Computational Study of the Radical Mediated Mechanism of the Formation of C8, C5, and C4 Guanine:Lysine Adducts in the Presence of the Benzophenone Photosensitizer

The
oxidation of guanine by triplet benzophenone in the presence of lysine
has been shown to produce mono- and dilysine-substituted spiroiminodihydantion
products, 8-Lys-Sp and 5,8-diLys-Sp. The potential energy surfaces
for C8, C5, and C4 nucleophilic addition have been mapped out using
the B3LYP/aug-cc-pVTZ//B3LYP/6-31+G­(d,p) level of density functional
theory with the SMD solvation model and employing methylamine as a
model for the side chain of lysine. Enthalpies, barrier heights, pKa’s, and reduction potentials were calculated
for intermediates to find the lowest energy paths. For neutral methylamine
plus guanine radical and neutral methylamine radical plus guanine,
the barrier for addition at C8 is ca. 10 kcal/mol lower than that
for addition at C5 and C4. The barriers for water addition at C8,
C5, and C4 of guanine radical are 13–20 kcal/mol higher than
that for methylamine addition at C8. Further oxidation and loss of
a proton leads to 8-methylaminoguanine, the methylamino analogue of
8-oxo-7,8-dihydroguanine (8-oxoG). The barrier for the addition of
a second methylamine at C5 of 8-methylaminoguanine is 4.5 kcal/mol
lower than that for the corresponding addition of water. Nevertheless,
if the concentration of methylamine (or lysine) is very low, water
addition could be competitive with methylamine addition. This would
lead to comparable fractions of 8-monosubstituted-Sp and 5–8-disubstituted-Sp,
in agreement with the experimental observations.