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Hypoxia-Selective Dissociation Mechanism of a Nitroimidazole Nucleoside in a DNA Environment

Authors :
Antonio Francés-Monerris
Iñaki Tuñón
Antonio Monari
Laboratoire de Physique et Chimie Théoriques (LPCT)
Institut de Chimie du CNRS (INC)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS)
Departament de QuÍmica Física
Universitat de València (UV)
Source :
Journal of Physical Chemistry Letters, Journal of Physical Chemistry Letters, American Chemical Society, 2019, ⟨10.1021/acs.jpclett.9b02760⟩
Publication Year :
2019
Publisher :
American Chemical Society (ACS), 2019.

Abstract

Photodynamic 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.

Details

ISSN :
19487185
Volume :
10
Database :
OpenAIRE
Journal :
The Journal of Physical Chemistry Letters
Accession number :
edsair.doi.dedup.....52a3c300e1bc6396ee4f78d21eb7c234