Reactions of Pd(dien)Cl+ with thione-containing nucleosides, nucleotides and oligonucleotides: increase of both enthalpy and entropy of activation in the DNA-environment

Ericson, Anders; Iljina, Yelena; McCary, Jason L.; Coleman, Robert S.; Elmroth, Sofi K. C.

doi:10.1016/s0020-1693(99)00257-1

Cited by 9 publications

(7 citation statements)

References 51 publications

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“…As expected for these good nucleophiles, the second-order rate constants for adduct formation are significantly larger compared with those found for adduct formation with N 7 in purines [29,30], while exhibiting a reactivity only slightly above that of phosphorothioates (see Table 1). Of the two thiones studied here, s6 IMP displays the higher reactivity, in agreement with previous kinetics studies for interaction with Pd(II) [47] and Au(III) [48] centres. The higher reactivity of s6 IMP might partly be explained by the more favourable conditions that can be expected for the initial electrostatic interaction of the positively charged platinum complex with the negative potential around the reactive sulfur atom.…”

Section: Monomerssupporting

confidence: 91%

Kinetics and mechanism for platination of thione-containing nucleotides and oligonucleotides: evaluation of the salt dependence

Kjellström

Elmroth

2003

J Biol Inorg Chem

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Reactions of cis-[PtCl(NH(3))(CyNH(2))(OH(2))](+) (Cy=cyclohexyl) with thione-containing single-stranded oligonucleotides d(T(8)XT(8)) and d(XT(16)) (X=(s6)I or (s4)U) and the mononucleotides 4-thiouridine ((s4)UMP) and 6-mercaptoinosine ((s6)IMP) have been studied in aqueous solution at pH 4.1. The reaction kinetics was followed using HPLC methodology as a function of ionic strength in the interval 5.0 mM

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Section: Monomerssupporting

confidence: 91%

Kinetics and mechanism for platination of thione-containing nucleotides and oligonucleotides: evaluation of the salt dependence

Kjellström

Elmroth

2003

J Biol Inorg Chem

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“…[22][23][24][25][26][27][28][29][30][31][32] Systematic studies of interactions between positively charged metal complexes of Pt(II), Pd(II), and Au(III) and target sites incorporated into short poly-d(T) oligomers have revealed a DNA-promoted effect in reactivity range spanning 6 orders of magnitude, when compared with reference reactions of monomers such as d(Tp(S)T), d(GpG), d( s4 U), and d( s6 I). 24,25,[28][29][30]33 Further, the dependence of the observed rate constants on the concentration of neutral salts in the reaction medium, which has been observed for some of these systems, fits qualitatively well with a reaction mechanism in which electrostatic preaccumulation of the cationic reactants on the oligomer takes place prior to the rate-determining formation of the adduct. 25,28 However, a detailed mechanistic interpretation of the salt dependence is hampered by a lack of more precise knowledge concerning the extent and dynamics of associated cations around the used oligonucleotide fragments.…”

Section: Introductionsupporting

confidence: 73%

“…For example, the apparent rate for thermal electron transfer and substitution reactions 20-30 of freely diffusing cationic metal complexes with various reactants has been found to increase in a polymeric DNA environment. For the latter type of reactions, the composition of the reaction medium and the detailed DNA environment have been shown to have a large influence on the observed rate constants. − Systematic studies of interactions between positively charged metal complexes of Pt(II), Pd(II), and Au(III) and target sites incorporated into short poly-d(T) oligomers have revealed a DNA-promoted effect in reactivity range spanning 6 orders of magnitude, when compared with reference reactions of monomers such as d(Tp(S)T), d(GpG), d( s4 U), and d( s6 I). ,,− , Further, the dependence of the observed rate constants on the concentration of neutral salts in the reaction medium, which has been observed for some of these systems, fits qualitatively well with a reaction mechanism in which electrostatic preaccumulation of the cationic reactants on the oligomer takes place prior to the rate-determining formation of the adduct. , However, a detailed mechanistic interpretation of the salt dependence is hampered by a lack of more precise knowledge concerning the extent and dynamics of associated cations around the used oligonucleotide fragments …”

Section: Introductionmentioning

confidence: 99%

Medium Effects on Reactivity Profiles for Platination of Phosphorothioate-Containing Oligonucleotides

Kjellström

Elmroth

1999

Inorg. Chem.

