title: Adjusting the DNA Interaction and Anticancer Activity of Pt(II) N-Heterocyclic Carbene Complexes by Steric Shielding of the Trans Leaving Group.
abstract: Five platinum(II) complexes bearing a (1,3-dibenzyl)imidazol-2-ylidene ligand but different leaving groups trans to it were examined for cytotoxicity, DNA and cell cycle interference, vascular disrupting properties, and nephrotoxicity. The cytotoxicity of complexes 3a-c increased with the steric shielding of their leaving chloride ligand, and complex 3c, featuring two triphenylphosphanes, was the most efficacious, with submicromolar IC50 concentrations. Complexes 3a-c interacted with DNA in electrophoretic mobility shift and ethidium bromide binding assays. The cationic complex 3c did not bind coordinatively to DNA but led to its aggregation, damage that is not amenable to the usual repair mechanisms. Accordingly, it arrested the cell cycle of melanoma cells in G1 phase, whereas cis-dichlorido[(1,3-dibenzyl)imidazol-2-ylidene](dimethyl sulfoxide) platinum(II) 3a induced G2/M phase arrest. Complex 3c also disrupted the blood vessels in the chorioallantoic membrane of fertilized chicken eggs. Ex vivo studies using precision-cut tissue slices suggested the nephrotoxicities of 3a-c to be clinically manageable.
authors.forename: Julienne K
authors.initials: JK
authors.lastname: Muenzner
authors.forename: Tobias
authors.initials: T
authors.lastname: Rehm
authors.forename: Bernhard
authors.initials: B
authors.lastname: Biersack
authors.affiliation: ‡Department of Pharmacokinetics, Toxicology and Targeting, Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Angela
authors.initials: A
authors.lastname: Casini
authors.affiliation: ‡Department of Pharmacokinetics, Toxicology and Targeting, Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Inge A M
authors.initials: IA
authors.lastname: de Graaf
authors.affiliation: ‡Department of Pharmacokinetics, Toxicology and Targeting, Research Institute of Pharmacy, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
authors.forename: Pawida
authors.initials: P
authors.lastname: Worawutputtapong
authors.forename: Awal
authors.initials: A
authors.lastname: Noor
authors.forename: Rhett
authors.initials: R
authors.lastname: Kempe
authors.affiliation: ∥Institute of Biophysics, Academy of Sciences of the Czech Republic, CZ-61265 Brno, Czech Republic.
authors.forename: Viktor
authors.initials: V
authors.lastname: Brabec
authors.affiliation: ⊥Department of Biophysics, Faculty of Science, Palacky University, 17. listopadu 12, CZ-77146 Olomouc, Czech Republic.
authors.forename: Jana
authors.initials: J
authors.lastname: Kasparkova
authors.forename: Rainer
authors.initials: R
authors.lastname: Schobert
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004247:DNA / Q000187:drug effects*; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry; D017671:Platinum Compounds / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D006571:Heterocyclic Compounds; D017671:Platinum Compounds; C030011:carbene; D004247:DNA; D008697:Methane