Equilibrium and kinetic studies of the aquation of the dinuclear platinum complex [{trans-PtCl(NH3)(2)}(2)(mu-NH2(CH2)(6)NH2)](2+): pK(a) determinations of aqua ligands via [H-1,N-15] NMR spectroscopy

By the use of [H-1,N-15] heteronuclear single quantum coherence (HSQC) 2D N MR spectroscopy and electrochemical methods we have determined the hydrolys is profile of the bifunctional dinuclear platinum complex [{trans-PtCl-((NH 3)-N-15)(2)}(2)(mu-(NH2)-N-15(CH2)(6)(NH2)-N-15)](2+) (1,1/t,t (n = 6), N-1 5-1), the prototype of a novel class of potential antitumor complexes. Repo rted are estimates for the rate and equilibrium constants for the first and second aquation steps, together with the acid dissociation constant (pK(a1 ) approximate to pK(a2) approximate to pK(a3)). The equilibrium constants d etermined by NMR at 25 and 37 degrees C (I = 0.1 M) were similar, pK(1) app roximate to pK(2) = 3.9 +/- 0.2, and from a chloride release experiment at 37 degrees C the values were found to be pK(1) = 4.11 +/- 0.05 and pK(2) = 4.2 +/- 0.5. The forward and reverse rate constants for aquation determined from this chloride release experiment were k(1) = (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 k(1) = (7.9 +/- 0.2) x 10(-5) s (-1), k(-1) = 1.18 +/- 0.06 M-1 s(-1), k(2) = (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 th e equilibrium of all these species favors the chloro form. A pK(a) value of 5.62 was determined for the diaquated species [{trans-Pt((NH3)-N-15)(2)-(H 2O)}(2)(mu-(NH2)-N-15(CH2)(6)(NH2)-N-15)](4+) (3) using [H-1,N-15] HSQC NMR spectroscopy. The speciation profile of 1 and its hydrolysis products unde r physiological conditions is explored.