Towards Identification of Essential Structural Elements of Organoruthenium(II)-Pyrithionato Complexes for Anticancer Activity |
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Authors: | Jerneja Kladnik Dr. Jakob Kljun Hilke Burmeister Prof. Dr. Ingo Ott Dr. Isolda Romero-Canelón Prof. Dr. Iztok Turel |
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Affiliation: | 1. Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, 1000 Ljubljana, Slovenia;2. Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, 38106 Braunschweig, Germany;3. School of Pharmacy, Institute of Clinical Sciences, University of Birmingham, Birmingham, B15 2TT UK |
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Abstract: | 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. |
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Keywords: | cancer complexes pyrithione ruthenium thioredoxin reductase |
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