| Autor: |
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, Milan Jakubek |
| Jazyk: |
angličtina |
| Rok vydání: |
2022 |
| Předmět: |
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| Zdroj: |
Pharmaceutics, Vol 14, Iss 8, p 1712 (2022) |
| Druh dokumentu: |
article |
| ISSN: |
1999-4923 |
| DOI: |
10.3390/pharmaceutics14081712 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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