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Reactions of cis-[Pt(NH(3))(NH(2)C(6)H(11))Cl(OH(2))](+) with d(Tp(S)T) and d(T(n)()p(S)T(16)(-)(n)()), n = 1, 4, 8, 12, and 15, were investigated by use of HPLC in an aqueous medium with pH 4.1 +/- 0.1 and sodium and magnesium ion concentrations varying between 1.5 mM and 0.50 M. Platination of the oligonucleotide fragments is favored over platination of d(Tp(S)T) in the whole salt concentration interval studied. The maximum rate enhancement after incorporation of the p(S)-site into the polymeric DNA environment is observed for d(T(8)p(S)T(8)), which reacts up to ca. 500 times faster than d(Tp(S)T), after suitable changes of the cation concentrations in the reaction medium. The platination rates of the oligonucleotide fragments d(T(n)()p(S)T(16)(-)(n)()) decrease with increasing salt concentration. For a given phosphorothioate position, the rate also decreases when the cations in the medium are changed from Na(+) or K(+) to Mg(2+), even at constant ionic strength. The reactions with embedded p(S)-sites in d(T(n)()p(S)T(16)(-)(n)()), n = 4, 8, and 12, were found to be kinetically favored over reactions with the 5'- and 3'-end positions. In a reaction medium containing monovalent cations there is a strong preference for platination of d(T(8)p(S)T(8)), whereas d(T(4)p(S)T(12)) and d(T(12)p(S)T(4)) show intermediate reactivity compared with fragments with n = 1 and 15. In contrast, no kinetic discrimination is found between the p(S)-sites in d(T(n)()p(S)T(16)(-)(n)()), n = 4, 8, and 12, in the presence of Mg(2+). The results are interpreted in terms of a general mechanism where preaccumulation of the cationic Pt(II) complex on the oligomers is required for product formation. The kinetics are consistent with a reaction model that includes release of cations from the DNA surface during the adduct formation process.

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“…[26][27][28][29][30][31] Previous studies by us and others indicate that preassociation on the DNA surface is an important reaction step in the reaction mechanism during covalent modification of DNA with cationic metal complexes in a broad reactivity range. [20][21][22][23]40,41 In addition, we have also been able to show how the local positioning of a given interaction site, in a constant sequence context, affects the rate by which adducts are being formed. 25,32 More specifically, the rate of adduct formation was studied as a function of target position within a given size DNA fragment, i.e.…”

Section: Discussionmentioning

confidence: 90%

“…We have previously shown that the formation of coordinate covalent bonds between cationic metal complexes and DNA models are facilitated, whereas reactions involving anionic metal complexes are inhibited. [20][21][22][23] The increased reactivity observed for cations can be explained by introduction of a preassociation step preceding the ratedetermining adduct formation reaction. Our previous studies of DNA model systems have indicated that the extent of preassociation influences the reaction kinetics already in small single-stranded systems.…”

Section: Introductionmentioning

confidence: 99%

A combination of access to preassociation sites and local accumulation tendency in the direct vicinity of G-N7 controls the rate of platination of single-stranded DNA

et al. 2005

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Adduct formation between cationic reagents and targets on DNA are facilitated by the ability of DNA to attract cations to its surface. The electrostatic interactions likely provide the basis for the documented preference exhibited by cisplatin and related compounds for nuclear DNA over other cellular constituents. As an extension of a previous communication, we here present an investigation illustrating how the rate of adduct formation with the naturally occurring base guanine (G-N7) can be modulated by i) bulk solvent conditions, ii) local nature and size of the surrounding DNA and, iii) increasing DNA concentration. A series of single-stranded DNA oligomers of the type d(TnGTm); n= 0, 2, 4, 6, 8, 10, 12, 14, 16 and m= 16 -n or n=m= 4, 6, 8, 12, 16, 24 were allowed to react with the active metabolite of a potential orally active platinumIV drug, cis-[PtCl(NH3))(c-C6H11NH2)(OH2)]+ in the presence of three different bulk cations; Na+, Mg2+, and Mn2+. For all positions along the oligomers, a change from monovalent bulk cations to divalent ones results in a decrease in reactivity, with Mn2+ as the more potent inhibitor as exemplified by the rate constants determined for interaction with d(T8GT8): 10(3) x k obs/s(-1)= 6.5 +/- 0.1 (Na+), 1.8 +/- 0.1 (Mg2+), 1.0 +/- 0.1 (Mn2+) at pH 4.2 and 25 degrees C. Further, the adduct formation rate was found to vary with the exact location of the binding site in the presence of both Na+ and Mg2+, giving rise to reactivity maxima at the middle position. Increasing the size of the DNA-fragments was found to increase the reactivity only up to a total length of ca. 20 bases. The influence from addition of further bases to the reacting DNA was found to be salt dependent. At [Na+]= 0.5 mM a retardation in reactivity was observed whereas [Na+] < or = 4.5 mM give rise to length independent kinetics. Finally, for the first time we have here been able to evaluate the influence from an increasing concentration of non-reactive DNA bases on the adduct formation process. The latter data were successfully fitted to an inhibition model suggesting that non-productive association of the platinum complex with sites distant from G-N7 competes with productive ones in the vicinity of the G-N7 target. Taken together, the kinetics support a reaction mechanism in which access to suitable association sites in the direct vicinity of the target site controls the rate of platination.

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Reactions of Pd(dien)Cl+ with thione-containing nucleosides, nucleotides and oligonucleotides: increase of both enthalpy and entropy of activation in the DNA-environment

Cited by 9 publications

References 51 publications

Kinetics and mechanism for platination of thione-containing nucleotides and oligonucleotides: evaluation of the salt dependence

Kinetics and mechanism for platination of thione-containing nucleotides and oligonucleotides: evaluation of the salt dependence

Medium Effects on Reactivity Profiles for Platination of Phosphorothioate-Containing Oligonucleotides

A combination of access to preassociation sites and local accumulation tendency in the direct vicinity of G-N7 controls the rate of platination of single-stranded DNA

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