Ruthenium(II) polypyridyl complexes with hydrophobic ancillary ligand as Aβ aggregation inhibitors

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

“…Most of the recent data in the field of ruthenium‐based cholinesterase inhibitors are built on those of Dwyer and Gyarfas from the early 1950s, and involve the tris‐phenanthroline ruthenium(II) complex . A structural analysis of compounds in more recent studies showed that the compounds investigated share structural similarities with the parent Dwyer complex, whereby the Ru II ion is either bound to three identical phenanthroline derivatives, as [Ru(phen‐R) 3 ] 2+ , or ruthenium(II) is coordinated by two phenanthroline ligands and either two monodentate N ‐ligands or one bidentate N , N ‐ligand, as [Ru(phen) 2 N 1 N 2 ] 2+ . From the chemical point of view, these compounds are considered inert for substitutions under physiological conditions, and can interact with target macromolecules through the side groups of the ligand substructures by intercalation or through electrostatic, covalent, or supramolecular interactions.…”

“…The inhibition of GSTs by ruthenium compounds is already well established . Furthermore, more recently, and now 66 years after the first report by Dwyer and Gyarfas in 1952, ruthenium‐based complexes have been rediscovered as potential anti‐cholinesterase agents with interesting pharmaceutical potential …”

“…[21][22][23][24] Furthermore, more recently, and now 66 years after the first report by Dwyer and Gyarfas in 1952, [10] ruthenium-based complexes have been rediscovered as potential anti-cholinesterase agents with interesting pharmaceutical potential. [25][26][27][28][29][30] In the present study, we evaluated the potential of a small library of ruthenium complexes with the general formula of [Ru II (fcl)(chel)(L)] n + , whereby: "fcl" defines a face-capping ligand, p-cymene or 1,4,7-trithicyclononane; "chel" defines a chelating bidentate ligand, including pyrithione, clioquinol, different b-diketonates, 2-(2'-azaaryl)pyridines, and pyridine-Noxides; and "L" defines a monodentate ligand, including Cl À , Sbound dimethylsulfoxide (S-dmso), and 1,3,5-triaza-7-phosphaadmantane (pta). These compounds were synthesized by the Turel research group (University of Ljubljana, Slovenia) over the last decade as potential inhibitors of AChE, BChE, and GSTs of animal and human origins.…”

Luminescent Ru(II) Phenanthroline Complexes as a Probe for Real-Time Imaging of Aβ Self-Aggregation and Therapeutic Applications in Alzheimer’s Disease

“…Binuclear complexes of Pt­(II)–Ru­(II) and mononuclear complexes of Ir­(III), Rh­(III), and Ru­(II/III) have also been investigated. − In particular, Ru complexes are of special interest due to their attractive biologic profiles compared with Pt­(II) . In this respect, the Ru­(III) complexes NAMI-A ([Him]­[ trans -RuCl 4 (DMSO)­(im)], im = imidazole) and KP1019 ([Hind]­[ trans -[RuCl 4 (ind) 2 ], ind = indazole) and its Na + analogue (KP1339) have been investigated using ThT fluorescence to follow the formation of Aβ fibril aggregates. − Although NAMI-A and KP1339 are currently under clinical trials owing to their anticancer activity and low toxicity properties, they were inactive or exhibited poor activity against Aβ binding and toxicity. , Nevertheless, a recent study using EPR, gel electrophoresis, and TEM images suggested a concentration dependent binding of KP1019 to Aβ 1–42 , and as observed for Pt­(II), KP1019 binds to the N-terminus of Aβ through Hist6, Hist13, and/or Hist14 …”

Structural Isomerism and Enhanced Lipophilicity of Pyrithione Ligands of Organoruthenium(II) Complexes Increase Inhibition on AChE and BuChE

“…However, as mentioned, cholinergic system seems to be the most promising therapeutic field to combat AD. Some ruthenium complexes, mainly ruthenium(II) polypyridyl compounds, have also been examined as AChE inhibitors [ 16 , 17 , 18 ], and some of them additionally inhibit Aβ aggregation [ 19 , 20 , 21 ]. Recently, we have reported a potent chlorido organoruthenium(II) complex with pyrithione 1a ( Scheme 1 ) ( a —pyrithione, also 1-hydroxypyridine-2(1 H )-thione or 2-mercaptopyridine N -oxide) [ 22 ], which is an excellent reversible competitive inhibitor of three ChEs, namely electric eel AChE (eeAChE), human AChE (hAChE), and horse serum BuChE (hsBuChE) with low micromolar IC 50 values (5.01 µM, 25.06 µM, and 7.52 µM, respectively).…”