Highly cytotoxic trithiophenolatodiruthenium complexes of the type [(η6-p-MeC6H4Pr i )2Ru2(SC6H4-p-X)3]+: synthesis, molecular structure, electrochemistry, cytotoxicity, and glutathione oxidation potential

Abstract

A series of cationic dinuclear p-cymene ruthenium trithiophenolato complexes of the type [(g 6-p-MeC 6 H 4 Pr i) 2 Ru 2 (SC 6 H 4-p-X) 3 ] ? (1 X is H, 2 X is Me, 3 X is Ph, 4 X is Br, 5 X is OH, 6 X is NO 2 , 7 X is OMe, 8 X is CF 3 , 9 X is F, 10 X is Pr i , 11 X is Bu t) have been synthesized from the reaction of [(g 6-p-MeC 6 H 4 Pr i)-RuCl 2 ] 2 with the corresponding thiol, isolated as the chloride salts, and further studied for their electrochemical properties, cytotoxicity towards human ovarian cancer cells, and catalytic activity for glutathione (GSH) oxidation. Complex 1 was also compared with the benzene and hexamethylbenzene analogues [(g 6-C 6 H 6) 2 Ru 2 (SC 6 H 5) 3 ] ? (12) and [(g 6-C 6 Me 6) 2 Ru 2 (SC 6 H 5) 3 ] ? (13). The most active compound [11]Cl was structurally studied by single-crystal X-ray diffraction analysis. The concentrations corresponding to 50 % inhibition of cancer cell growth (IC 50 values) in the A2780 and A2780cisR cell lines of these complexes except for 6 were in the submicromolar range, complex 11 showing an IC 50 value of 0.03 lM in both cell lines. The high in vitro anticancer activity of these complexes may be at least partially due to their catalytic potential for the oxidation of GSH, although there is no clear correlation between the IC 50 values and the turnover frequencies at about 50 % conversion. However, the cytotoxicity is tentatively correlated to the physicochemical properties of the compounds determined by the electronic influence of the substituents X (Hammett constants r p) and the lipophilicity of the thiols p-XC 6 H 4 SH (calculated log P parameters).

Arene ruthenium complexes with phosphinoferrocene amino acid conjugates: Synthesis, characterization and cytotoxicity

“…Most compounds show only moderate cytotoxicities, only 7, 12c and 13c approach that of cisplatin in the A2789 cell line (IC 50 1.6 mM for A2780 and 8.6 mM for A2780 [15]). There is no clear-cut correlation between redox potentials and cytotoxicities, suggesting that catalytic glutathione oxidation, assumed for some other cytotoxic arene ruthenium complexes [24e26], in particular for dinuclear trithiolato derivatives [25,26] is not involved.…”

[(p-MeC6H4Pr )2Ru2(SC6H4-p-Bu )3]Cl (diruthenium-1), a dinuclear arene ruthenium compound with very high anticancer activity: An in vitro and in vivo study

“…The complex [(p-MeC 6 H 4 Pr i ) 2 Ru 2 (SC 6 H 4 -p-Bu t ) 3 ] þ was prepared by a simple one-step synthetic process from the commercially available p-cymene ruthenium dichloride dimer and p-tertbutylthiophenol in refluxing ethanol; it was obtained as the chloride salt in high yield by a slight variation of the published method [24]. The molecular structure of the cation, solved by single-crystal X-ray structure analysis of [(p-MeC 6 H 4 Pr i ) 2 Ru 2 (SC 6 H 4 -p-Bu t ) 3 ]Cl [24], can be described as a trigonal-bipyramidal Ru 2 S 3 framework, in which each ruthenium atom adopts a pseudo-octahedral coordination geometry due to the presence of three sulphur atoms and the h 6 -bonded p-cymene ligand that formally occupies three coordination sites.…”

“…The molecular structure of the cation, solved by single-crystal X-ray structure analysis of [(p-MeC 6 H 4 Pr i ) 2 Ru 2 (SC 6 H 4 -p-Bu t ) 3 ]Cl [24], can be described as a trigonal-bipyramidal Ru 2 S 3 framework, in which each ruthenium atom adopts a pseudo-octahedral coordination geometry due to the presence of three sulphur atoms and the h 6 -bonded p-cymene ligand that formally occupies three coordination sites. In accordance with the noble gas rule, there is no direct metalemetal bond between the two ruthenium atoms (Fig.…”

“…We observed in 2010 that cationic complexes of this family [(arene) 2 Ru 2 (SR) 3 ] þ are highly cytotoxic towards human ovarian cancer cells [23]; a systematic study showed the p-cymene derivatives with aliphatic substituents on the aromatic rings of the three thiophenolato bridges to be the most active ones [24,25].…”

“…In this paper we report on the in vitro and in vivo anticancer activity of the tert-butyl derivative [(p-MeC 6 H 4 Pr i ) 2 Ru 2 (SC 6 H 4 -pBu t ) 3 ]Cl (diruthenium-1), which we selected from 21 compounds of the three series [(p-MeC 6 H 4 Pr i ) 2 Ru 2 (SC 6 H 4 -p-X) 3 [24,28].…”