title: Pyrithione-based ruthenium complexes as inhibitors of aldo-keto reductase 1C enzymes and anticancer agents.
abstract: Four ruthenium complexes of clinically used zinc ionophore pyrithione and its oxygen analog 2-hydroxypyridine N-oxide were prepared and evaluated as inhibitors of enzymes of the aldo-keto reductase subfamily 1C (AKR1C). A kinetic study assisted with docking simulations showed a mixed type of inhibition consisting of a fast reversible and a slow irreversible step in the case of both organometallic compounds 1A and 1B. Both compounds also showed a remarkable selectivity towards AKR1C1 and AKR1C3 which are targets for breast cancer drug design. The organoruthenium complex of ligand pyrithione as well as pyrithione itself also displayed toxicity on the hormone-dependent MCF-7 breast cancer cell line with EC50 values in the low micromolar range.
authors.affiliation: Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, SI-1000 Ljubljana, Slovenia. iztok.turel@fkkt.uni-lj.si.
authors.forename: Jakob
authors.initials: J
authors.lastname: Kljun
authors.forename: Maja
authors.initials: M
authors.lastname: Anko
authors.forename: Katja
authors.initials: K
authors.lastname: Traven
authors.forename: Maša
authors.initials: M
authors.lastname: Sinreih
authors.forename: Renata
authors.initials: R
authors.lastname: Pavlič
authors.forename: Špela
authors.initials: Š
authors.lastname: Peršič
authors.forename: Žiga
authors.initials: Ž
authors.lastname: Ude
authors.forename: Elisa Esteve
authors.initials: EE
authors.lastname: Codina
authors.forename: Jure
authors.initials: J
authors.lastname: Stojan
authors.forename: Tea
authors.initials: T
authors.lastname: Lanišnik Rižner
authors.forename: Iztok
authors.initials: I
authors.lastname: Turel
mesh_terms: D000074408:Aldo-Keto Reductases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D061986:MCF-7 Cells; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology*; D012428:Ruthenium / Q000737:chemistry / Q000494:pharmacology*; D013871:Thiones / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D011725:Pyridines; D013871:Thiones; C008704:pyrithione; D012428:Ruthenium; D000074408:Aldo-Keto Reductases