Cytotoxic hydrogen bridged ruthenium quinaldamide complexes showing induced cancer cell death by apoptosis

This report presents the first known p -cymene ruthenium quinaldamide complexes which are stabilised by a hydrogen-bridging atom, [{( p -cym)Ru II X( N , N )}{H + }{( N , N )XRu II ( p -cym)}][PF 6 ] ( N , N = functionalised quinaldamide and X = Cl or Br). These complexes are formed by a reaction of [ p -cymRu(μ-X) 2 ] 2 with a functionalised quinaldamide ligand. When filtered over NH 4 PF 6 , and under aerobic conditions the equilibrium of NH 4 PF 6 ⇔ NH 3 + HPF 6 enables incorporation of HPF 6 and the stabilisation of two monomeric ruthenium complexes by a bridging H + , which are counter-balanced by a PF 6 counterion. X-ray crystallographic analysis is presented for six new structures with O O distances of 2.420(4)-2.448(15) Å, which is significant for strong hydrogen bonds. Chemosensitivity studies against HCT116, A2780 and cisplatin-resistant A2780cis human cancer cells showed the ruthenium complexes with a bromide ancillary ligand to be more potent than those with a chloride ligand. The 4′-fluoro compounds show a reduction in potency for both chloride and bromide complexes against all cell lines, but an increase in selectivity towards cancer cells compared to non-cancer ARPE-19 cells, with a selectivity index >1. Mechanistic studies showed a clear correlation between IC 50 values and induction of cell death by apoptosis. This report presents the first known p -cymene ruthenium quinaldamide complexes stabilised by a hydrogen-bridging atom, which are cytotoxic and show induced cancer cell death by apoptosis.