title: Cytotoxic hydrogen bridged ruthenium quinaldamide complexes showing induced cancer cell death by apoptosis.
abstract: 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)}][PF6] (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 NH4PF6, and under aerobic conditions the equilibrium of NH4PF6 ⇔ NH3 + HPF6 enables incorporation of HPF6 and the stabilisation of two monomeric ruthenium complexes by a bridging H(+), which are counter-balanced by a PF6 counterion. X-ray crystallographic analysis is presented for six new structures with OO 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 IC50 values and induction of cell death by apoptosis.
authors.affiliation: School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK. p.c.mcgowan@leeds.ac.uk.
authors.forename: Rianne M
authors.initials: RM
authors.lastname: Lord
authors.affiliation: Department of Pharmacy, School of Applied Sciences, University of Huddersfield, Huddersfield, HD1 3DH, UK.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Allison
authors.affiliation: School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK. p.c.mcgowan@leeds.ac.uk.
authors.forename: Karen
authors.initials: K
authors.lastname: Rafferty
authors.affiliation: School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK. p.c.mcgowan@leeds.ac.uk.
authors.forename: Laura
authors.initials: L
authors.lastname: Ghandhi
authors.affiliation: School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK. p.c.mcgowan@leeds.ac.uk.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Pask
authors.affiliation: School of Chemistry, University of Leeds, Woodhouse Lane, Leeds, LS2 9JT, UK. p.c.mcgowan@leeds.ac.uk.
authors.forename: Patrick C
authors.initials: PC
authors.lastname: McGowan
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D056831:Coordination Complexes / Q000737:chemistry / Q000494:pharmacology*; D000081007:Cymenes; D006801:Humans; D006859:Hydrogen / Q000737:chemistry; D039821:Monoterpenes / Q000737:chemistry / Q000494:pharmacology*; D012428:Ruthenium / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D056831:Coordination Complexes; D000081007:Cymenes; D039821:Monoterpenes; C007210:4-cymene; D012428:Ruthenium; D006859:Hydrogen