Influence of dT 20 and [d(AT) 10 ] 2 on Cisplatin Hydrolysis Studied by Two‐Dimensional [ 1 H, 15 N] HMQC NMR Spectroscopy

The influence of the presence of DNA on the kinetics of cisplatin ( cis ‐[PtCl 2 (NH 3 ) 2 ]) aquation (replacement of Cl − by H 2 O) and anation (replacement of H 2 O by Cl − ) involved in the hydrolysis of cisplatin have been determined by two‐dimensional [ 1 H, 15 N] HMQC NMR spectroscopy. Single‐stranded dT 20 and double‐stranded [d(AT) 10 ] 2 oligonucleotides were used as DNA models, avoiding guanines which are known to react rapidly with aquated cisplatin forms. Reactions starting from cis ‐[PtCl 2 ( 15 NH 3 ) 2 ], or from a stoichiometric mixture of cis ‐[Pt( 15 NH 3 ) 2 (H 2 O) 2 ] 2+ and Cl − (all 0.5 m M Pt II ; in ionic strength, adjusted to 0.095  M or 0.011  M with NaClO 4 , pH between 3.0 and 4.0) were followed in an NMR tube in both the absence and presence of 0.7 m M dT 20 or [d(AT) 10 ] 2 . In the presence of dT 20 , we observed a slight and ionic‐strength‐independent decrease (15–20 %) of the first aquation rate constant, and a more significant decrease of the second anation rate constant. The latter was more important at low ionic strength, and can be explained by efficient condensation of cis ‐[Pt( 15 NH 3 ) 2 (H 2 O) 2 ] 2+ on the surface of single‐stranded DNA, in a region depleted of chloride anions. At low ionic strength, we observed an additional set of [ 1 H, 15 N] HMQC spectral signals indicative of an asymmetric species of PtN 2 O 2 coordination, and we assigned them to phosphate‐bound monoadducts of cis ‐[Pt( 15 NH 3 ) 2 (H 2 O) 2 ] 2+ . Double‐stranded [d(AT) 10 ] 2 slowed down the first aquation step also by approximately 15 %; however, we could not determine the influence on the second hydrolysis step because of a significant background reaction with cis ‐[Pt(NH 3 ) 2 (H 2 O) 2 ] 2+ .