Federico Giannini

Efficient Oxidation of Cysteine and Glutathione Catalyzed by a Dinuclear Areneruthenium Trithiolato Anticancer Complex

The highly cytotoxic diruthenium complex [(p-MeC(6)H(4)Pr(i))(2)Ru(2)(SC(6)H(4)-p-Me)(3)](+) (1), water-soluble as the chloride salt, is shown to efficiently catalyze oxidation of the thiols cysteine and glutathione to give the corresponding disulfides, which may explain its high in vitro anticancer activity.

Synthesis, molecular structure, computational study and in vitro anticancer activity of dinuclear thiolato-bridged pentamethylcyclopentadienyl Rh(III) and Ir(III) complexes

Neutral dinuclear dithiolato-bridged pentamethylcyclopentadienyl Rh(III) complexes of the type (C5Me5)2Rh2(μ-SR)2Cl2 (R = CH2Ph, 1; R = CH2CH2Ph, 2) and cationic dinuclear trithiolato-bridged pentamethylcyclopentadienyl Rh(III) and Ir(III) complexes of the type [(C5Me5)2M2(μ-SR)3](+) (M = Rh, R = CH2Ph, 3; M = Rh, R = CH2CH2Ph, 5; M = Rh, R = CH2C6H4-p-(t)Bu, 7: M = Ir, R = CH2Ph, 4; M = Ir, R = CH2CH2Ph, 6; M = Ir, R = CH2C6H4-p-(t)Bu, 8) have been synthesized from the chloro-bridged pentamethylcyclopentadienyl Rh(III) and Ir(III) dimers (C5Me5)2M2(μ-Cl)2Cl2 by reaction with the corresponding thiol derivative (RSH). Complexes 3-8 were isolated as chloride salts. All complexes were obtained in good yield and were fully characterized by spectroscopic methods. The molecular structures of the neutral complexes (1 and 2) show interesting features: the two rhodium atoms are bridged by two thiolato ligands with no metal-metal bonds and the pentamethylcyclopentadienyl and chlorido ligands are oriented syn to each other, an uncommon conformation for such dinuclear complexes. These structural features were rationalized using DFT calculations. Additionally, the antiproliferative activity of the complexes was evaluated against the cancerous A2780 (cisplatin sensitive) and A2780cisR (cisplatin resistant) human ovarian cell lines and on the noncancerous HEK293 human embryonic kidney cells. All complexes were found to be active and the cationic iridium complexes , and are particularly cytotoxic, with IC50 values in the nanomolar range (IC50 < 0.1 μM). The catalytic activity of the complexes for the oxidation of glutathione (GSH) to GSSG was evaluated by NMR spectroscopy.

Synthesis, characterisation and in vitro anticancer activity of hexanuclear thiolato-bridged arene ruthenium metalla-prisms.

Hexanuclear thiolato-bridged arene ruthenium metalla-prisms of the general formula [(p-cymene)(6)Ru(6)(SR)(6)(tpt)(2) ](6+) (R=CH(2)Ph, CH(2)C(6)H(4)-p-tBu, CH(2)CH(2)Ph; tpt=2,4,6-tris(4-pyridyl)-1,3,5-triazine), obtained from the dinuclear precursors [(p-cymene)(2)Ru(2)(SR)(2)Cl(2)], AgCF(3)SO(3) and tpt, have been isolated and fully characterised as triflate salts. The metalla-prisms are highly cytotoxic against human ovarian cancer cells, especially towards the cisplatin-resistant cell line A2780cisR (IC(50) <0.25 μM).

Insights into the mechanism of action and cellular targets of ruthenium complexes from NMR spectroscopy.

NMR spectroscopy has proved extremely beneficial in the investigation of inorganic drugs from the time that cisplatin was first introduced into the clinic more than 30 years ago. Both (195)Pt and (15)N NMR were used in early studies and made a major contribution in the understanding of the molecular mechanism of action from model studies involving reactions with amino acids and nucleotides. Over the past decade, ruthenium drugs have proved to be a valuable alternative to platinum drugs, and NMR has also provided unique insights into their molecular mechanism of action including investigations of simple aquation reactions, protein binding and the kinetics and sequence selectivity of DNA binding interactions. In this article, emphasis is given to define the cellular targets and elucidate some of the mechanistic profiles of recent ruthenium-based organometallic compounds offering efficacy toward cancer cells, by various NMR techniques.

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.

Characterization of the Activities of Dinuclear Thiolato-Bridged Arene Ruthenium Complexes against Toxoplasma gondii

ABSTRACT The in vitro effects of 18 dinuclear thiolato-bridged arene ruthenium complexes (1 monohiolato compound, 4 dithiolato compounds, and 13 trithiolato compounds), originally designed as anticancer agents, on the apicomplexan parasite Toxoplasma gondii grown in human foreskin fibroblast (HFF) host cells were studied. Some trithiolato compounds exhibited antiparasitic efficacy at concentrations of 250 nM and below. Among those, complex 1 and complex 2 inhibited T. gondii proliferation with 50% inhibitory concentrations (IC50s) of 34 and 62 nM, respectively, and they did not affect HFFs at dosages of 200 μM or above, resulting in selectivity indices of >23,000. The IC50s of complex 9 were 1.2 nM for T. gondii and above 5 μM for HFFs. Transmission electron microscopy detected ultrastructural alterations in the matrix of the parasite mitochondria at the early stages of treatment, followed by a more pronounced destruction of tachyzoites. However, none of the three compounds applied at 250 nM for 15 days was parasiticidal. By affinity chromatography using complex 9 coupled to epoxy-activated Sepharose followed by mass spectrometry, T. gondii translation elongation factor 1α and two ribosomal proteins, RPS18 and RPL27, were identified to be potential binding proteins. In conclusion, organometallic ruthenium complexes exhibit promising activities against Toxoplasma, and the potential mechanisms of action of these compounds as well as their prospective applications for the treatment of toxoplasmosis are discussed.