Your browser doesn't support javascript.
Hypoxia-Selective Dissociation Mechanism of a Nitroimidazole Nucleoside in a DNA Environment.
J Phys Chem Lett ; 10(21): 6750-6754, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31609626
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.





Texto completo: Disponível Coleções: Bases de dados internacionais Base de dados: MEDLINE Assunto principal: DNA / Nitroimidazóis Idioma: Inglês Revista: J Phys Chem Lett Ano de publicação: 2019 Tipo de documento: Artigo País de afiliação: França