jz9b02760_si_001.pdf (2.32 MB)
Hypoxia-Selective Dissociation Mechanism of a Nitroimidazole Nucleoside in a DNA Environment
journal contribution
posted on 2019-10-17, 18:03 authored by Antonio Francés-Monerris, Iñaki Tuñón, Antonio MonariPhotodynamic
therapy is a promising approach to treat a variety
of superficial tumors and other diseases. One of its major limitations
arises from its dependence on molecular oxygen, which decreases the
efficiency of the therapy in hypoxia conditions commonly developed
by solid tumors. The present contribution reveals the molecular mechanism
of a modified thymine bearing a nitroimidazole substituent, a photosensitizer
able to produce highly harmful interstrand cross-links in the DNA
double strand after irradiation selectively in absence of oxygen.
The mechanism is resolved at a fully atomistic and electronic level
relying on quantum mechanics (CASPT2, coupled-cluster, DFT, and TD-DFT
methods), classical molecular dynamics, and advanced biased QM/MM
simulations, revealing an energy penalty of ∼8 kcal/mol for
the anionic nitromidazole release. Our findings indicate that the
global interstrand cross-link production is driven by a combination
of multiple factors, namely, the reverse energy penalty, the diffusion
of the nitroimidazole anion, and the further reactivity of the formed
thymine radical. On the basis of these results, we also suggest some
possible strategies to improve the efficiency of interstrand cross-link
production.