Back to Search
Start Over
Hypoxia-Selective Dissociation Mechanism of a Nitroimidazole Nucleoside in a DNA Environment
- 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.
- Subjects :
- Substituent
Molecular Dynamics Simulation
010402 general chemistry
01 natural sciences
chemistry.chemical_compound
Molecular dynamics
[CHIM]Chemical Sciences
General Materials Science
Photosensitizer
A-DNA
Physical and Theoretical Chemistry
ComputingMilieux_MISCELLANEOUS
Photosensitizing Agents
Nitroimidazole
010405 organic chemistry
Hydrogen bond
Hydrogen Bonding
DNA
0104 chemical sciences
Thymine
chemistry
Nitroimidazoles
Biophysics
Nucleic Acid Conformation
Quantum Theory
Subjects
Details
- ISSN :
- 19487185
- Volume :
- 10
- Database :
- OpenAIRE
- Journal :
- The Journal of Physical Chemistry Letters
- Accession number :
- edsair.doi.dedup.....52a3c300e1bc6396ee4f78d21eb7c234