Influence of dT₂₀ and [d(AT)₁₀]₂ on Cisplatin Hydrolysis Studied by Two‐Dimensional [¹H,¹⁵N] HMQC NMR Spectroscopy

Abstract

The influence of the presence of DNA on the kinetics of cisplatin (cis-[PtCl2(NH3)2]) aquation (replacement of Cl- by H2O) and anation (replacement of H2O by Cl-) involved in the hydrolysis of cisplatin have been determined by two-dimensional [1H,15N] HMQC NMR spectroscopy. Single-stranded dT20 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-[PtCl2(15NH3)2], or from a stoichiometric mixture of cis-[Pt(15NH3)2(H2O)2]2+ and Cl- (all 0.5 mM Pt(II); in ionic strength, adjusted to 0.095 M or 0.011 M with NaClO4, pH between 3.0 and 4.0) were followed in an NMR tube in both the absence and presence of 0.7 mM dT20 or [d(AT)10]2. In the presence of dT20, 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(15NH3)2(H2O)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 [1H,15N] HMQC spectral signals indicative of an asymmetric species of PtN2O2 coordination, and we assigned them to phosphate-bound monoadducts of cis-[Pt(15NH3)2(H2O)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(NH3)2(H2O)2]2+.

Theoretical study on aquation reaction of cis-platin complex: RISM–SCF–SEDD, a hybrid approach of accurate quantum chemical method and statistical mechanics

“…In fact, NMR study reported that a large fraction of the complexes exists as the chloroaqua form [Pt(NH 3 ) 2 Cl(H 2 O)] + (1). 4,5 Inelastic neutron scattering spectra were reported very recently. 6 It is of great interest how these compounds are hydrated, namely, what is the role of solvent water molecule in the process.…”

Dispersion‐Driven Hydrogen Bonding: Predicted Hydrogen Bond between Water and Platinum(II) Identified by Neutron Diffraction

“…In this context, it is interesting to recall the puzzling finding by Martin [19] that the aquation rates for mixed chlorido-ammine-aqua complexes of Pt II are not appreciably dependent on the complex charge. For instance, the first and second aquation rate constants for the antitumor drug cis-[PtCl 2 (NH 3 ) 2 ] (cisplatin) are nearly identical [20,21] even though the positive charge of the chlorido-aqua complex (formed after the first aquation) would be expected to strongly impede the departure of the second chlorido ligand. Although the substitution mechanism is associative, the scissile Pt À Cl bond is considerably elongated in the transition state.…”

Rare Tautomers of 1‐Methyluracil and 1‐Methylthymine: Tuning Relative Stabilities through Coordination to PtII Complexes

“…Nevertheless, there can be no doubt that cisplatin is capable of binding to N3 of T or U, both in the free state and when present in DNA (or RNA). [33] It does so in moderately alkaline medium at, neutral pH and, surprisingly, even at a pH as low as 3. 5-4 [33b, 34] despite a relatively high pK a of 9-10 for N(3)H!…”

“…Nevertheless, there can be no doubt that cisplatin is capable of binding to N3 of T or U, both in the free state and when present in DNA (or RNA). [33] It does so in moderately alkaline medium at, neutral pH and, surprisingly, even at a pH as low as 3.5-4 [33b, 34] despite a relatively high pK a of 9-10 for N(3)H! [35] There are at least two factors facilitating Pt II binding to N3 at pH values well below the pK a of N(3)H (Scheme 7): First, initial Pt II binding to O4 and/or O2 of the canonical tautomer will acidify the proton at N3.…”