title: Cytotoxic gold(I) N-heterocyclic carbene complexes with phosphane ligands as potent enzyme inhibitors.
abstract: Organometallic gold complexes with N-heterocyclic carbene (NHC) ligands have been demonstrating promising properties as novel anticancer agents. Gold(I) NHC complexes containing different phosphanes as secondary ligands were shown to trigger strong cytotoxic effects in cancer cells, and their effective uptake into the cells was quantified by atomic absorption spectroscopy. Moreover, the new compounds strongly inhibited the activity of the seleno-enzyme thioredoxin reductase (TrxR) and of the zinc-finger enzyme poly(ADP-ribose) polymerase 1 (PARP-1). In the case of TrxR inhibition, their activity depended clearly on the size of the alkyl/aryl residues of phosphorus atoms. Density functional theory (DFT) calculations showed that the Au-P bond of the triphenylphosphane complex [Au(I) (NHC)(PPh3 )]I had a lower bond dissociation energy compared to trialkylphosphane complexes [Au(I) (NHC)(PR3 )]I, indicating a higher kinetic reactivity of this particular compound. In fact, [Au(I) (NHC)(PPh3 )]I triggered an enhanced inhibitory activity against PARP-1.
authors.affiliation: Institute of Medicinal and Pharmaceutical Chemistry, Technische Universität Braunschweig, Beethovenstrasse 55, 38106 Braunschweig (Germany).
authors.forename: Riccardo
authors.initials: R
authors.lastname: Rubbiani
authors.forename: Luca
authors.initials: L
authors.lastname: Salassa
authors.forename: Andreia
authors.initials: A
authors.lastname: de Almeida
authors.forename: Angela
authors.initials: A
authors.lastname: Casini
authors.forename: Ingo
authors.initials: I
authors.lastname: Ott
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D056831:Coordination Complexes / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000633:toxicity; D006046:Gold / Q000737:chemistry*; D019073:HT29 Cells; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D061986:MCF-7 Cells; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry; D010720:Phosphines / Q000737:chemistry*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D011789:Quantum Theory
chemical_list: D056831:Coordination Complexes; D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D008024:Ligands; D010720:Phosphines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C030011:carbene; D006046:Gold; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases; C044646:phosphine; D008697:Methane
keywords: N-heterocyclic carbene complexes; anticancer compounds; bioorganometallics; gold complexes; poly(ADP-ribose) polymerase 1; thioredoxin reductase