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Search Results (8)

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Authors = Zdeněk Kejík

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30 pages, 12528 KiB  
Article
Preparation of Tryptanthrin Derivates Bearing a Thiosemicarbazone Moiety to Inhibit SARS-CoV-2 Replication
by Kateřina Veselá, Zora Mělková, Nikita Abramenko, Zdeněk Kejík, Robert Kaplánek, Petr Dytrych, Alla Sinica, Oleksandra Vozniuk, Pavel Martásek and Milan Jakubek
Separations 2023, 10(2), 73; https://doi.org/10.3390/separations10020073 - 20 Jan 2023
Cited by 4 | Viewed by 2979
Abstract
SARS-CoV-2 is a serious viral pathogen, and agents that inhibit its replication are in high demand. In the present work, we prepared two novel tryptanthrin derivates bearing a thiosemicarbazone moiety as potential antiviral agents. Both compounds displayed potent chelation activity against Fe(III/II) ion-associated [...] Read more.
SARS-CoV-2 is a serious viral pathogen, and agents that inhibit its replication are in high demand. In the present work, we prepared two novel tryptanthrin derivates bearing a thiosemicarbazone moiety as potential antiviral agents. Both compounds displayed potent chelation activity against Fe(III/II) ion-associated COVID-19. The molecular docking results suggest that the compounds can display significant affinity towards SARS-CoV-2 papain-like proteases and SARS-CoV-2 main proteases. In addition, administering T8H-TSC can repress viral replication in the used model (Vero cells). Moreover, the therapeutic potential of the prepared compounds was predicted and analysed in terms of Lipinski’s rules, drug-likeness and drug score. Full article
(This article belongs to the Special Issue Novel Applications of Separation Technology)
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23 pages, 4341 KiB  
Review
The Role of IL-6 in Cancer Cell Invasiveness and Metastasis—Overview and Therapeutic Opportunities
by Magdalena Rašková, Lukáš Lacina, Zdeněk Kejík, Anna Venhauerová, Markéta Skaličková, Michal Kolář, Milan Jakubek, Daniel Rosel, Karel Smetana and Jan Brábek
Cells 2022, 11(22), 3698; https://doi.org/10.3390/cells11223698 - 21 Nov 2022
Cited by 136 | Viewed by 10137
Abstract
Interleukin 6 (IL-6) belongs to a broad class of cytokines involved in the regulation of various homeostatic and pathological processes. These activities range from regulating embryonic development, wound healing and ageing, inflammation, and immunity, including COVID-19. In this review, we summarise the role [...] Read more.
Interleukin 6 (IL-6) belongs to a broad class of cytokines involved in the regulation of various homeostatic and pathological processes. These activities range from regulating embryonic development, wound healing and ageing, inflammation, and immunity, including COVID-19. In this review, we summarise the role of IL-6 signalling pathways in cancer biology, with particular emphasis on cancer cell invasiveness and metastasis formation. Targeting principal components of IL-6 signalling (e.g., IL-6Rs, gp130, STAT3, NF-κB) is an intensively studied approach in preclinical cancer research. It is of significant translational potential; numerous studies strongly imply the remarkable potential of IL-6 signalling inhibitors, especially in metastasis suppression. Full article
(This article belongs to the Special Issue Role of Cytokines and Other Soluble Factors in Tumor Development: Rationale for New Therapeutic Strategies)
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25 pages, 6284 KiB  
Article
Targeting of the Mitochondrial TET1 Protein by Pyrrolo[3,2-b]pyrrole Chelators
by Veronika Antonyová, Ameneh Tatar, Tereza Brogyányi, Zdeněk Kejík, Robert Kaplánek, Fréderic Vellieux, Nikita Abramenko, Alla Sinica, Jan Hajduch, Petr Novotný, Bettie Sue Masters, Pavel Martásek and Milan Jakubek
Int. J. Mol. Sci. 2022, 23(18), 10850; https://doi.org/10.3390/ijms231810850 - 16 Sep 2022
Cited by 8 | Viewed by 2816
Abstract
Targeting of epigenetic mechanisms, such as the hydroxymethylation of DNA, has been intensively studied, with respect to the treatment of many serious pathologies, including oncological disorders. Recent studies demonstrated that promising therapeutic strategies could potentially be based on the inhibition of the TET1 [...] Read more.
