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Influence of dT 20 and [d(AT) 10 ] 2 on Cisplatin Hydrolysis Studied by Two‐Dimensional [ 1 H, 15 N] HMQC NMR Spectroscopy
Author(s) -
Vinje Jo,
Sletten Einar,
Kozelka Jiří
Publication year - 2005
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200500002
Subject(s) - aquation , chemistry , ionic strength , reaction rate constant , stoichiometry , hydrolysis , crystallography , chloride , ionic bonding , kinetics , nuclear magnetic resonance spectroscopy , stereochemistry , inorganic chemistry , medicinal chemistry , ion , aqueous solution , organic chemistry , physics , quantum mechanics
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+ .