Piano-Stool Ruthenium(II) Complexes with Delayed Cytotoxic Activity: Origin of the Lag Time

[Image: see text] We have recently reported a series of piano-stool ruthenium(II) complexes of the general formula [RuCl(2)(η(6)-arene)(P(1-pyrenyl)R(2)R(3))] showing excellent cytotoxic activities (particularly when R(2) = R(3) = methyl). In the present study, new members of this family of compounds have been prepared with the objective to investigate the effect of the steric hindrance of a bulky phosphane ligand, namely diisopropyl(1-pyrenyl)phosphane (L), on exchange reactions involving the coordinated halides (X = Cl, I). Two η(6)-arene rings were used, i.e. η(6)-methyl benzoate (mba) and η(6)-p-cymene (p-cym), and four complexes were synthesized, namely [RuCl(2)(mba)(L)] (1(Cl(2))(iPr)), [RuI(2)(mba)(L)] (1(I(2))(iPr)), [RuCl(2)(p-cym)(L)] (2(Cl(2))(iPr)), and [RuI(2)(p-cym)(L)] (2(I(2))(iPr)). Unexpectedly, all of the complexes exhibited poor cytotoxic activities after 24 h of incubation with cells, in contrast to the related compounds previously reported. However, it was observed that aged DMSO solutions of 2(I(2))(iPr) (from 2 to 7 days) exhibited better activities in comparison to freshly prepared solutions and that the activity improved over “aging” time. Thorough studies were therefore performed to uncover the origin of this lag time in the cytotoxicity efficiency. The data achieved clearly demonstrated that compounds 2(I(2))(iPr) and 2(Cl(2))(iPr) were undergoing a series of transformation reactions in DMSO (with higher rates for the iodido complex 2(I(2))(iPr)), ultimately generating cyclometalated species through a mechanism involving DMSO as a coordinated proton abstractor. The cyclometalated complexes detected in solution were subsequently prepared; hence, pure [RuCl(p-cym)(κ(2)C-diisopropyl(1-pyrenyl)phosphane)] (3(Cl)(iPr)), [RuI(p-cym)(κ(2)C-diisopropyl(1-pyrenyl)phosphane)] (3(I)(iPr)), and [Ru(p-cym)(κS-dmso)(κ(2)C-diisopropyl(1-pyrenyl)phosphane)]PF(6) (3(dmso)(iPr)) were synthesized and fully characterized. Remarkably, 3(Cl)(iPr), 3(I)(iPr), and 3(dmso)(iPr) are all very efficient cytotoxic agents, exhibiting slightly better activities in comparison to the chlorido noncyclometalated complexes [RuCl(2)(η(6)-arene)(P(1-pyrenyl)R(2)R(3))] described in an earlier report. For comparison purposes, the iodido compounds [RuI(2)(mba)(dimethyl(1-pyrenyl)phosphane)] (1(I(2))(Me)) and [RuI(2)(p-cym)(dimethyl(1-pyrenyl)phosphane)] (2(I(2))(Me)), bearing the less hindered dimethyl(1-pyrenyl)phosphane ligand, have also been prepared. The cytotoxic and chemical behaviors of 1(I(2))(Me) and 1(I(2))(Me) were comparable to those of their chlorido counterparts reported previously.