Targeting of epigenetic mechanisms, such as the hydroxymethylation of DNA, has been intensively studied, with respect to the treatment of many serious pathologies, including oncological disorders. Recent studies demonstrated that promising therapeutic strategies could potentially be based on the inhibition of the TET1 protein (ten-eleven translocation methylcytosine dioxygenase 1) by specific iron chelators. Therefore, in the present work, we prepared a series of pyrrolopyrrole derivatives with hydrazide (1) or hydrazone (2–6) iron-binding groups. As a result, we determined that the basic pyrrolo[3,2-b]pyrrole derivative 1 was a strong inhibitor of the TET1 protein (IC50 = 1.33 μM), supported by microscale thermophoresis and molecular docking. Pyrrolo[3,2-b]pyrroles 2–6, bearing substituted 2-hydroxybenzylidene moieties, displayed no significant inhibitory activity. In addition, in vitro studies demonstrated that derivative 1 exhibits potent anticancer activity and an exclusive mitochondrial localization, confirmed by Pearson’s correlation coefficient of 0.92. Full article
(This article belongs to the Special Issue Enzymes and Enzyme Inhibitors—Applications in Medicine and Diagnosis 2.0)
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20 pages, 3312 KiB  
Article
New-Generation Heterocyclic Bis-Pentamethinium Salts as Potential Cytostatic Drugs with Dual IL-6R and Mitochondria-Targeting Activity
by Veronika Talianová, Zdeněk Kejík, Robert Kaplánek, Kateřina Veselá, Nikita Abramenko, Lukáš Lacina, Karolína Strnadová, Barbora Dvořánková, Pavel Martásek, Michal Masařík, Magdalena Houdová Megová, Petr Bušek, Jana Křížová, Lucie Zdražilová, Hana Hansíková, Erik Vlčák, Vlada Filimonenko, Aleksi Šedo, Karel Smetana and Milan Jakubek
Pharmaceutics 2022, 14(8), 1712; https://doi.org/10.3390/pharmaceutics14081712 - 17 Aug 2022
Cited by 4 | Viewed by 3644
Abstract
IL-6 signaling is involved in the pathogenesis of a number of serious diseases, including chronic inflammation and cancer. Targeting of IL-6 receptor (IL-6R) by small molecules is therefore an intensively studied strategy in cancer treatment. We describe the design, synthesis, and characteristics of [...] Read more.
IL-6 signaling is involved in the pathogenesis of a number of serious diseases, including chronic inflammation and cancer. Targeting of IL-6 receptor (IL-6R) by small molecules is therefore an intensively studied strategy in cancer treatment. We describe the design, synthesis, and characteristics of two new bis-pentamethinium salts 5 and 6 (meta and para) bearing indole moieties. Molecular docking studies showed that both compounds have the potential to bind IL-6R (free energy of binding −9.5 and −8.1 kcal/mol). The interaction with IL-6R was confirmed using microscale thermophoresis analyses, which revealed that both compounds had strong affinity for the IL-6R (experimentally determined dissociation constants 26.5 ± 2.5 nM and 304 ± 27.6 nM, respectively). In addition, both compounds were cytotoxic for a broad spectrum of cancer cell lines in micromolar concentrations, most likely due to their accumulation in mitochondria and inhibition of mitochondrial respiration. In summary, the structure motif of bis-pentamethinium salts represents a promising starting point for the design of novel multitargeting compounds with the potential to inhibit IL-6 signaling and simultaneously target mitochondrial metabolism in cancer cells. Full article
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51 pages, 2005 KiB  
Review
Circulating Tumour Cells (CTCs) in NSCLC: From Prognosis to Therapy Design
by Zdeněk Kejík, Robert Kaplánek, Petr Dytrych, Michal Masařík, Kateřina Veselá, Nikita Abramenko, David Hoskovec, Martina Vašáková, Jarmila Králová, Pavel Martásek and Milan Jakubek
Pharmaceutics 2021, 13(11), 1879; https://doi.org/10.3390/pharmaceutics13111879 - 5 Nov 2021
Cited by 18 | Viewed by 7786
Abstract
Designing optimal (neo)adjuvant therapy is a crucial aspect of the treatment of non-small-cell lung carcinoma (NSCLC). Standard methods of chemotherapy, radiotherapy, and immunotherapy represent effective strategies for treatment. However, in some cases with high metastatic activity and high levels of circulating tumour cells [...] Read more.
Designing optimal (neo)adjuvant therapy is a crucial aspect of the treatment of non-small-cell lung carcinoma (NSCLC). Standard methods of chemotherapy, radiotherapy, and immunotherapy represent effective strategies for treatment. However, in some cases with high metastatic activity and high levels of circulating tumour cells (CTCs), the efficacy of standard treatment methods is insufficient and results in treatment failure and reduced patient survival. CTCs are seen not only as an isolated phenomenon but also a key inherent part of the formation of metastasis and a key factor in cancer death. This review discusses the impact of NSCLC therapy strategies based on a meta-analysis of clinical studies. In addition, possible therapeutic strategies for repression when standard methods fail, such as the administration of low-toxicity natural anticancer agents targeting these phenomena (curcumin and flavonoids), are also discussed. These strategies are presented in the context of key mechanisms of tumour biology with a strong influence on CTC spread and metastasis (mechanisms related to tumour-associated and -infiltrating cells, epithelial–mesenchymal transition, and migration of cancer cells). Full article
(This article belongs to the Special Issue Novel Anticancer Strategies (Volume II))
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10 pages, 1429 KiB  
Article
Pentamethinium Salts Nanocomposite for Electrochemical Detection of Heparin
by Tatiana V. Shishkanova, Tomáš Bříza, Pavel Řezanka, Zdeněk Kejík and Milan Jakubek
Materials 2021, 14(18), 5357; https://doi.org/10.3390/ma14185357 - 17 Sep 2021
Cited by 5 | Viewed by 2479
Abstract
This study presents a simple route to heparin detection and develops a voltammetric approach using supramolecular principles and nanomaterials. Nanocomposites, including gold nanoparticles (AuNPs) and γ-substituted pentamethinium salts (PMS) deposited on a glass carbon (GC) electrode surface (GC/AuNPs/PMS) and covered by a plasticized [...] Read more.
