Highly effective Ru(II) and Os(II) half-sandwich complexes induce cytotoxicity in cancer cells through combined mitochondrial and endoplasmic reticulum stress

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00027162%3A_____%2F25%3AN0000064" target="_blank" >RIV/00027162:_____/25:N0000064 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/61989592:15310/25:73633985

Výsledek na webu

<a href="https://www.sciencedirect.com/science/article/pii/S0223523425007354" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0223523425007354</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1016/j.ejmech.2025.117970" target="_blank" >10.1016/j.ejmech.2025.117970</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Highly effective Ru(II) and Os(II) half-sandwich complexes induce cytotoxicity in cancer cells through combined mitochondrial and endoplasmic reticulum stress

Popis výsledku v původním jazyce

A series of ruthenium(II) and osmium(II) half-sandwich complexes was synthesized and characterized for its potential as a new class of anticancer agents. The complexes feature polycyclic aromatic hydrocarbon (PAH)- substituted Schiff bases and were rationally designed to combine the redox-modulating MoA of half-sandwich Ru, Rh, Os and Ir complexes, connected with their ability to induce the formation of various reactive oxygen species (ROS), with the ability of PAH-substituents to target and disrupt DNA. The complexes [Ru(η6-pcym)Cl(L)] PF6 (1–4) and [Os(η6-pcym)Cl(L)]PF6 (5–8) were stable in aqueous environments, in contrast to the rapid degradation observed for the co-studied rhodium(III) (9–12) and iridium(III) (13–16) [M(η5-Cp*)Cl(L)]PF6 complexes; L = ethane-1,2-diamine-based Schiff bases (L1–L4) bearing two terminal PAH substituents 2-naphtyl (for L1), 9-anthracenyl (for L2), 9-phenanthrenyl (L3) or 1-pyrenyl (L4); pcym = 1-methyl-4-(propan-2-yl)benzene (p-cymene), Cp* = pentamethylcyclopentadienyl. Biological testing demonstrated that 1–8 possess significant antiproliferative activity against various lung cancer cell lines, including those resistant to cisplatin, with Os(II) complex 5 showing the highest cytotoxicity. Treatment with these complexes led to the activation of stress-related gene pathways, including unconventional endoplasmic reticulum stress, apoptotic signalling, and mitochondrial membrane depolarization. Activation of p21/GADD45A pathway indicates DNA-damage response, as well. Notably, these complexes did not induce significant inflammatory responses, a notable advantage over cisplatin. The results highlight the potential of Ru and Os half-sandwich complexes as alternative metallodrugs, capable of overcoming platinum resistance and minimizing inflammatory side effects. This study suggests that these compounds could serve as a promising class of anticancer agents for future clinical development.

Název v anglickém jazyce

Highly effective Ru(II) and Os(II) half-sandwich complexes induce cytotoxicity in cancer cells through combined mitochondrial and endoplasmic reticulum stress

Popis výsledku anglicky

A series of ruthenium(II) and osmium(II) half-sandwich complexes was synthesized and characterized for its potential as a new class of anticancer agents. The complexes feature polycyclic aromatic hydrocarbon (PAH)- substituted Schiff bases and were rationally designed to combine the redox-modulating MoA of half-sandwich Ru, Rh, Os and Ir complexes, connected with their ability to induce the formation of various reactive oxygen species (ROS), with the ability of PAH-substituents to target and disrupt DNA. The complexes [Ru(η6-pcym)Cl(L)] PF6 (1–4) and [Os(η6-pcym)Cl(L)]PF6 (5–8) were stable in aqueous environments, in contrast to the rapid degradation observed for the co-studied rhodium(III) (9–12) and iridium(III) (13–16) [M(η5-Cp*)Cl(L)]PF6 complexes; L = ethane-1,2-diamine-based Schiff bases (L1–L4) bearing two terminal PAH substituents 2-naphtyl (for L1), 9-anthracenyl (for L2), 9-phenanthrenyl (L3) or 1-pyrenyl (L4); pcym = 1-methyl-4-(propan-2-yl)benzene (p-cymene), Cp* = pentamethylcyclopentadienyl. Biological testing demonstrated that 1–8 possess significant antiproliferative activity against various lung cancer cell lines, including those resistant to cisplatin, with Os(II) complex 5 showing the highest cytotoxicity. Treatment with these complexes led to the activation of stress-related gene pathways, including unconventional endoplasmic reticulum stress, apoptotic signalling, and mitochondrial membrane depolarization. Activation of p21/GADD45A pathway indicates DNA-damage response, as well. Notably, these complexes did not induce significant inflammatory responses, a notable advantage over cisplatin. The results highlight the potential of Ru and Os half-sandwich complexes as alternative metallodrugs, capable of overcoming platinum resistance and minimizing inflammatory side effects. This study suggests that these compounds could serve as a promising class of anticancer agents for future clinical development.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30104 - Pharmacology and pharmacy

Projekt

<a href="/cs/project/NU22-08-00236" target="_blank" >NU22-08-00236: Preklinické studie neplatinových metaloléčiv v terapii rakoviny plic</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)<br>I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

European Journal of Medicinal Chemistry

ISSN

0223-5234

e-ISSN

1768-3254

Svazek periodika

297

Číslo periodika v rámci svazku

November 2025

Stát vydavatele periodika

FR - Francouzská republika

Počet stran výsledku

16

Strana od-do

"117970"

Kód UT WoS článku

001540981800001

EID výsledku v databázi Scopus

2-s2.0-105011059555