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.

Organoruthenium Prodrugs as a New Class of Cholinesterase and Glutathione‐S‐Transferase Inhibitors

“…These data and the data from our previous study indicate compound C1 a , [(η 6 ‐ p ‐cymene)Ru(pyrithionato)Cl], as an interesting multitarget drug (Figure ). C1a showed potent inhibition of the aldo–keto reductase subfamily of enzymes, which are involved in the development of several hormone‐dependent cancers.…”

“…C1a showed potent inhibition of the aldo–keto reductase subfamily of enzymes, which are involved in the development of several hormone‐dependent cancers. This inhibition appears to be one of the reasons for the high cytotoxicity of C1 a against the breast cancer cell model . Indeed, based on additional data presented in this paper, the cytotoxicity of C1 a appears to be highly selective.…”

“…The lower C1 a concentrations (1, 5, 10 μ m ) did not affect the cell viability to any great extent, and the significant drop in cell viability was seen at 200 μ m for HUVEC cells and at 100 μ m for NHEK‐1 cells. In a previous study, a dose‐dependent inhibitory effect of C1 a on proliferation of breast cancer cell line MCF‐7 was observed. The EC 50 value for these cancer cells was approximately 3.5 μ m , whereas in the present study on noncancer cells, the EC 50 values exceeded 10 μ m .…”

“…The complexes included in the present study have been previously found to inhibit several molecular targets relevant to anticancer chemotherapy such as enzymes aldo–keto reductases AKR1C1–3 ( C1 a , and C5 a , C7 a , C7 c , C8 c ), the cysteine protease cathepsin B ( C2 a ), and human lipoxygenase 15‐LOX‐1 ( C5 c , C6 c , C8 c ). Moreover, the C3 a and C3 b organoruthenium complexes studied here which include β‐diketonate ligands were previously evaluated as anticancer agents .…”

Aldo–Keto Reductase AKR1C1–AKR1C4: Functions, Regulation, and Intervention for Anti-cancer Therapy

“…AKR1C3 is inhibited by several classes of AKR1C3 inhibitors, including cinnamic acid (Brozic et al, 2006a), non-steroidal anti-inflammatory drugs (NSAIDs) and their derivatives (Gobec et al, 2005; Byrns et al, 2008; Liedtke et al, 2013), steroid hormone analoges (Bydal et al, 2009), flavonoids (Skarydova et al, 2009), cyclopentanes (Stefane et al, 2009), benzoic acids (Adeniji et al, 2011; Jamieson et al, 2012), progestins (Beranic et al, 2011), baccharin analogs (Zang et al, 2015), ruthenium complexes (Kljun et al, 2016), and the most widely used anti-diabetes drugs, sulfonylureas (Zhao et al, 2015). Most inhibitors of AKR1C3 are carboxylic acids, whose transport into cells is likely dominated by carrier-mediated processes.…”