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Towards Identification of Essential Structural Elements of Organoruthenium(II)‐Pyrithionato Complexes for Anticancer Activity
Author(s) -
Kladnik Jerneja,
Kljun Jakob,
Burmeister Hilke,
Ott Ingo,
RomeroCanelón Isolda,
Turel Iztok
Publication year - 2019
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201903109
Subject(s) - ruthenium , chemistry , cytotoxicity , reactive oxygen species , thioredoxin reductase , apoptosis , stereochemistry , ligand (biochemistry) , combinatorial chemistry , in vitro , thioredoxin , biochemistry , receptor , oxidative stress , catalysis
An organoruthenium(II) complex with pyrithione (2‐mercaptopyridine N ‐oxide) 1 a has previously been identified by our group as a compound with promising anticancer potential without cytotoxicity towards non‐cancerous cells. To expand the rather limited research on compounds of this type, an array of novel chlorido and 1,3,5‐triaza‐7‐phosphaadamantane (pta) organoruthenium(II) complexes with methyl‐substituted pyrithiones has been prepared. After thorough investigation of the aqueous stability of these complexes, their modes of action have been elucidated at the cellular level. Minor structural alterations in the ruthenium‐pyrithionato compounds resulted in fine‐tuning of their cytotoxicities. The best performing compounds, 1 b and 2 b , with a chlorido or pta ligand bound to ruthenium, respectively, and a methyl group at the 3‐position of the pyrithione scaffold, have been further investigated. Both compounds trigger early apoptosis, induce the generation of reactive oxygen species and G1 arrest in A549 cancer cells, and show no strong interaction with DNA. However, only 1 b also inhibits thioredoxin reductase. Wound healing assays and mitochondrial function evaluation have revealed differences between these two compounds at the cellular level.