Conjugates Containing Two and Three Trithiolato-Bridged Dinuclear Ruthenium(II)-Arene Units as In Vitro Antiparasitic and Anticancer Agents

Abstract

The synthesis, characterization, and in vitro antiparasitic and anticancer activity evaluation of new conjugates containing two and three dinuclear trithiolato-bridged ruthenium(II)-arene units are presented. Antiparasitic activity was evaluated using transgenic Toxoplasmagondii tachyzoites constitutively expressing β-galactosidase grown in human foreskin fibroblasts (HFF). The compounds inhibited T.gondii proliferation with IC50 values ranging from 90 to 539 nM, and seven derivatives displayed IC50 values lower than the reference compound pyrimethamine, which is currently used for treatment of toxoplasmosis. Overall, compound flexibility and size impacted on the anti-Toxoplasma activity. The anticancer activity of 14 compounds was assessed against cancer cell lines A2780, A2780cisR (human ovarian cisplatin sensitive and resistant), A24, (D-)A24cisPt8.0 (human lung adenocarcinoma cells wild type and cisPt resistant subline). The compounds displayed IC50 values ranging from 23 to 650 nM. In A2780cisR, A24 and (D-)A24cisPt8.0 cells, all compounds were considerably more cytotoxic than cisplatin, with IC50 values lower by two orders of magnitude. Irrespective of the nature of the connectors (alkyl/aryl) or the numbers of the di-ruthenium units (two/three), ester conjugates 6–10 and 20 exhibited similar antiproliferative profiles, and were more cytotoxic than amide analogues 11–14, 23, and 24. Polynuclear conjugates with multiple trithiolato-bridged di-ruthenium(II)-arene moieties deserve further investigation.

Cellular and Molecular Targets of Nucleotide-Tagged Trithiolato-Bridged Arene Ruthenium Complexes in the Protozoan Parasites Toxoplasma gondii and Trypanosoma brucei

“…Inhibition of T. gondii tachyzoite proliferation and IC 50 determination were performed using a transgenic T. gondii RH strain constitutively expressing β-galactosidase ( T. gondii β-gal) as described for other trithiolato-bridged ruthenium–arene complexes [ 15 , 16 ]. Compounds were prepared as 1 mM stock solutions in DMSO (dimethyl sulfoxide, Sigma, St. Louis, MO, USA).…”

“…In the last decade, extensive research has been carried out to identify suitable molecular drug targets in protozoan parasites that cause diseases in animals and humans [ 12 , 13 ]. Previously published in vitro studies have revealed that trithiolato-bridged dinuclear ruthenium(II)–arene complexes were effective against T. gondii [ 14 , 15 , 16 , 17 ], Neospora caninum [ 17 , 18 ], and T. brucei [ 19 ]. To improve the effectivity of these ruthenium complexes, their organic substituents have attracted special attention [ 20 ].…”

Synthesis and Antiparasitic Activity of New Conjugates—Organic Drugs Tethered to Trithiolato-Bridged Dinuclear Ruthenium(II)–Arene Complexes

“…For the assessment of the biological activity, the compounds were prepared as stock solutions in dimethylsulfoxide (DMSO), in which the compounds are well soluble. 1 H-NMR spectra of similar conjugates (with polypeptides, coumarin units or derivatives with two or three diruthenium units) dissolved in DMSO-d 6 or deuterated water, recorded at 25 • C 5 min and 28 days after sample preparation showed no visible changes, demonstrating very good stability of the compounds in this highly complexing solvent and in water [42,43,80,96].…”

“…T. gondii tachyzoites were released from host cells, and HFF monolayers were infected with freshly isolated parasites (1 × 10 3 /well), and compounds were added concomitantly with infection. In the primary screening, HFF monolayers infected with T. gondii β-gal received 0.1 and 1 µM of each compound, or the corresponding concentration of DMSO (0.01 or 0.1% respectively) as controls and incubated for 72 h at 37 • C/5% CO 2 as previously described [96].…”

Carboranes as unique pharmacophores in antitumor medicinal chemistry

“…Ruthenium and osmium are a class of transition metals widely used in cancer therapy. 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 Complexes containing electron-deficient ruthenium and osmium carborane were reported by the Sadler and Hanna groups. 50 , 51 The redox-active response of these carborane-containing complexes to biomolecules have resulted in their potential application in cancer therapy.…”