Ionic Ruthenium and Iron Based Complexes Bearing Silver Containing Anions as a Potent New Class of Anticancer Agents

Abstract A series of salt complexes of the type [RuCl(η6-arene)(κ2-dppm)]+[AgCl(hfac)(PMe3)]−(arene = benzene (1a) or p-cymene (1b), hfac = hexafluoroacetylacetato, dppm = 1,1-bis(diphenylphosphino)methane) have been prepared in a facile route by reaction of [RuCl2(η6-arene)(κ1-dppm)] with [Ag(hfac)(PMe3)]. The iron complex: [CpFe(CO)(κ2-dppm)]+ [AgI(hfac)(PMe3)]− (4) (Cp = η5-C5H5) was also isolated in an analogous fashion by reacting the known complex [CpFeI(CO)(κ1-dppm)] with [Ag(hfac)(PMe3)]. The complexes were fully characterised by spectroscopic means including multinuclear NMR spectroscopy, IR, ESI-MS and UV-Vis. In all cases broad signals are observed in the 31P{1H} NMR spectra corresponding to the P atom in the anion [AgX(hfac)(PMe3)]− (X = Cl or I) which suggests fluxional behaviour. Confirming this picture, the single crystal X-ray diffraction analysis of [CpFe(CO)(κ2-dppm)]+[hfac]− (4-D) is presented, obtained as a decomposition product of compound 4 corresponding with the loss of “AgI(PMe3)”. The nature of the elusive anion [AgX(hfac)(PMe3)]− was investigated by DFT methods (BP86 functional, the ma-def2-SVP basis set for all atoms) showing a weak interaction between the oxygen atoms of the hfac− moiety and the Ag centre. Calculated IR spectra were compared to those obtained experimentally and show an excellent agreement, confirming this picture. The in vitro cytotoxicity on two breast cancer cell-lines (MCF-7 and MDA-MB-231) of all compounds is reported and compared to cisplatin as positive control. The tetrafluoroborate complexes: type [RuCl(η6-arene)(κ2-dppm)]+BF4− (arene = benzene (2a) or p-cymene (2b)) were also prepared and tested in order to elucidate the effect of the silver anion on cytotoxicity and selectivity in 1a and 1b. Moreover, the complex [CpFe(CO)(κ2-dppm)]+BF4− (3) was also prepared for comparison to 4, bearing the silver anion. In general, all complexes exhibit remarkable cytotoxicity and selectivity profiles on both cell-lines, and out-perform cisplatin. The presence of silver in the anion (in compounds 1a, 1b and 4) on average enhance their cytotoxicity compared to their corresponding BF4 analogues. The most active and selective in the entire series is compound 4, which demonstrates that these compounds represent high potential in anticancer applications. Moreover, compounds 4 and 1a inhibited the long-term survival and migration of oestrogen receptor positive (MCF-7) and triple negative (MDA-MB-231) breast cancer cell lines tested respectively. Additionally, compounds 4 and 1a induced morphological and molecular characteristics of apoptosis in MCF-7 and MDA-MB-231 breast cancer cells respectively.