| Abstract
| - The hydrolysis profile of the bifunctional trinuclear phase II clinical agent [{trans-PtCl(NH3)2}2{μ-trans-Pt(NH3)2(NH2(CH2)6NH2)2}]4+ (BBR3464, 1) has been examined using [1H,15N] heteronuclear single quantum coherence(HSQC) 2D NMR spectroscopy. Reported are estimates of the rate and equilibrium constants for the first andsecond aquation steps, together with the acid dissociation constant (pKa1 ≈ pKa2 ≈ pKa3). The equilibrium constantsfor the aquation determined by NMR at 298 and 310 K (I = 0.1 M, pH 5.3) are similar, pK1 = pK2 = 3.35 ± 0.04and 3.42 ± 0.04, respectively. At lower ionic strength (I = 0.015 M, pH 5.3) the values at 288, 293, and 298 K arepK1 = pK2 = 3.63 ± 0.05. This indicates that the equilibrium is not strongly ionic strength or temperature dependent.The aquation and anation rate constants for the two-step aquation model at 298 K in 0.1 M NaClO4 (pH 5.3) arek1 = (7.1 ± 0.2) × 10-5 s-1, k-1 = 0.158 ± 0.013 M-1 s-1, k2 = (7.1 ± 1.5) × 10-5 s-1, and k-2 = 0.16 ± 0.05M-1 s-1. The rate constants in both directions increase 2-fold with an increase in temperature of 5 K, and rateconstants increase with a decrease in solution ionic strength. A pKa value of 5.62 ± 0.04 was determined for thediaqua species [{trans-Pt(NH3)2(OH2)}2{μ-trans-Pt(NH3)2(NH2(CH2)6−NH2)2}]6+ (3). The speciation profile of 1 underphysiological conditions is explored and suggests that the dichloro form predominates. The aquation of 1 in 15 mMphosphate was also examined. No slowing of the initial aquation was observed, but reversible reaction betweenaquated species and phosphate does occur.
- The rate and equilibrium constants for the aquation of [{trans-PtCl(NH3)2}2{μ-trans-Pt(NH3)2(NH2(CH2)6NH2)2}]4+ (BBR3464, 1,0,1/t,t,t) and the pKa values of the aquated analogue are reported. The aquation in 15 mM phosphate buffer (pH 5.3) is described.
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