Ruthenium complexes show potent inhibition of AKR1C1, AKR1C2, and AKR1C3 enzymes and anti-proliferative action against chemoresistant ovarian cancer cell line

Kljun, Jakob (author), Pavlič, Renata (author), Hafner, Eva (author), Lipec, Tanja (author), Moreno-Da Silva, Sara (author), Tič, Primož (author), Turel, Iztok (author), Büdefeld, Tomaž (author), Stojan, Jure (author), Lanišnik-Rižner, Tea (author)

In this study, we present the synthesis, kinetic studies of inhibitory activity toward aldo-keto reductase 1C (AKR1C) enzymes, and anticancer potential toward chemoresistant ovarian cancer of 10 organoruthenium compounds bearing diketonate (1–6) and hydroxyquinolinate (7–10) chelating ligands with the general formula [(η$^6$-p-cymene)Ru(chel)(X)]$^{n+}$ where chel represents the chelating ligand and X the chlorido or pta ligand. Our studies show that these compounds are potent inhibitors of the AKR enzymes with an uncommon inhibitory mechanism, where two inhibitor molecules bind to the enzyme in a first fast and reversible step and a second slower and irreversible step. The binding potency of each step is dependent on the chemical structure of the monodentate ligands in the metalloinhibitors with the chlorido complexes generally acting as reversible inhibitors and pta complexes as irreversible inhibitors. Our study also shows that compounds 1–9 have a moderate yet better anti-proliferative and anti-migration action on the chemoresistant ovarian cancer cell line COV362 compared to carboplatin and similar effects to cisplatin.

• Language: English
• Keywords: ruthenium complexes, synthesis, crystal structure, anticancer, aldo-keto reductase, enzyme inhibition
• Work type: Article
• Typology: 1.01 - Original Scientific Article
• Organization: FKKT - Faculty of Chemistry and Chemical Technology; MF - Faculty of Medicine
• Publication status: Published
• Publication version: Version of Record
• Year: 2022
• Number of pages: 15 str.
• Numbering: Vol. 13, art. 920379
• PID: 20.500.12556/RUL-145365
• UDC: 618.1
• ISSN on article: 1663-9812
• DOI: 10.3389/fphar.2022.920379
• COBISS.SI-ID: 115794691
• Publication date in RUL: 19.04.2023

Record is a part of a journal

• Title: Frontiers in pharmacology
• Shortened title: Front Pharmacol
• Publisher: Frontiers Media
• ISSN: 1663-9812
• COBISS.SI-ID: 29551833

Licences

• License: CC BY 4.0, Creative Commons Attribution 4.0 International
• Link: http://creativecommons.org/licenses/by/4.0/
• Description: This is the standard Creative Commons license that gives others maximum freedom to do what they want with the work as long as they credit the author.

Secondary language

• Language: Slovenian
• Keywords: rutenijevi kompleksi, sinteza, kristalna struktura