Catalytic organometallic anticancer complexes

Abstract

Organometallic complexes offer chemistry that is not accessible to purely organic molecules and, hence, potentially new mechanisms of drug action. We show here that the presence of both an iodido ligand and a -donor/ -acceptor phenylazopyridine ligand confers remarkable inertness toward ligand substitution on the half-sandwich ''piano-stool'' ruthenium arene complexes [( 6 -arene)Ru(azpy)I] ؉ (where arene ‫؍‬ p-cymene or biphenyl, and azpy ‫؍‬ N,Ndimethylphenyl-or hydroxyphenyl-azopyridine) in aqueous solution. Surprisingly, despite this inertness, these complexes are highly cytotoxic to human ovarian A2780 and human lung A549 cancer cells. Fluorescence-trapping experiments in A549 cells suggest that the cytotoxicity arises from an increase in reactive oxygen species. Redox activity of these azopyridine Ru II complexes was confirmed by electrochemical measurements. The first one-electron reduction step (half-wave potential ؊0.2 to ؊0.4 V) is assignable to reduction of the azo group of the ligand. In contrast, the unbound azopyridine ligands are not readily reduced. Intriguingly the ruthenium complex acted as a catalyst in reactions with the tripeptide glutathione (␥-L-Glu-L-Cys-Gly), a strong reducing agent present in cells at millimolar concentrations; millimolar amounts of glutathione were oxidized to glutathione disulfide in the presence of micromolar ruthenium concentrations. A redox cycle involving glutathione attack on the azo bond of coordinated azopyridine is proposed. Such ligand-based redox reactions provide new concepts for the design of catalytic drugs.arenes ͉ cytotoxicity ͉ glutathione ͉ redox reactions ͉ ruthenium complexes O rganometallic complexes offer potential for the development of new materials with a wide range of applications (1, 2). Organometallic complexes can exhibit chemical reactivity not possessed by either the metal or organic ligands alone and this reactivity can be fine-tuned by subtle changes in the electronic and steric properties of the bound ligands, or by variation of the metal and its oxidation state. These features provide a versatile platform for drug design that is now being exploited in several areas. For example, the redox activity of the organometallic ferrocenylphenol substitutents enhances the anticancer activity of tamoxifen derivatives by conferring an ability to generate reactive oxygen species in cells (3). Here we consider the anticancer activity of ruthenium(II) arene complexes. Such complexes are well known as catalysts in industry, for example, for hydrogenation reactions (4). Although organometallic complexes can catalyze hydrogenation of intracellular biomolecules (5), metal-centered catalysts might be readily poisoned and be ineffective in biological media.Organometallic half-sandwich Ru II arenes of the type [( 6 -arene)Ru(YZ)(X)] ϩ where YZ is typically a chelating diamine ligand (e.g., ethylenediamine, en) and X is a halide (e.g., Cl) exhibit anticancer activity in vitro and in vivo (6, 7). As with many metal-based anticancer drugs, the primary cellula...

Structure–activity relationships for organometallic osmium arene phenylazopyridine complexes with potent anticancer activity

“…For ten complexes, X-ray crystal structures were determined. (26) were also determined by X-ray crystallography (Fig 1, Tables S1 and S2). All adopt the familiar halfsandwich 'piano-stool' geometry.…”

“…26 Phenylazopyridine ligands are not only σ-donors (like en), but also strong π-acceptors. The aim of the current work was to investigate the effects on anticancer activity of introducing substituents into the pyridine ring especially when the phenyl ring is left unsubstituted.…”

“…12 We have also reported that certain half-sandwich organometallic iodido osmium phenylazopyridine arene complexes exhibit potent in vitro and in vivo anticancer activity, higher activity than the clinical drug cisplatin to a panel of cancer cell lines in vitro. 24,25 Similar to Ru II , 26 we have found that the introduction of the strong π-acceptor azopyridine as a ligand in organometallic Os II complexes has a major effect on their chemical and biological properties. 12 For Os II arene picolinate complexes, log P values correlate with cellular uptake, which…”

Efficient Oxidation of Cysteine and Glutathione Catalyzed by a Dinuclear Areneruthenium Trithiolato Anticancer Complex

“…It is worth pointing out that, for an identical complex/GSH ratio (1:100), TOF 50 obtained for complex 1 is about 1 order of magnitude higher than TOF obtained for iodo-containing ruthenium(II) arene organometallic derivatives (0.37 h À1 ). 11 In addition, incubation of 10 mM GSH with these complexes led to steady oxidation of only 4.6 mM GSH to GSSG, whereas oxidation is complete for complex 1. Moreover, complex 1 is stable during the reactions and can be recovered unchanged as the chloride salt, as shown by 1 H NMR spectra of the reaction of 1 with Cys and GSH recorded at t = 0 and 24 h ( Figures S8 and S9 in the SI).…”

Synthesis, Characterization, and Biological Evaluation of New Ru(II) Polypyridyl Photosensitizers for Photodynamic Therapy

“…[13][14][15][16][17][18] They have gained widespread attention since two complexes, namely NAMI-A and KP1019 (and the respective sodium salt KP1339), passed early clinical trials. [19][20][21] The use of ruthenium in PDT however, has been quite limited so far.…”