In Vitro and in Vivo Evaluation of Water-Soluble Iminophosphorane Ruthenium(II) Compounds. A Potential Chemotherapeutic Agent for Triple Negative Breast Cancer

Abstract

A series of organometallic ruthenium(II) complexes containing iminophosphorane ligands have been synthesized and characterized. Cationic compounds with chloride as counterion are soluble in water (70–100 mg/mL). Most compounds (especially highly water-soluble 2) are more cytotoxic to a number of human cancer cell lines than cisplatin. Initial mechanistic studies indicate that the cell death type for these compounds is mainly through canonical or caspase-dependent apoptosis, nondependent on p53, and that the compounds do not interact with DNA or inhibit protease cathepsin B. In vivo experiments of 2 on MDA-MB-231 xenografts in NOD.CB17-Prkdc SCID/J mice showed an impressive tumor reduction (shrinkage) of 56% after 28 days of treatment (14 doses of 5 mg/kg every other day) with low systemic toxicity. Pharmacokinetic studies showed a quick absorption of 2 in plasma with preferential accumulation in the breast tumor tissues when compared to kidney and liver, which may explain its high efficacy in vivo.

Hydrogen Bonding and Anticancer Properties of Water‐Soluble Chiral p‐Cymene RuII Compounds with Amino‐Oxime Ligands

“…While a linear Stern-Volmer plot is indicative of a single quenching mechanism, either dynamic or static, the positive deviation observed in the plots of F 0 /F versus [Q] of 1a or 1b (Figure 7(B)) suggests the presence of different binding sites in the protein. [81] A similar behavior was observed for iminophosphorane complexes of Ru(II), [6] Pd(II) or Pt(II) [82] reported by some of us. In the case of [MCl 2 (TPA=N-C(O)-2-NC 5 H 4 )] (M = Pd, Pt), isothermal titration calorimetry (ITC) [82] showed two different binding interactions which explained the lack of linearity observed in the fluorescence quenching studies, as the Stern-Volmer method assumes all binding sites to be equivalent.…”

Synthesis and anticancer activity of carbosilane metallodendrimers based on arene ruthenium(ii) complexes

“…2) which displayed similar IC 50 values in vitro for human cancer cell versus HEK-293T but which was very effective in vivo on MDA-MB-231 xenografts in NOD.CB17-Prkdc SCID/J mice while having low systemic toxicity. 33 The cytotoxicity of the most active dendrimers is in the range of the cytotoxicity obtained for two arene-ruthenium octanuclear dendrimers on cervical cancer cell lines (A2780 and A2780cisR). 49 In the case of these previously reported compounds (containing chelating N,O - and N,N -ruthenium (II) arene functionalized poly(propyleneimine) dendrimer scaffolds a correlation between size dependency of the dendrimers and cytotoxicity was found.…”

The development of anticancer ruthenium(ii) complexes: from single molecule compounds to nanomaterials

“…Most of the complexes were found to be more cytotoxic than cisplatin in several human cancer cell lines. 158 The most effective complex, 6k , produced a 56% decrease in tumor size in mice with xenografted breast carcinoma MDA-MB-231 cells, with low systemic toxicity after 28 days of treatment (14 doses of 5 mg/kg, every other day). Pharmacokinetic studies indicated that 6k appeared rapidly in plasma, with high uptake in the breast tumor tissues compared to the kidneys and liver.…”