532935-73-2Relevant academic research and scientific papers
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
Snygg, Ase Sykfont,Brindell, Malgorzata,Stochel, Grazyna,Elmroth, Sofi K. C.
, p. 1221 - 1227 (2005)
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 occuring 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 platinum(IV) drug, cis-[PtCl(NH 3)(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(T8GT 8): 103 × Kobs/s-1 = 6.5 ± 0.1 (Na+), 1.8 ± 0.1 (Mg2+), 1.0 ± 0.1 (Mn2+) at pH 4.2 and 25°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+] ≥ 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. The Royal Society of Chemistry 2005.
pKa values of aqua ligands of platinum(II) anticancer complexes: [1H, 15N] and 195Pt NMR studies of cis- and trans-[PtCl2 (NH3)(cyclohexylamine)]
Barton, Sarah J.,Barnham, Kevin J.,Habtemariam, Abraha,Sue, Rodney E.,Sadler, Peter J.
, p. 8 - 13 (2008/10/08)
Syntheses and NMR studies are reported of two 15N-labelled Pt(II) complexes of anticancer interest: cis-[PtCl2(15NH3)(c-C6H 1115NH2)], a metabolite of the orally-active Pt(IV) complex cis,trans,cis-[PtCl2(acetate)2(c-C6H 11NH2)(NH3)], and trans-[PtCl2(15NH3)(c-C6H 1115NH2)], a reduction product of the active Pt(IV) complex trans,trans,trans-[PtCl2(OH)2(c-C6H 11NH2)]. For cis-[PtCl2(15NH3)(c-C6H 1115NH2)], hydrolysis was faster for the chloride ligand trans to cyclohexylamine, and the pKa values determined by [1H, 15N] NMR spectroscopy for the two cis monoaqua isomers were the same (6.73). The trans monoaqua complex was a stronger acid with pKa of 5.4 (determined by 195Pt NMR). For the cis diaqua complex, pKa values of 5.68 and 7.68 were determined.
