Selenium, Trace Elements and Transition Metals in Anticancer Drug Discovery

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 18126

Special Issue Editors


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Division of Bioorganic Chemistry, School of Pharmacy, Saarland University, D-66123 Saarbruecken, Germany
Interests: bioorganic chemistry; catalytic sensor/effector agents; epistemology; intracellular diagnostics; nanotechnology; natural products; reactive sulfur and selenium species; redox regulation via the cellular thiolstat
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Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland
Interests: medicinal chemistry; synthesis; CADD; multidrug resistance; memory disorders; depression; Alzheimer’s disease; arrhythmia; ADMET; imidazolone; hydantoin; thiohydantoin; piperazine; selenium; chalcogen
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Guest Editor
Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland
Interests: ADMETox; pharmacology; anticancer research; multidrug resistance; efflux pumps; cytotoxicity; apoptosis; antibacterial assays; pharmaceutical biotechnology; drug discovery & development; selenocompounds; small molecules; probiotics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The search for new anticancer drugs and adjuvants in cancer therapy is an important challenge of the pharmaceutical sciences. Many in vitro and in vivo experimental models demonstrated the efficacy of Se compounds as anticancer agents. Selenocompounds possess the ability to interfere with the redox homeostasis and signalling of cancer cells to produce anticancer effects. Similarly, compounds and/or nanoparticles containing tellurium, cadmium, gold, rhodium and ruthenium have proven also to show anticancer effects. Taking into account their interesting activity, both selenocompounds, trace elements and transition metals are the object of intensive chemical modifications in order to find new active structures that can serve as a potential anticancer drug candidates or adjuvants in the future cancer therapy. In this Special Issue we want to present the recent advances in the drug design and potential pharmacological applications of all these elements. Articles that report the anticancer or cancer MDR reversing activity of novel compounds containing selenium, tellurium, or novel organic complexes of metals from the d-block are welcomed

Prof. Dr. Claus Jacob
Prof. Dr. Jadwiga Handzlik
Dr. Małgorzata Anna Marć
Guest Editors

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Keywords

  • selenium chemistry
  • anticancer activity of novel compounds
  • cancer multidrug resistance
  • ADMET
  • medicinal chemistry
  • bioorganic chemistry
  • transition metals
  • trace elements

Published Papers (8 papers)

