title: The impact of different chelating leaving groups on the substitution kinetics of mononuclear Pt(II)(1,2-trans-R,R-diaminocyclohexane)(X-Y) complexes.
abstract: A set of three oxaliplatin derivatives containing 1,2-trans-R,R-diaminocyclohexane (dach) as a spectator ligand and different chelating leaving groups X-Y, viz., [Pt(dach)(O,O-cyclobutane-1,1-dicarboxylate)], or Pt(dach)(CBDCA), [Pt(dach)(N,O-glycine)]+, or Pt(dach)(gly), and [Pt(dach)(N,S-methionine)]+, or Pt(dach)(L-Met), where L-Met is L-methionine, were synthesized and the crystal structure of Pt(dach)(gly) was determined by X-ray diffraction. The effect of the leaving group on the reactivity of the resulting Pt(II) complexes was studied for the nucleophiles thiourea, glutathione (GSH) and L-Met under pseudo-first-order conditions as a function of nucleophile concentration and temperature, using UV-vis spectrophotometric techniques. 1H NMR spectroscopy was used to follow the substitution of the leaving group by guanosine 5'-monophosphate (5'-GMP2-) under second-order conditions. The rate constants indicate for all reactions a direct substitution of the X-Y chelate by the selected nucleophiles, thereby showing that the nature of the chelate, viz., O-O (CBDCA2-), N-O (glycine) or S-N (L-Met), respectively, plays an important role in the kinetic and mechanistic behavior of the Pt(II) complex. The k1 values for the reaction with thiourea, L-Met, GSH and 5'-GMP2- were found to be as follows (10(3) k1, 37.5 degrees C, M(-1) s(-1)): Pt(dach)(CBDCA) 61 +/- 2, 21.6 +/- 0.1, 23 +/- 1, 0.352 +/- 0.002; Pt(dach)(gly) 82 +/- 3, 6.2 +/- 0.2, 37 +/- 1, 1.77 +/- 0.01; Pt(dach)(L-Met) (thiourea, GSH) 62 +/- 2, 24 +/- 1. The activation parameters for all reactions studied suggest an associative substitution mechanism.
authors.affiliation: Institute for Inorganic Chemistry, University of Erlangen-Nürnberg, Egerlandstrasse 1, 91058, Erlangen, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Summa
authors.forename: Tanja
authors.initials: T
authors.lastname: Soldatović
authors.forename: Lutz
authors.initials: L
authors.lastname: Dahlenburg
authors.forename: Zivadin D
authors.initials: ZD
authors.lastname: Bugarcić
authors.forename: Rudi
authors.initials: R
authors.lastname: van Eldik
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D002614:Chelating Agents / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D003514:Cyclohexylamines / Q000737:chemistry*; D005978:Glutathione / Q000037:antagonists & inhibitors / Q000378:metabolism; D006157:Guanosine Monophosphate / Q000737:chemistry; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D015394:Molecular Structure; D017671:Platinum Compounds / Q000737:chemistry* / Q000494:pharmacology; D013890:Thiourea / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000596:Amino Acids; D002614:Chelating Agents; D003514:Cyclohexylamines; D017671:Platinum Compounds; D006157:Guanosine Monophosphate; C030435:1,2-cyclohexanediamine; D005978:Glutathione; D013890:Thiourea