Five complexes of formula [Ru(η-CHCHCOOH)(XY)Cl]Cl/Na (XY = ethylenediamine (1), o-phenylenediamine (2), phenanthroline (3), and oxalato (4)) and [Ru(η:κ-CHCHCOO)(tmen)]Cl (tmen = N, N, N', N'-tetramethylethylenediamine, 5C) have been synthesized and fully characterized. Five new X-ray crystal structures ([Ru(η-CHCHCOOH)(μ-Cl)Cl], 1, 3, 4, and 5C·PF) have been determined, which are the first examples of ruthenium(II) structures with phenylacetic acid as arene ligand. Furthermore, 5C·PF is the first example of a five-membered tether ring with a Ru(η:κ-arene:O) bond. The tether ring in these complexes opens in acidic pH (<5) and closes reversibly in aqueous solution. The chlorido open-form undergoes aquation, and the aqua adduct can be observed (prior to ring closure) by NMR. The speciation has an attractive complexity in the pH range 0-12, showing interconversion of the three species (chlorido, aqua, and closed tether), dependent on the proton concentration and the nature of the XY chelating ligand. The closed tether version of 3, complex 3C, with σ-donor/π-acceptor phenanthroline as chelating ligand, opens up more readily (pH 4), while the tether ring in complex 5C hardly opens even at pH as low as 1. We have determined the p K of the pendant carboxylic group and that of the aqua adduct (ca. 3 and ca. 7, respectively), which can be finely tuned by the appropriate choice of XY. Complexes 1 and 2, which predominate in their inactive (closed-tether) form in intracellular conditions, show some cytotoxic activity (IC 130 and 117 μM, respectively) in A2780 ovarian cancer cells. Complex 1 catalyzes the reduction through transfer hydrogenation of pyruvate to lactate and NAD to NADH in the presence of formate as H-source. Co-incubation with sodium formate decreases the IC value of 1 in A2780 cancer cells significantly.

Aquation is often acknowledged as a necessary step for metallodrug activity inside the cell. Hemilabile ligands can be used for reversible metallodrug activation. We report a new family of osmium(II)...

In situ activation of Pt(IV) to Pt(II) species is a promising strategy to control the anticancer activity and overcome the off-target toxicity linked to classic platinum chemotherapeutic agents. Herein, we present the design and synthesis of two new asymmetric Pt(IV) derivatives of cisplatin and oxaliplatin (1•TARF and 2•TARF, respectively) bearing a covalently bonded 2′,3′,4′,5′tetraacetylriboflavin moiety (TARF). 1 H and 195 Pt NMR spectroscopy shows that 1•TARF and 2•TARF can be effectively activated into toxic Pt(II) species, when incubated with nicotinamide adenine dinucleotide, sodium ascorbate, and glutathione in the dark and under light irradiation. Density functional theory studies of the dark Pt(IV)-to-Pt(II) conversion of 2•TARF indicate that the process involves first hydride transfer from the donor to the flavin moiety of the complex, followed by electron transfer to the Pt(IV) center. When administered to MDA-MB-231 breast cancer cells preincubated with nontoxic amounts of ascorbate, 2•TARF displays enhanced toxicity (between 1 and 2 orders of magnitude), suggesting that the generation of oxaliplatin can selectively be triggered by redox activation. Such an effect is not observed when 2 and TARF are coadministered under the same conditions, demonstrating that covalent binding of the flavin to the Pt complex is pivotal.

Complexes of the formula [Os(η6-arene)(C,N-phenylpyridine)Z] (where Z is chlorido or a tethered oxygen) undergo very fast Os–Z hydrolysis (<5 min), and the high basicity of the coordinated water molecule of the aqua adducts (Os–OH2; pK a > 8) very much contrasts with previously reported Os-aqua adducts bearing NN- and NO-chelating ligands (pK a < 6). The Os–Cl bond is unreactive in pure DMSO, yet the complexes readily form DMSO adducts upon aquation when dimethyl sulfoxide is present. Such a peculiar aqueous behavior is directly related to the negatively charged CN ligand. Potent Os-CN compounds (but not their Os-NN analogues) are particularly reactive; they bind to cysteine in vitro and decrease the activity of thioredoxin reductase (TrxR) in living cancer cells. By revealing some interesting structure–activity relationship on Os-CN vs Os-NN complexes, we start uncovering the molecular rationale for the successful biological applications of osmium(II) half-sandwich compounds.

Tethered ruthenium(II) complexes [Ru(η 6 :κ 1 -arene:N)Cl 2 ] (where arene:N is 2-aminobiphenyl (1) and 2-benzylpyridine (2)) can convert into their open-tethered chlorido counterparts [Ru(η 6 -arene:NH)Cl 3 ], 1•HCl and 2•HCl, at room temperature via solid-state reaction in the presence of HCl vapors. The reaction is accompanied by a change in color, is fully reversible, and crystallinity is maintained in both molecular materials. Organoruthenium tethers are presented as nonporous materials capable of capturing and releasing HCl reversibly in the crystalline solid state.