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

0561287 - ÚMG 2023 RIV CH eng J - Článek v odborném periodiku
Talianova, V. - Kejik, Z. - Kaplánek, R. - Veselá, K. - Abramenko, N. - Lacina, L. - Strnadová, K. - Dvořánková, B. - Martásek, P. - Masarik, M. - Houdová Megová, M. - Bušek, P. - Křížová, J. - Zdražilová, L. - Hansíková, H. - Vlčák, Erik - Filimonenko, Vlada - Šedo, A. - Smetana, K. - Jakubek, M.
New-Generation Heterocyclic Bis-Pentamethinium Salts as Potential Cytostatic Drugs with Dual IL-6R and Mitochondria-Targeting Activity.
Pharmaceutics. Roč. 14, č. 8 (2022), č. článku 1712. E-ISSN 1999-4923
Grant CEP: GA MŠMT(CZ) EF16_019/0000785; GA MŠMT LX22NPO5102; GA MŠMT(CZ) LM2018129; GA MŠMT(CZ) EF18_046/0016045; GA MŠMT(CZ) EF16_013/0001775
Výzkumná infrastruktura: EATRIS-CZ III - 90133
Institucionální podpora: RVO:68378050
Klíčová slova: IL-6R synthetic inhibitors * mitochondria * cancer
Obor OECD: Pharmacology and pharmacy
Impakt faktor: 5.4, rok: 2022
Způsob publikování: Open access
https://www.mdpi.com/1999-4923/14/8/1712

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.
Trvalý link: https://hdl.handle.net/11104/0333975