title: Reactivity of a cytostatic active N,N-donor-containing dinuclear Pt(II) complex with biological relevant nucleophiles.
abstract: A dinuclear platinum(II) complex that was recently investigated in our group was tested for its cytostatic activity and found to be active against HeLa S3 cells. The complex consists of a bidentate N,N-donor chelating ligand system in which the two platinum centers are connected by an aliphatic chain of 10 methylene groups. The complex [Pt(2)(N(1),N(10)-bis(2-pyridylmethyl)-1,10-decanediamine)(OH(2))(4)](4+) (10NNpy) is of further special interest, since only little is known about the substitution behavior of such dinuclear platinum complexes that contain a bidentate coordination sphere. The complex was investigated using different biologically relevant nucleophiles, such as thiourea (tu), L-methionine (L-Met), glutathione (GSH), and guanine-5'-monophosphate (5'-GMP), at two different pH values (2 and 7.4). The substitution of coordinated water by these nucleophiles was studied under pseudo-first-order conditions as a function of nucleophile concentration, temperature, and pressure, using stopped-flow techniques and UV-vis spectroscopy. The reactivity of 10NNpy with the selected nucleophiles was found to be tu ≫ 5'-GMP > L-Met > GSH at pH 2 and GSH > tu > L-Met at pH 7.4. The results for the dinuclear 10NNpy complex were compared to those for the corresponding mononuclear reference complex [Pt(aminomethylpyridine)(OH(2))(2)](2+), Pt(amp), studied before in our group, by which the effect of the addition of an aliphatic chain, an increase in the overall charge, and a shift in the pK(a) values of the coordinated water ligands could be investigated. The reactivity order for Pt(amp) was found to be tu > GSH > L-Met at pH 7.4.
authors.affiliation: Inorganic Chemistry, Department of Chemistry and Pharmacy, University of Erlangen-Nürnberg, Egerlandstr. 1, 91058 Erlangen, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hochreuther
authors.forename: Rudi
authors.initials: R
authors.lastname: van Eldik
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D002614:Chelating Agents / Q000737:chemistry / Q000494:pharmacology; D054697:Cytostatic Agents / Q000737:chemistry* / Q000494:pharmacology*; D005978:Glutathione / Q000737:chemistry; D006157:Guanosine Monophosphate / Q000737:chemistry; D006367:HeLa Cells; D006801:Humans; D008715:Methionine / Q000737:chemistry; D009369:Neoplasms / Q000188:drug therapy; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000494:pharmacology*; D013890:Thiourea / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D002614:Chelating Agents; D054697:Cytostatic Agents; D009944:Organoplatinum Compounds; D006157:Guanosine Monophosphate; D008715:Methionine; D005978:Glutathione; D013890:Thiourea