title: Equilibrium and kinetic studies of the aquation of the dinuclear platinum complex [[trans-PtCl(NH3)2]2(mu-NH2(CH2)6NH2)]2+: pKa determinations of aqua ligands via [1H,15N] NMR spectroscopy.
abstract: By the use of [1H,15N] heteronuclear single quantum coherence (HSQC) 2D NMR spectroscopy and electrochemical methods we have determined the hydrolysis profile of the bifunctional dinuclear platinum complex [[trans-PtCl(15NH3)2]2(mu-15NH2(CH2)(6)15NH2)]2+ (1,1/t,t (n = 6), 15N-1), the prototype of a novel class of potential antitumor complexes. Reported are estimates for the rate and equilibrium constants for the first and second aquation steps, together with the acid dissociation constant (pKa1 approximately pKa2 approximately pKa3). The equilibrium constants determined by NMR at 25 and 37 degrees C (I = 0.1 M) were similar, pK1 approximately pK2 = 3.9 +/- 0.2, and from a chloride release experiment at 37 degrees C the values were found to be pK1 = 4.11 +/- 0.05 and pK2 = 4.2 +/- 0.5. The forward and reverse rate constants for aquation determined from this chloride release experiment were k1 = (8.5 +/- 0.3) x 10(-5) s-1 and k-1 = 0.91 +/- 0.06 M-1 s-1, where the model assumed that all the liberated chloride came from 1. When the second aquation step was also taken into account, the rate constants were k1 = (7.9 +/- 0.2) x 10(-5) s-1, k-1 = 1.18 +/- 0.06 M-1 s-1, k2 = (10.6 +/- 3.0) x 10(-4) s-1, k-2 = 1.5 +/- 0.6 M-1 s-1. The rate constants compare favorably with other complexes with the [PtCl(am(m)ine)3]+ moiety and indicate that the equilibrium of all these species favors the chloro form. A pKa value of 5.62 was determined for the diaquated species [[trans-Pt(15NH3)2(H2O)]2(mu-15NH2(CH2)(6)15NH2)]4+ (3) using [1H,15N] HSQC NMR spectroscopy. The speciation profile of 1 and its hydrolysis products under physiological conditions is explored.
authors.affiliation: School of Science, Griffith University, Nathan, Brisbane, Queensland 4111, Australia.
authors.forename: M S
authors.initials: MS
authors.lastname: Davies
authors.forename: J W
authors.initials: JW
authors.lastname: Cox
authors.forename: S J
authors.initials: SJ
authors.lastname: Berners-Price
authors.forename: W
authors.initials: W
authors.lastname: Barklage
authors.forename: Y
authors.initials: Y
authors.lastname: Qu
authors.forename: N
authors.initials: N
authors.lastname: Farrell
mesh_terms: D002945:Cisplatin / Q000737:chemistry; D018736:DNA Adducts / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D007553:Isotope Labeling; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D015394:Molecular Structure; D009944:Organoplatinum Compounds / Q000737:chemistry*; D000644:Quaternary Ammonium Compounds / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013997:Time Factors
chemical_list: D018736:DNA Adducts; D009944:Organoplatinum Compounds; D000644:Quaternary Ammonium Compounds; D002945:Cisplatin