The change in the electronic character upon cisplatin binding to guanine nucleotide is transmitted to drive the conformation of the local sugar-phosphate backbone—a quantitative study (original) (raw)
1999, Journal of the Chemical Society, Perkin Transactions 1
The microstructure alteration as a result of cisplatin binding to N7 of guanines in DNA has been herein assessed through the multinuclear temperature-, pH*-and concentration-dependent NMR study of the effect of Pt 2ϩ complexation to 2Ј-deoxyguanosine 3Ј,5Ј-bis(ethyl hydrogen phosphate) 1 and its ribo analogue 3 which mimic the central nucleotide moiety in a trinucleoside diphosphate in the complete absence of intramolecular base-base stacking interactions. The N S pseudorotational equilibrium shifts towards N-type conformers by 17 and 21 percentage points at 298 K, respectively, thereby showing that free energy of platination is transmitted to drive the sugar conformation. The increase in the population of N-type conformers was rationalized with the strengthening of the anomeric effect in both 2Ј-deoxy and ribo nucleotides upon the formation of the Pt-N7 bond which promotes n O4Ј → σ* C1Ј-N9 orbital interactions due to the reduction of π-electron density in the imidazole part of guanine. The additional stabilization of N-type conformers in Pt 2ϩ complexes of ribonucleotides is due to the tuning of the gauche effect of the [N9-C1Ј-C2Ј-O2Ј] fragment, which is absent in 2Ј-deoxy-ribo counterparts. The platination of N7 favours N1 deprotonation in 2 and 4 by ∆pK a of 0.7 and 0.9 units in comparison with parent nucleotides 1 and 3, respectively. The N S pseudorotational equilibrium in 1-4 showed classical sigmoidal dependence as a function of pH with pK a -values at the inflection points. The population of S-type conformers has increased upon N1 deprotonation in 1-4 because the anomeric effect weakened due to the increased π-electron density in the imidazole part of the guanine moiety. The formation of the Pt-N7 bond in bifunctional complexes 2 and 4 simultaneously causes a shift of the syn anti equilibrium towards anti by 43 and 63 percentage points, and the increase in the population of ε t,N conformers by 20 and 32 percentage points at 278 K, respectively. Only a minor conformational redistribution along β, γ, β ϩ1 and ε Ϫ1 torsion angles has been observed, which suggests their weak conformational cooperativity with the N S pseudorotational equilibrium as a result of platination to guanine. In comparison with nucleotide phosphodiesters, apurinic 3Ј,5Ј-bis(ethyl hydrogen phosphate) sugars 5 and 6 showed no interaction with Pt 2ϩ and therefore no conformational changes.
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