Discovery of a Highly Tumor-Selective Organometallic Ruthenium(II)–Arene Complex

Abstract

A ruthenium(II)-arene complex with a perfluoroalkyl-ligand was found to display remarkable selectivity toward cancer cells. IC50 values on several cancer cell lines are in the range of 25-45 μM, and no cytotoxic effect was observed on nontumorigenic (HEK-293) cells at concentrations up to 500 μM (the maximum concentration tested). Consequently, this complex was used as the basis for the development of a number of related derivatives, which were screened in cancerous and noncancerous cell lines. The lead compound was then evaluated in vivo for antiangiogenic activity in the CAM model and in a xenografted ovarian carcinoma tumor (A2780) grown on the CAM. A 90% reduction in the tumor growth was observed.

Antiangiogenic and Anticancer Properties of Bifunctional Ruthenium(II)–p-Cymene Complexes: Influence of Pendant Perfluorous Chains

“…43 Complex 1 administered at 50 μM (0.5 mg/kg) was previously shown to induce an antivascular effect represented by a 26.3% reduction in the number of branching points/ mm 2 . 28 The presence of avascular zones (black areas in fluorescence angiographies indicated by arrows, Figure 4) was observed for 2 administered at 42 μM (0.47 mg/kg), with a 38% reduction of the number branching points/mm 2 versus the control (***p = 2.8 × 10 −5 ), mainly along the larger vessels. The avascular zones observed are most likely due to antiangiogenic activity of 2.…”

“…The antitumor activity of 1 was previously studied in vivo using the preclinical model of human ovarian A2780 carcinoma grown on the chicken chorioallantoic membrane CAM ( Figure 5A). 28 For comparison, 2 and a combination treatment of 1 + 2 were evaluated using the same model and protocol. Embryos were randomized and treated within the following groups via intravenous administration of 0.1% DMSO (CTRL), 2 (50 μM; 0.56 mg/kg, 80 μL), or the mixture of 1 + 2 (premixed at ratio 1:1; 25 μM each; 0.5 mg/kg, 80 μL).…”

“…30 Compound 1 was also found to inhibit A2780 tumor growth in a CAM preclinical model. 28 Moreover, 2, which displays little activity at 37°C toward all tumor cell types tested, showed thermoactive properties in vitro, i.e., inhibiting cell viability when combined with mild hyperthermia (41.5°C). 30 Based on these observations further studies of the biological properties of 1 and 2 were undertaken, and, herein, we show that, at nontoxic doses, 1 has direct anticancer properties whereas 2 exerts predominately an antiangiogenic effect that leads to effective tumor growth inhibition.…”

“…28,29 These derivatives are structurally related to the RAPTA class of compounds presenting the same "piano-stool" motif, with the PTA ligand being replaced by a pyridine ligand modified with a perfluorinated chain ( Figure 1). We have previously shown that 1 (Figure 1), when evaluated at 37°C, i.e., in the absence of a hyperthermia signal, displays a remarkable cancer cell selectivity.…”

Design, synthesis, characterization, cytotoxic and structure activity relationships of novel Ru(II) complexes

“…This diversity arises from not only the choice of the metal itself and its oxidation state, but from the types and numbers of coordinated ligands and the coordination geometry of the complex [2]. Platinum-based drugs are widely used to treat cancer, but their therapeutic use can be altered by intrinsic or acquired resistance and the occurrence of numerous side effects including neurotoxicity, nephrotoxicity, neuropathy, myelosuppression, thrombocytopenia and neutropenia [3]. Ruthenium, a second row transition metal, continues to attract much attention in the world of scientific research, as it possesses a wide array of applicable properties.…”