Reaction of Polynuclear Platinum Antitumor Compounds with Reduced Glutathione Studied by Multinuclear (1H, 1H−15N Gradient Heteronuclear Single-Quantum Coherence, and 195Pt) NMR Spectroscopy

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Abstract
A possible explanation for the low bioavailability of platinum antitumor compounds is their high reactivity with the sulfur-containing tripeptide glutathione (GSH; deprotonated GSH = SG). GSH is located in the intracellular matrix of the cell with a normal concentration of 5−10 mM. In vivo, only a small fraction of the administered drug will migrate into the cell, resulting in relatively high concentrations of GSH compared to that of the drug. The products of the reactions of [{trans-PtCl(NH3)2}2-μ-{trans-Pt(NH3)2(NH2(CH2)6NH2)2}](NO3)4 (BBR3464; 1,0,1/t,t,t, n = 6), [{trans-PtCl(NH3)2}2-μ-(H2N(CH2)6NH2)](NO3)2 (BBR3005; 1,1/t,t, n = 6), [{trans-PtCl(NH3)2}2-μ-(H2N(CH2)3NH2(CH2)4NH2)]Cl3 (BBR3571; 1,1/t,t-spermidine, n = 3, 4), and trans-[PtCl2(NH3)2] (t-DDP) with reduced GSH in phosphate-buffered saline (pH 7.35) have been characterized by 1H, 195Pt, and 1H-15N gradient heteronuclear single-quantum coherence NMR spectroscopy and high-performance liquid chromatography (HPLC) coupled with electrospray ionization time-of-flight mass spectrometry to determine likely metabolites of the complexes with GSH. Chemical shifts (NMR) and retention times (HPLC) established via analysis of the t-DDP profile served as a fingerprint to compare results obtained for the products afforded by the degradation of the polynuclear compounds by GSH. Identical kinetic profiles and chemical shifts between the metabolites and the t-DDP/GSH products allowed identification of the final product for the 1:2 Pt:GSH reaction as a dinuclear species [{trans-Pt(SG)(NH3)2}2-μ-SG], in which glutathione bridges the two platinum centers via only the sulfur atom.