This study presents a simple route to heparin detection and develops a voltammetric approach using supramolecular principles and nanomaterials. Nanocomposites, including gold nanoparticles (AuNPs) and γ-substituted pentamethinium salts (PMS) deposited on a glass carbon (GC) electrode surface (GC/AuNPs/PMS) and covered by a plasticized poly(vinyl chloride) (PVC) membrane, are proposed for heparin detection. The conductivity of the nonconducting PVC-plasticized membrane is guaranteed by AuNPs, and the selectivity is provided by the interaction between γ-substituted PMS and anionic analytes. In order to extend the linear range, it is necessary to apply a solvent compatible with PVC-plasticized membrane, namely tetrahydrofuran. The proposed voltammetric sensor showed a concentration dependence from 1.72 up to 45.02 IU mL−1 heparin and was used for heparin detection in saline and biological samples with recovery of 95.1–100.9%. Full article
(This article belongs to the Special Issue Advances in Organic Synthesis of Functionalized Nanomaterials and Their Application)
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18 pages, 3823 KiB  
Review
Estrogen Receptor Modulators in Viral Infections Such as SARS−CoV−2: Therapeutic Consequences
by Nikita Abramenko, Fréderic Vellieux, Petra Tesařová, Zdeněk Kejík, Robert Kaplánek, Lukáš Lacina, Barbora Dvořánková, Daniel Rösel, Jan Brábek, Adam Tesař, Milan Jakubek and Karel Smetana
Int. J. Mol. Sci. 2021, 22(12), 6551; https://doi.org/10.3390/ijms22126551 - 18 Jun 2021
Cited by 22 | Viewed by 5450
Abstract
COVID-19 is a pandemic respiratory disease caused by the SARS−CoV−2 coronavirus. The worldwide epidemiologic data showed higher mortality in males compared to females, suggesting a hypothesis about the protective effect of estrogens against severe disease progression with the ultimate end being patient’s death. [...] Read more.
COVID-19 is a pandemic respiratory disease caused by the SARS−CoV−2 coronavirus. The worldwide epidemiologic data showed higher mortality in males compared to females, suggesting a hypothesis about the protective effect of estrogens against severe disease progression with the ultimate end being patient’s death. This article summarizes the current knowledge regarding the potential effect of estrogens and other modulators of estrogen receptors on COVID-19. While estrogen receptor activation shows complex effects on the patient’s organism, such as an influence on the cardiovascular/pulmonary/immune system which includes lower production of cytokines responsible for the cytokine storm, the receptor-independent effects directly inhibits viral replication. Furthermore, it inhibits the interaction of IL-6 with its receptor complex. Interestingly, in addition to natural hormones, phytestrogens and even synthetic molecules are able to interact with the estrogen receptor and exhibit some anti-COVID-19 activity. From this point of view, estrogen receptor modulators have the potential to be included in the anti-COVID-19 therapeutic arsenal. Full article
(This article belongs to the Special Issue Molecular Interactions and Mechanisms of COVID-19 Inhibition)
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20 pages, 1372 KiB  
Review
Iron Complexes of Flavonoids-Antioxidant Capacity and Beyond
by Zdeněk Kejík, Robert Kaplánek, Michal Masařík, Petr Babula, Adam Matkowski, Petr Filipenský, Kateřina Veselá, Jakub Gburek, David Sýkora, Pavel Martásek and Milan Jakubek
Int. J. Mol. Sci. 2021, 22(2), 646; https://doi.org/10.3390/ijms22020646 - 11 Jan 2021
Cited by 121 | Viewed by 10934
Abstract
Flavonoids are common plant natural products able to suppress ROS-related damage and alleviate oxidative stress. One of key mechanisms, involved in this phenomenon is chelation of transition metal ions. From a physiological perspective, iron is the most significant transition metal, because of its [...] Read more.
Flavonoids are common plant natural products able to suppress ROS-related damage and alleviate oxidative stress. One of key mechanisms, involved in this phenomenon is chelation of transition metal ions. From a physiological perspective, iron is the most significant transition metal, because of its abundance in living organisms and ubiquitous involvement in redox processes. The chemical, pharmaceutical, and biological properties of flavonoids can be significantly affected by their interaction with transition metal ions, mainly iron. In this review, we explain the interaction of various flavonoid structures with Fe(II) and Fe(III) ions and critically discuss the influence of chelated ions on the flavonoid biochemical properties. In addition, specific biological effects of their iron metallocomplexes, such as the inhibition of iron-containing enzymes, have been included in this review. Full article
(This article belongs to the Special Issue Antioxidant and Prooxidant Properties of Flavonoids)
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