Synthesis and anticancer activity of long-chain isonicotinic ester ligand-containing arene ruthenium complexes and nanoparticles

Arene ruthenium complexes containing long-chain N-ligands L1 = NC5H4-4-COO-C6H4-4-O-(CH2)9-CH3 or L2 = NC5H4-4-COO-(CH2)10-O-C6H4-4-COO-C6H4-4-C6H4-4-CN derived from isonicotinic acid, of the type [(arene)Ru(L)Cl2] (arene = C6H6, L = L1: 1; arene = p-MeC6H4Pr i , L = L1: 2; arene = C6Me6, L = L1: 3; arene = C6H6, L = L2: 4; arene = p-MeC6H4Pr i , L = L2: 5; arene = C6Me6, L = L2: 6) have been synthesized from the corresponding [(arene)RuCl2]2 precursor with the long-chain N-ligand L in dichloromethane. Ruthenium nanoparticles stabilized by L1 have been prepared by the solvent-free reduction of 1 with hydrogen or by reducing [(arene)Ru(H2O)3]SO4 in ethanol in the presence of L1 with hydrogen. These complexes and nanoparticles show a high anticancer activity towards human ovarian cell lines, the highest cytotoxicity being obtained for complex 2 (IC50 = 2 μM for A2780 and 7 μM for A2780cisR)

Cellular delivery of pyrenyl-arene ruthenium complexes by a water-soluble arene ruthenium metalla-cage.

Three pyrenyl-arene ruthenium complexes (M(1)-M(3)) of the general formula [Ru(η(6)-arene-pyrenyl)Cl(2)(pta)] (pta = 1,3,5-triaza-7-phosphaadamantane) have been synthesised and characterised. Prior to the coordination to ruthenium, pyrene was connected to the arene ligand via an alkane chain containing different functional groups: ester (L(1)), ether (L(2)) and amide (L(3)), respectively. Furthermore, the pyrenyl moieties of the M(n) complexes were encapsulated within the hydrophobic cavity of the water soluble metalla-cage, [Ru(6)(η(6)-p-cymene)(6)(tpt)(2)(donq)(3)](6+) (tpt = 2,4,6-tri-(pyridin-4-yl)-1,3,5-triazine; donq = 5,8-dioxydo-1,4-naphthoquinonato), while the arene ruthenium end was pointing out of the cage, thus giving rise to the corresponding host-guest systems [M(n)⊂Ru(6)(η(6)-p-cymene)(6)(tpt)(2)(donq)(3)](6+) ([M(n)⊂cage](6+)). The antitumor activity of the pyrenyl-arene ruthenium complexes (M(n)) and the corresponding host-guest systems [M(n)⊂cage][CF(3)SO(3)](6) were evaluated in vitro in different types of human cancer cell lines (A549, A2780, A2780cisR, Me300 and HeLa). Complex M(2), which contains an ether group within the alkane chain, demonstrated at least a 10 times higher cytotoxicity than the reference compound [Ru(η(6)-p-cymene)Cl(2)(pta)] (RAPTA-C). All host-guest systems [M(n)⊂cage](6+) showed good anticancer activity with IC(50) values ranging from 2 to 8 μM after 72 h exposure. The fluorescence of the pyrenyl moiety allowed the monitoring of the cellular uptake and revealed an increase of uptake by a factor two of the M(2) complex when encapsulated in the metalla-cage [Ru(6)(η(6)-p-cymene)(6)(tpt)(2)(donq)(3)](6+).

Structure and spectroelectrochemical response of arene− ruthenium and arene−osmium complexes with potentially hemilabile noninnocent ligands

Nine of the compounds [M(L2−)(p-cymene)] (M = Ru, Os, L2− = 4,6-di-tert-butyl-N-aryl-o-amidophenolate) were prepared and structurally characterized (Ru complexes) as coordinatively unsaturated, formally 16 valence electron species. On L2−-ligand based oxidation to EPR-active iminosemiquinone radical complexes, the compounds seek to bind a donor atom (if available) from the N-aryl substituent, as structurally certified for thioether and selenoether functions, or from the donor solvent. Simulated cyclic voltammograms and spectroelectrochemistry at ambient and low temperatures in combination with DFT results confirm a square scheme behavior (ECEC mechanism) involving the Ln ligand as the main electron transfer site and the metal with fractional (δ) oxidation as the center for redox-activated coordination. Attempts to crystallize [Ru(Cym)(QSMe)](PF6) produced single crystals of [RuIII(QSMe •−)2](PF6) after apparent dissociation of the arene ligand.

The Biological Side of Water-Soluble Arene Ruthenium Assemblies

This review article covers the synthetic strategies, structural aspects, and host-guest properties of ruthenium metalla-assemblies, with a special focus on their use as drug delivery vectors. The two-dimensional metalla-rectangles show interesting host-guest possibilities but seem less appropriate for being used as drug carriers. On the other hand, metalla-prisms allow encapsulation and possible targeted release of bioactive molecules and consequently show some potential as drug delivery vectors. The reactivity of these metalla-prisms can be fine-tuned to allow a fine control of the guest’s release. The larger metalla-cubes can be used to stabilize the formation of G-quadruplex DNA and can be used to encapsulate and release photoactive molecules such as porphins. These metalla-assemblies demonstrate great prospective in photodynamic therapy.

Insight into the dynamic ligand exchange process involved in bipyridyl linked arene ruthenium metalla-rectangles

The dynamic ligand exchange behavior of cationic arene ruthenium metalla-rectangles of the type [(pcymene) 4Ru4(OOXOO)2(NXN)2]4+ (OOXOO ¼ oxalato, 2,5-dioxydo-1,4-benzoquinonato, 5,8-dioxydo-1,4-naphthoquinonato; NXN ¼ 4,40-bipyridine-H8, 4,40-bipyridine-D8) has been studied in solution. The robustness of the rectangular architecture has been evidenced by NMR and ESI mass spectrometry. Thermodynamic and kinetic aspects of the ligand exchange process have been explored using 1H/2D isotope labeling of the 4,40-bipyridine connectors. This study shows that ligand exchange does not proceed spontaneously for these metalla-assemblies, even at high temperature, unless an external stimulus is applied.

Cytotoxic peptide conjugates of dinuclear arene ruthenium trithiolato complexes

In order to improve the water-solubility of dinuclear thiolato-bridged arene ruthenium complexes, a new series was synthesized by conjugating octaarginine, octalysine, and cyclo[Lys-Arg-Gly-Asp-D-Phe] using chloroacetyl thioether (ClAc) ligation, resulting in cytotoxic conjugates against A2780 human ovarian cancer cells (IC50 = 2–8 μM) and against the cisplatin resistant line A2780cisR (IC50 = 7–15 μM). These metal complexes represent, to the best of our knowledge, the most cytotoxic ruthenium bioconjugates reported so far.