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New-Generation Heterocyclic Bis-Pentamethinium Salts as Potential Cytostatic Drugs with Dual IL-6R and Mitochondria-Targeting Activity

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Authors

TALIANOVÁ Veronika KEJÍK Zdeněk KAPLÁNEK Robert VESELÁ Kateřina ABRAMENKO Nikita LACINA Lukáš STRNADOVÁ Karolína DVOŘÁNKOVÁ Barbora MARTÁSEK Pavel MASAŘÍK Michal MEGOVÁ HOUDOVÁ Magdalena BUŠEK Petr KŘÍŽOVÁ Jana ZDRAŽILOVÁ Lucie HANSÍKOVÁ Hana VLČÁK Erik FILIMONENKO Vlada ŠEDO Aleksi SMETANA JR. Karel JAKUBEK Milan

Year of publication 2022
Type Article in Periodical
Magazine / Source Pharmaceutics
MU Faculty or unit

Faculty of Medicine

Citation
Web https://www.mdpi.com/1999-4923/14/8/1712
Doi http://dx.doi.org/10.3390/pharmaceutics14081712
Keywords IL-6R synthetic inhibitors; mitochondria; cancer
Attached files
Description 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.
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