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Research

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13 pages, 1686 KiB  
Article
Reversal of Multidrug Resistance by Symmetrical Selenoesters in Colon Adenocarcinoma Cells
by Bálint Rácz, Annamária Kincses, Krisztián Laczi, Gábor Rákhely, Enrique Domínguez-Álvarez and Gabriella Spengler
Pharmaceutics 2023, 15(2), 610; https://doi.org/10.3390/pharmaceutics15020610 - 11 Feb 2023
Cited by 2 | Viewed by 1417
Abstract
Recently, selenium containing derivatives have attracted more attention in medicinal chemistry. In the present work, the anticancer activity of symmetrical selenoesters was investigated by studying the reversal of efflux pump-related and apoptosis resistance in sensitive and resistant human colon adenocarcinoma cells expressing the [...] Read more.
Recently, selenium containing derivatives have attracted more attention in medicinal chemistry. In the present work, the anticancer activity of symmetrical selenoesters was investigated by studying the reversal of efflux pump-related and apoptosis resistance in sensitive and resistant human colon adenocarcinoma cells expressing the ABCB1 protein. The combined effect of the compounds with doxorubicin was demonstrated with a checkerboard assay. The ABCB1 inhibitory and the apoptosis-inducing effects of the derivatives were measured with flow cytometry. Whole transcriptome sequencing was carried out on Illumina platform upon the treatment of resistant cells with the most potent derivatives. One ketone and three methyl ester selenoesters showed synergistic or weak synergistic interaction with doxorubicin, respectively. Ketone selenoesters were the most potent ABCB1 inhibitors and apoptosis inducers. Nitrile selenoesters could induce moderate early and late apoptotic processes that could be explained by their ABCB1 modulating properties. The transcriptome analysis revealed that symmetrical selenoesters may influence the redox state of the cells and interfere with metastasis formation. It can be assumed that these symmetrical selenocompounds possess toxic, DNA-damaging effects due to the presence of two selenium atoms in the molecule, which may be augmented by the presence of symmetrical groups. Full article
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24 pages, 2719 KiB  
Article
Antioxidant and Anticancer Potential of the New Cu(II) Complexes Bearing Imine-Phenolate Ligands with Pendant Amine N-Donor Groups
by Adriana Castro Pinheiro, Ianka Jacondino Nunes, Wesley Vieira Ferreira, Paula Pellenz Tomasini, Cristiano Trindade, Carolina Cristóvão Martins, Ethel Antunes Wilhelm, Robson da Silva Oliboni, Paulo Augusto Netz, Rafael Stieler, Osvaldo de Lazaro Casagrande, Jr. and Jenifer Saffi
Pharmaceutics 2023, 15(2), 376; https://doi.org/10.3390/pharmaceutics15020376 - 22 Jan 2023
Cited by 7 | Viewed by 2170
Abstract
Cu(II) complexes bearing NNO-donor Schiff base ligands (2a, b) have been synthesized and characterized. The single crystal X-ray analysis of the 2a complex revealed that a mononuclear and a dinuclear complex co-crystallize in the solid state. The electronic structures of [...] Read more.
Cu(II) complexes bearing NNO-donor Schiff base ligands (2a, b) have been synthesized and characterized. The single crystal X-ray analysis of the 2a complex revealed that a mononuclear and a dinuclear complex co-crystallize in the solid state. The electronic structures of the complexes are optimized by Density Functional Theory (DFT) calculations. The monomeric nature of 2a and 2b species is maintained in solution. Antioxidant activities of the ligands (1a, b) and Cu(II) complexes (2a, b) were determined by in vitro assays such as 1,1-diphenyl-2-picrylhydrazyl free radicals (DPPH.) and 2,2′-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) radicals (ABTS+). Our results demonstrated that 2a showed better antioxidant activity. MTT assays were performed to assess the toxicity of ligands and Cu(II) complexes in V79 cells. The antiproliferative activity of compounds was tested against two human tumor cell lines: MCF-7 (breast adenocarcinoma) and SW620 (colorectal carcinoma) and on MRC-5 (normal lung fibroblast). All compounds showed high cytotoxicity in the all-cell lines but showed no selectivity for tumor cell lines. Antiproliferative activity by clonogenic assay 2b showed a more significant inhibitory effect on the MCF-7 cell lines than on MRC-5. DNA damage for the 2b compound at 10 µM concentration was about three times higher in MCF-7 cells than in MRC-5 cells. Full article
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10 pages, 2321 KiB  
Article
Olaparib Conjugates with Selenopheno[3,2-c]quinolinone Inhibit PARP1 and Reverse ABCB1-Related Multidrug Resistance
by Marina Makrecka-Kuka, Jelena Vasiljeva, Pavels Dimitrijevs and Pavel Arsenyan
Pharmaceutics 2022, 14(12), 2571; https://doi.org/10.3390/pharmaceutics14122571 - 23 Nov 2022
Cited by 2 | Viewed by 1418
Abstract
The restoration of the efficacy of antitumor medicines is a cornerstone in the combat with multidrug resistant (MDR) cancers. The overexpression of the ABCB1 transporter is a major obstacle to conventional doxorubicin therapy. The synergy of ABCB1 suppression and PARP1 activity inhibition that [...] Read more.
The restoration of the efficacy of antitumor medicines is a cornerstone in the combat with multidrug resistant (MDR) cancers. The overexpression of the ABCB1 transporter is a major obstacle to conventional doxorubicin therapy. The synergy of ABCB1 suppression and PARP1 activity inhibition that hampers malignant cell DNA repair could be a powerful tool in anticancer therapy. Herein, we report the design and synthesis of three novel olaparib conjugates with selenophenoquinolinones, their ability to reverse doxorubicin resistance in uterus sarcoma cells as well as their mechanism of action. It was found that the most potent chemosensitizer among studied compounds preserves PARP1 inhibitory activity and attenuates cells’ resistance to doxorubicin by inhibiting ABCB1 transporter activity. These results demonstrate that the conjugation of PARP inhibitors with selenophenoquinolinones is a prospective direction for the development of agents for the treatment of MDR cancers. Full article
