Theoretical Studies On Thermodynamics And Dynamics Of 2, 6-dithiopurine Tautomers

Abstract Purine and its thio derivatives are found in many biological systems and many experiments results show that these thio derivatives can be proposed as a possible chemopreventive agent duo to its ability to react with electrophilic toxic metabolits of anticancer drugs. They are very important from the clinical point of view. But the tautomerism of these activity thio derivatives molecular can exist in biology systems and the different tautomers have variable activity effects. However the relative stabilities and the changes among these tautomers have very important influences on the properties of biology activities molecular. In this work, we have investigated a kind of important biology activities molecule 2,6-dithiopurine and its thermodynamical and dynamical properties, and the main contents are arranged as follows:(1) The structures of thirteen possible 2,6-dithiopurine tautomers have been optimized by density functional theory (DFT) method at B3LYP/6-311G(d,p) level both in the gas and aqueous phases. The Onsager solvation model in the self-consistent reaction field (SCRP) was used in aqueous calculations. The thermodynamic parameters, dipole moments and atomic total charges were obtained at the same level. The calculations show that the dithione-N7H is the most stable tautomer in the gas and aqueous phases. The stabilities of all the tautomers increase in aqueous phases, moreover, the tautomers with large dipole moments are more stable in the aqueous phase. The solvation Gibbs free energies of 2,6-dithiopurine tautomers well correlates with the differences of the dipole moments between the gas and aqueous phases. When the tautomer DTP(1,3,7) reacts with the electrophilic carcinogen BPDE, the atomic S10 of DTP( 1,3,7) prefers to attack the BPDE.(2) The reaction mechanism of thione-thiol tautomerism for 2,6-dithiopurine which resulted from proton transfer was investigated by B3LYP functional with 6-311+G(d,p) basis set. The reaction enthalpies, activation energies, activation free energies and the rate constants of tautomerism were obtained. The results showed that the dithione DTP(1,3,7) is the most stable isomer of all the tautomers in the form of isolated or hydrated isomers. The 6 reaction pathways from dithione to dithiol through intramolecular proton transfer were also found. The activation energy in the main...