Błażejak and Joanna Szpunar

Int. J. Mol. Sci. 2020, 21(15), 5287; https://doi.org/10.3390/ijms21155287 - 25 Jul 2020

Cited by 48 | Viewed by 4527

Abstract

Selenium (Se) was found to inhibit the growth of the yeast Candida utilis ATCC 9950. Cells cultured in 30 mg selenite/L supplemented medium could bind 1368 µg Se/g of dry weight in their structures. Increased accumulation of trehalose and glycogen was observed, which indicated cell response to stress conditions. The activity of antioxidative enzymes (glutathione peroxidase, glutathione reductase, thioredoxin reductase, and glutathione S-transferase) was significantly higher than that of the control without Se addition. Most Se was bound to water-insoluble protein fraction; in addition, the yeast produced 20–30 nm Se nanoparticles (SeNPs). Part of Se was metabolized to selenomethionine (10%) and selenocysteine (20%). The HPLC-ESI-Orbitrap MS analysis showed the presence of five Se compounds combined with glutathione in the yeast. The obtained results form the basis for further research on the mechanisms of Se metabolism in yeast cells. Full article

(This article belongs to the Special Issue Small Molecules Containing Sulfur, Selenium, or Tellurium as Bioactive Compounds)

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14 pages, 2080 KiB

Open AccessArticle

Molecular Mapping of Hydrogen Sulfide Targets in Normal Human Keratinocytes

by Olivia Gross-Amat, Marine Guillen, Jean-Pascal Gimeno, Michel Salzet, Nicolas Lebonvallet, Laurent Misery, Céline Auxenfans and Serge Nataf

Int. J. Mol. Sci. 2020, 21(13), 4648; https://doi.org/10.3390/ijms21134648 - 30 Jun 2020

Cited by 4 | Viewed by 2301

Abstract

Although sulfur-rich thermal waters have ancestrally been used in the context of dermatological conditions, a global mapping of the molecular effects exerted by H₂S on human keratinocytes is still lacking. To fill this knowledge gap, we subjected cultured human keratinocytes to distinct amounts of the non-gaseous hydrogen sulfur donor NaHS. We first checked that H₂S accumulated in the cytoplasm of keratinocytes under our experimental conditions andused a combination of proteomics, genomics and biochemical approaches to unravel functionally relevant H₂S targets in human keratinocytes. We found that the identified targets fall into two main categories: (i) the oxidative stress response molecules superoxide dismutase 2 (SOD2), NAD(P)H quinone dehydrogenase 1 (NQO1) and culin 3 (CUL3) and (ii) the chemokines interleukin-8 (IL-8) and CXCL2. Interestingly, NaHS also stimulated the caspase-1 inflammasome pathway, leading to increased secretion of the pro-inflammatory molecule interleukin-18 (IL-18). Interestingly, the secretion of interleukin-1 beta (IL-1β) was only modestly impacted by NaHS exposure despite a significant accumulation of IL-1β pro-form. Finally, we observed that NaHS significantly hampered the growth of human keratinocyte progenitors and stem cells cultured under clonogenic conditions or as epidermal cell sheets. We conclude that H₂S exerts specific molecular effects on normal human keratinocytes. Full article

(This article belongs to the Special Issue Small Molecules Containing Sulfur, Selenium, or Tellurium as Bioactive Compounds)

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