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25 pages, 4592 KiB  
Article
Pharmaceutical and Safety Profile Evaluation of Novel Selenocompounds with Noteworthy Anticancer Activity
by Małgorzata Anna Marć, Enrique Domínguez-Álvarez, Gniewomir Latacz, Agata Doroz-Płonka, Carmen Sanmartín, Gabriella Spengler and Jadwiga Handzlik
Pharmaceutics 2022, 14(2), 367; https://doi.org/10.3390/pharmaceutics14020367 - 6 Feb 2022
Cited by 11 | Viewed by 2234
Abstract
Prior studies have reported the potent and selective cytotoxic, pro-apoptotic, and chemopreventive activities of a cyclic selenoanhydride and of a series of selenoesters. Some of these selenium derivatives demonstrated multidrug resistance (MDR)-reversing activity in different resistant cancer cell lines. Thus, the aim of [...] Read more.
Prior studies have reported the potent and selective cytotoxic, pro-apoptotic, and chemopreventive activities of a cyclic selenoanhydride and of a series of selenoesters. Some of these selenium derivatives demonstrated multidrug resistance (MDR)-reversing activity in different resistant cancer cell lines. Thus, the aim of this study was to evaluate the pharmaceutical and safety profiles of these selected selenocompounds using alternative methods in silico and in vitro. One of the main tasks of this work was to determine both the physicochemical properties and metabolic stability of these selenoesters. The obtained results proved that these tested selenocompounds could become potential candidates for novel and safe anticancer drugs with good ADMET parameters. The most favorable selenocompounds turned out to be the phthalic selenoanhydride (EDA-A6), two ketone-containing selenoesters with a 4-chlorophenyl moiety (EDA-71 and EDA-73), and a symmetrical selenodiester with a pyridine ring and two selenium atoms (EDA-119). Full article
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8 pages, 1300 KiB  
Article
77Se-Enriched Selenoglycoside Enables Significant Enhancement in NMR Spectroscopic Monitoring of Glycan–Protein Interactions
by István Timári, Sára Balla, Krisztina Fehér, Katalin E. Kövér and László Szilágyi
Pharmaceutics 2022, 14(1), 201; https://doi.org/10.3390/pharmaceutics14010201 - 15 Jan 2022
Cited by 5 | Viewed by 1870
Abstract
Detailed investigation of ligand–protein interactions is essential for better understanding of biological processes at the molecular level. Among these binding interactions, the recognition of glycans by lectins is of particular importance in several diseases, such as cancer; therefore, inhibition of glycan-lectin/galectin interactions represents [...] Read more.
Detailed investigation of ligand–protein interactions is essential for better understanding of biological processes at the molecular level. Among these binding interactions, the recognition of glycans by lectins is of particular importance in several diseases, such as cancer; therefore, inhibition of glycan-lectin/galectin interactions represents a promising perspective towards developing therapeutics controlling cancer development. The recent introduction of 77Se NMR spectroscopy for monitoring the binding of a selenoglycoside to galectins prompted interest to optimize the sensitivity by increasing the 77Se content from the natural 7.63% abundance to 99%. Here, we report a convenient synthesis of 77Se-enriched selenodigalactoside (SeDG), which is a potent ligand of the medically relevant human galectin-3 protein, and proof of the expected sensitivity gain in 2D 1H, 77Se correlation NMR experiments. Our work opens perspectives for adding isotopically enriched selenoglycans for rapid monitoring of lectin-binding of selenated as well as non-selenated ligands and for ligand screening in competition experiments. Full article
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20 pages, 6494 KiB  
Article
Ultrasound and Transcriptomics Identify a Differential Impact of Cisplatin and Histone Deacetylation on Tumor Structure and Microenvironment in a Patient-Derived In Vivo Model of Gastric Cancer
by Aina Venkatasamy, Eric Guerin, Anais Blanchet, Christophe Orvain, Véronique Devignot, Matthieu Jung, Alain C. Jung, Marie-Pierre Chenard, Benoit Romain, Christian Gaiddon and Georg Mellitzer
Pharmaceutics 2021, 13(9), 1485; https://doi.org/10.3390/pharmaceutics13091485 - 16 Sep 2021
Cited by 4 | Viewed by 2558
Abstract
The reasons behind the poor efficacy of transition metal-based chemotherapies (e.g., cisplatin) or targeted therapies (e.g., histone deacetylase inhibitors, HDACi) on gastric cancer (GC) remain elusive and recent studies suggested that the tumor microenvironment could contribute to the resistance. Hence, our objective was [...] Read more.
The reasons behind the poor efficacy of transition metal-based chemotherapies (e.g., cisplatin) or targeted therapies (e.g., histone deacetylase inhibitors, HDACi) on gastric cancer (GC) remain elusive and recent studies suggested that the tumor microenvironment could contribute to the resistance. Hence, our objective was to gain information on the impact of cisplatin and the pan-HDACi SAHA (suberanilohydroxamic acid) on the tumor substructure and microenvironment of GC, by establishing patient-derived xenografts of GC and a combination of ultrasound, immunohistochemistry, and transcriptomics to analyze. The tumors responded partially to SAHA and cisplatin. An ultrasound gave more accurate tumor measures than a caliper. Importantly, an ultrasound allowed a noninvasive real-time access to the tumor substructure, showing differences between cisplatin and SAHA. These differences were confirmed by immunohistochemistry and transcriptomic analyses of the tumor microenvironment, identifying specific cell type signatures and transcription factor activation. For instance, cisplatin induced an “epithelial cell like” signature while SAHA favored a “mesenchymal cell like” one. Altogether, an ultrasound allowed a precise follow-up of the tumor progression while enabling a noninvasive real-time access to the tumor substructure. Combined with transcriptomics, our results underline the different intra-tumoral structural changes caused by both drugs that impact differently on the tumor microenvironment. Full article
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Review

