Conformational studies and electronic structures of tamoxifen and toremifene and their allylic carbocations proposed as reactive intermediates leading to DNA adduct formation.

Toremifene, a compound which differs from tamoxifen by the substitution of a chlorine atom for a hydrogen atom in the ethyl group, is significantly less potent than tamoxifen in causing DNA adduct formation in rats. To examine the relationship of the DNA adduct-forming ability of these compounds with their physicochemical properties such as stable conformation and chemical reactivity, we carried out molecular mechanics, molecular dynamics, and quantum mechanics calculations for the two compounds. For tamoxifen, six stable conformers were identified by conformational search with CFF91 force field. Molecular dynamics simulations showed that these were often interconverted within 1.0 ns. On the other hand, although the conformation of stable conformers and dynamical behavior of toremifene were almost the same as those of tamoxifen, a few conformations were slightly different from those of tamoxifen owing to the effect of the chlorine atom at chloroethyl group. In addition, the stability of the allylic carbocation, which had been proposed as the reactive intermediate leading to DNA adduct formation, was calculated with both semiempirical and density functional methods. Results showed that the carbocation intermediate of toremifene was less stable than that of tamoxifen by 4-5 kcal/mol, suggesting that toremifene was less frequently activated to the intermediate than tamoxifen. Furthermore, the carbocation intermediates of two other tamoxifen derivatives, 4-iodotamoxifen and droxifene, which show no DNA adduct-forming ability, were also less stable compared with that of tamoxifen. These calculated results suggest a close relation between the stability of the proposed carbocation intermediate and DNA adduct-forming ability.