Ruthenium complexes as inhibitors of the aldo–keto reductases AKR1C1–1C3

Pyrithione-based ruthenium complexes as inhibitors of aldo–keto reductase 1C enzymes and anticancer agents

“…To the best of our knowledge Ru complexes reported in this and our previous study 41 represent the first quasiirreversible inhibitors of AKR1C enzymes. We have determined their structure in solid state by means of single crystal X-ray diffraction and evaluated the potential of both ligands and the four ruthenium complexes as prospective anticancer agents.…”

“…29 Structure-activity studies involving ruthenium complexes with diamine, 30 polypyridyl, 30 phosphine 31 and diketone ligands 32 were made during the last 15 years with clear patterns emerging, however proving different modes of action depending on the ligand types. 41 In our previous study we identified one ruthenium complex and two precursor compounds which inhibited AKR1C1-AKR1C3 enzymes, and one ruthenium complex as a specific inhibitor of AKR1C3 with nM Ki value. 33 Our previous research focused on the design of novel drug candidates in which clinically used drugs (quinolone antibacterials and azole antifungals) were complexed to different ruthenium species with proven biological activity.…”

“…Moreover, a targeted approach can be applied to the development of novel drugs using ruthenium scaffolds as successfully shown by the Meggers group. 41 Continuing our study on ruthenium complexes with clinically used transition metal ionophores, herein we report the study of the biological activity of two types of ruthenium complexes of zinc ionophores pyrithione and its oxygen-containing analog 2-hydroxypyridine N-oxide (Scheme 1). [34][35][36][37][38][39] While these complexes displayed a various degree of toxicity in different cancer cell lines, the study of their biological properties such as binding to serum proteins 35,40 was coupled with investigations of possible targets including DNA, 35,39 cysteine proteases cathepsin B and S, 35,36 and, recently, enzymes of the aldo-keto reductase subfamily 1C (AKR1C1-3).…”

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

“…Several types of AKR1C1 inhibitors have been identified, including, benzodiazepines, steroid carboxylates, phytoestrogens, derivatives of pyrimidine, phthalimide, anthranilic acid and cyclopentane, flavones and ruthenium complexes (Usami et al, 2002; Bauman et al, 2005; Brozic et al, 2006b, 2009; Stefane et al, 2009; Liu et al, 2011; Traven et al, 2015). Notably, 3-bromo-5-phenylsalicylic acid, an inhibitor designed based on the structure of AKR1C1 in ternary complex with NADP + and DCL, its phenyl group targets a non-conserved hydrophobic pocket in the active site of the enzyme lined by residues Leu54, Leu308 and Phe311, resulting in a 21-fold improved potency ( K i = 4 nM) over the structurally similar AKR1C2 (Carbone et al, 2009).…”

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

“…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 .…”