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32 pages, 5080 KiB  
Review
Selenium-Containing Agents Acting on Cancer—A New Hope?
by Sabrina Garbo, Silvia Di Giacomo, Dorota Łażewska, Ewelina Honkisz-Orzechowska, Antonella Di Sotto, Rossella Fioravanti, Clemens Zwergel and Cecilia Battistelli
Pharmaceutics 2023, 15(1), 104; https://doi.org/10.3390/pharmaceutics15010104 - 28 Dec 2022
Cited by 12 | Viewed by 3136
Abstract
Selenium-containing agents are more and more considered as an innovative potential treatment option for cancer. Light is shed not only on the considerable advancements made in understanding the complex biology and chemistry related to selenium-containing small molecules but also on Se-nanoparticles. Numerous Se-containing [...] Read more.
Selenium-containing agents are more and more considered as an innovative potential treatment option for cancer. Light is shed not only on the considerable advancements made in understanding the complex biology and chemistry related to selenium-containing small molecules but also on Se-nanoparticles. Numerous Se-containing agents have been widely investigated in recent years in cancer therapy in relation to tumour development and dissemination, drug delivery, multidrug resistance (MDR) and immune system-related (anti)cancer effects. Despite numerous efforts, Se-agents apart from selenocysteine and selenomethionine have not yet reached clinical trials for cancer therapy. The purpose of this review is to provide a concise critical overview of the current state of the art in the development of highly potent target-specific Se-containing agents. Full article
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19 pages, 1780 KiB  
Review
Biosynthesized Gold, Silver, Palladium, Platinum, Copper, and Other Transition Metal Nanoparticles
by Piotr Roszczenko, Olga Klaudia Szewczyk, Robert Czarnomysy, Krzysztof Bielawski and Anna Bielawska
Pharmaceutics 2022, 14(11), 2286; https://doi.org/10.3390/pharmaceutics14112286 - 25 Oct 2022
Cited by 8 | Viewed by 1898
Abstract
Nanomedicine is a potential provider of novel therapeutic and diagnostic routes of treatment. Considering the development of multidrug resistance in pathogenic bacteria and the commonness of cancer, novel approaches are being sought for the safe and efficient synthesis of new nanoparticles, which have [...] Read more.
Nanomedicine is a potential provider of novel therapeutic and diagnostic routes of treatment. Considering the development of multidrug resistance in pathogenic bacteria and the commonness of cancer, novel approaches are being sought for the safe and efficient synthesis of new nanoparticles, which have multifaceted applications in medicine. Unfortunately, the chemical synthesis of nanoparticles raises justified environmental concerns. A significant problem in their widespread use is also the toxicity of compounds that maintain nanoparticle stability, which significantly limits their clinical use. An opportunity for their more extensive application is the utilization of plants, fungi, and bacteria for nanoparticle biosynthesis. Extracts from natural sources can reduce metal ions in nanoparticles and stabilize them with non-toxic extract components. Full article
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