Half-Sandwich Ru(p-cymene) Compounds with Diphosphanes: In Vitro and In Vivo Evaluation As Potential Anticancer Metallodrugs

Abstract

Ruthenium(II) complexes are currently considered attractive alternatives to the widely used platinum-based drugs. We present herein the synthesis and characterization of half-sandwich ruthenium compounds formulated as [Ru(p-cymene)(L)Cl]-[CF 3 SO 3 ] (L = 1,1-bis(methylenediphenylphosphano)ethylene, 1; L = 1,1-bis(diphenylphosphano)ethylene, 2), which were characterized by elemental analysis, mass spectrometry, 1 H and 31 P{ 1 H} NMR, UV−vis and IR spectroscopy, conductivity measurements and cyclic voltammetry. The molecular structures for both complexes were determined by single-crystal X-ray diffraction. Their cytotoxic activity was evaluated using the MTT assay against human tumor cells, namely ovarian (A2780) and breast (MCF7 and MDA-MB-231). Both complexes were active against breast adenocarcinoma cells, with complex 1 exhibiting a quite remarkable cytotoxicity in the submicromolar range. Interestingly, at concentrations equivalent to the IC 50 values in the MCF7 cancer cells, complexes 1 and 2 presented lower cytotoxicity in normal human primary fibroblasts. The antiproliferative effects of 1 and 2 in MCF7 cells might be associated with the induction of reactive oxygen species (ROS), leading to a combined cell death mechanism via apoptosis and autophagy. Despite the fact that in vitro a partial intercalation between complexes and DNA was observed, no MCF7 cell cycle delay or arrest was observed, indicating that DNA might not be a direct target. Complexes 1 and 2 both exhibited a moderate to strong interaction with human serum albumin, suggesting that protein targets may be involved in their mode of action. Their acute toxicity was evaluated in the zebrafish model. Complex 1 (the most toxic of the two) exhibited a lethal toxicity LC 50 value about 1 order of magnitude higher than any IC 50 concentrations found for the cancer cell models used, highlighting its therapeutic relevance as a drug candidate in cancer chemotherapy.

Ionic mononuclear [Fe] and heterodinuclear [Fe,Ru] bis(diphenylphosphino)alkane complexes: Synthesis, spectroscopy, DFT structures, cytotoxicity, and biomolecular interactions

“…From Figure 6a, notable time-dependent changes in the UV-vis spectra of 10 occur at pH 7.6 in 90% aqueous buffer. In the first 10-15 minutes (Phase I) after addition of a DMSO solution of the compound to the aqueous buffer, the UV-vis absorption spectra clearly increase in intensity and the shoulder band at 343 nm (normally assigned to Ru(II) 4d* MLCT transitions) 94 becomes somewhat less distinct. The spectra then remain constant in intensity for a considerable length of time (12-60 min), giving rise to a stationary phase, before beginning to decrease in intensity over a period of 3 h (Phase II), after which the reaction is > 95% complete.…”

A Ru(ii)-arene-ferrocene complex with promising antibacterial activity

“…Furthermore, the observed binding affinities are similar to other Ru(II)-arene complexes. 79,80 To determine the mechanism of quenching involved, the UV-vis spectra of HSA in the absence and presence of each complex were measured. Overall, the absorption intensity of HSA decreased with no shift observed in the position of the absorption bands (Fig.…”

Triazole-Based Half-Sandwich Ruthenium(II) Compounds: From In Vitro Antiproliferative Potential to In Vivo Toxicity Evaluation

“…In particular, some ruthenium compounds have exhibited very promising antiproliferative activity, being less toxic than platinum drugs . The ruthenium compound NKP1339 (Scheme ) has shown high in vitro and in vivo antitumor activity, reaching clinical trials for advanced solid tumors (NCT01415297). − In addition, the arene ruthenium based complexes RM175 and RAPTA-C are currently in the preclinical stage (Scheme ). − Despite the fact that RAPTA-C generally has shown low cytotoxicity in vitro , , it displays important antimetastatic and antiangiogenic properties in vivo .…”

“…Intrigued by the activities of organometallic complexes with triazole-derived ligands, and in a continuation of our interest in developing Ru-based anticancer drugs, − herein we report the anticancer activity of four new chelating N ∧ N Ru­(II) arene compounds bearing ditriazole and mixed triazole-pyridine ligands. The effect of the presence of triazole, pyridine rings, and arene ( p -cymene and benzene) units in the biological activity of the ruthenium compounds has been investigated.…”