AUTHOR=Kljun Jakob , Pavlič Renata , Hafner Eva , Lipec Tanja , Moreno-Da Silva Sara , Tič Primož , Turel Iztok , Büdefeld Tomaž , Stojan Jure , Rižner Tea Lanišnik TITLE=Ruthenium complexes show potent inhibition of AKR1C1, AKR1C2, and AKR1C3 enzymes and anti-proliferative action against chemoresistant ovarian cancer cell line JOURNAL=Frontiers in Pharmacology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2022.920379 DOI=10.3389/fphar.2022.920379 ISSN=1663-9812 ABSTRACT=

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 [(η6-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.