Mechanism of the Oxaliplatin Binding to the Double-Stranded 1,2-ds(pGpG) Dinucleotide in Aqueous Solution
Zdeněk Chval,a Martin Kabeláč,b,c and Jaroslav V. Burdad
a Department of Laboratory Methods and Medical Technology, Faculty of Health and Social Studies, University of South Bohemia, J. Boreckého 27, 370 11 České Budějovice, Czech Republic
b Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Prague 6, Czech Republic
c Department of Chemistry, Faculty of Natural Sciences, University of South Bohemia, Branišovská 31, 37005 České Budějovice, Czech Republic
d Department of Chemical Physics and Optics, Faculty of Mathematics and Physics, Charles University, Ke Karlovu 3, 121 16 Prague 2, Czech Republic.
A mechanism of the formation of the intrastrand 1,2-crosslink between ds(pGpG) dinucleotide and hydrolyzed oxaliplatin is studied using theoretical RI-DFT-D and ONIOM/MP2/B3LYP methods. It is a two-step reaction in which the monoadduct formation is the rate-determining step with activation free energy of ~ 20 kcal/mol followed by the diadduct formation step with activation free energy of ~ 15 kcal/mol. The binding in the 5’-G → 3’-G direction is kinetically preferred over the 3’-G → 5’-G direction. Non-bonded interactions and steric effects influence considerably the structure of transition states affecting energetics of the reaction. The overall reaction is exergonic by more than 20 kcal/mol. The changes of the ds(pGpG) structure and charge transfer effects upon the oxaliplatin binding will be discussed.
We gratefully acknowledge support