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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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SYSNO ASEP 0561287 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title New-Generation Heterocyclic Bis-Pentamethinium Salts as Potential Cytostatic Drugs with Dual IL-6R and Mitochondria-Targeting Activity Author(s) Talianova, V. (CZ)
Kejik, Z. (CZ)
Kaplánek, R. (CZ)
Veselá, K. (CZ)
Abramenko, N. (CZ)
Lacina, L. (CZ)
Strnadová, K. (CZ)
Dvořánková, B. (CZ)
Martásek, P. (CZ)
Masarik, M. (CZ)
Houdová Megová, M. (CZ)
Bušek, P. (CZ)
Křížová, J. (CZ)
Zdražilová, L. (CZ)
Hansíková, H. (CZ)
Vlčák, Erik (UMG-J)
Filimonenko, Vlada (UMG-J) RID, ORCID
Šedo, A. (CZ)
Smetana, K. (CZ)
Jakubek, M. (CZ)Number of authors 20 Article number 1712 Source Title Pharmaceutics. - : MDPI
Roč. 14, č. 8 (2022)Number of pages 20 s. Publication form Online - E Language eng - English Country CH - Switzerland Keywords IL-6R synthetic inhibitors ; mitochondria ; cancer Subject RIV EB - Genetics ; Molecular Biology OECD category Pharmacology and pharmacy R&D Projects EF16_019/0000785 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LX22NPO5102 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) LM2018129 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF18_046/0016045 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) EF16_013/0001775 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Research Infrastructure EATRIS-CZ III - 90133 - Univerzita Palackého v Olomouci Method of publishing Open access Institutional support UMG-J - RVO:68378050 UT WOS 000845735400001 DOI 10.3390/pharmaceutics14081712 Annotation 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 binding9.5 and8.1 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. Workplace Institute of Molecular Genetics Contact Nikol Škňouřilová, nikol.sknourilova@img.cas.cz, Tel.: 241 063 217 Year of Publishing 2023 Electronic address https://www.mdpi.com/1999-4923/14/8/1712
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