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

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, coupledcluster, 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.

Photoinduced DNA Lesions in Dormant Bacteria: The Peculiar Route Leading to Spore Photoproducts Characterized by Multiscale Molecular Dynamics**

“…Gas‐phase calculations were performed with the Gaussian 09 software, [62] whereas QM/MM simulations were performed with the Amber 16 program [63] interfaced with the ORCA 4.0 code [64–66] . The PMF corresponding to the free energy profiles of the hydrogen transfers were computed through umbrella sampling techniques following a protocol used in previous studies [67, 68] . The QM partition was composed of the two reactive nucleobases described by DFT, making use of the ω B97‐XD functional [69] and the 6‐31G basis set, given the very good accuracy provided by this level of theory (see the Supporting Information), together with a computational cost that was coherent with an extended sampling of the reaction space.…”

Optical properties of photodynamic therapy drugs in different environments: the paradigmatic case of temoporfin

“…28 Hence, the exploitation of different photochemical pathways, such as photodissociation, have been proposed under the general name of light-assisted chemotherapy (LAC). [29][30][31][32] The displacement of the absorption spectrum towards the red is also pursued via different chemical strategies, including the use of organometallic complexes, 33,34 or enlarging the conjugation pattern of the sensitizers. 35 More recently, the exploitation of non-linear optics, two-photon absorption (TPA) [36][37][38][39] in particular, has been suggested.…”

Optical Properties of Photodynamic Therapy Drugs in Different Environments: The Paradigmatic Case of Temoporfin

“…28 Hence, the exploitation of different photochemical pathways, such as photodissociation, have been proposed under the general name of light-assisted chemotherapy (LAC). [29][30][31][32] The displacement of the absorption spectrum towards the red is also pursued via different chemical strategies, including the use of organometallic complexes, 33,34 or enlarging the conjugation pattern of the sensitizers. 35 More recently, the exploitation of non-linear optics, two-photon absorption (TPA) [36][37][38][39] in particular, has been suggested.…”