Dataset Information

DNA interstrand cross-linking upon irradiation of aryl halide C-nucleotides.

ABSTRACT: ?-Radiolysis kills cells by damaging DNA via radical processes. Many of the radical pathways are O2 dependent, which results in a reduction in the cytotoxicity of ionizing radiation in hypoxic tumor cells. Consequently, there is a need for chemical agents that increase DNA damage by ionizing radiation under O2-deficient conditions. Modified nucleotides that are incorporated in DNA and produce highly reactive ?-radicals are useful as radiosensitizing agents. Aryl halide C-nucleotides (4-6) were incorporated into oligonucleotides by solid-phase synthesis. Duplex DNA containing 4-6 forms interstrand cross-links upon ?-radiolysis under anaerobic conditions or UV irradiation. Deep Vent (exo(-)) DNA polymerase accepted the nucleotide triphosphate of C-nucleotide 6 as a substrate and preferentially incorporated it opposite pyrimidines, but no further extension was detected. Incorporation of 6 in extended products by Deep Vent (exo(-)) during PCR or by Sequenase during copying of single stranded DNA plasmid was undetectable. Aryl halide nucleotide analogues that produce DNA interstrand cross-links under anaerobic conditions upon irradiation are potentially useful as radiosensitizing agents, but further research is needed to identify molecules that are incorporated by DNA polymerases and do not block further polymerization for this approach to be useful in cells.

SUBMITTER: Hou D

PROVIDER: S-EPMC3982193 | biostudies-literature | 2014 Mar

REPOSITORIES: biostudies-literature

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DNA interstrand cross-linking upon irradiation of aryl halide C-nucleotides.

Hou Dianjie D Greenberg Marc M MM

The Journal of organic chemistry 20140224 5

γ-Radiolysis kills cells by damaging DNA via radical processes. Many of the radical pathways are O2 dependent, which results in a reduction in the cytotoxicity of ionizing radiation in hypoxic tumor cells. Consequently, there is a need for chemical agents that increase DNA damage by ionizing radiation under O2-deficient conditions. Modified nucleotides that are incorporated in DNA and produce highly reactive σ-radicals are useful as radiosensitizing agents. Aryl halide C-nucleotides (4-6) were i ...[more]

PMID: 24559326

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Project description:DNA damage is ubiquitous in nature and is at the basis of emergent treatments such as photodynamic therapy, which is based on the activation of highly oxidative reactive oxygen species by photosensitizing O2. However, hypoxia observed in solid tumors imposes the necessity to devise oxygen-independent modes of action able to induce DNA damage under a low oxygen concentration. The complexity of these DNA damage mechanisms in realistic environments grows exponentially when taking into account light absorption and subsequent excited-state population, photochemical and (photo)-redox reactions, the multiple species involved in different electronic states, noncovalent interactions, multiple reaction steps, and the large number of DNA reactive sites. This work tackles all the intricate reactivity of a photosensitizer based on a nitroimidazole derivative reacting toward DNA in solution under UV light exposition. This is performed through a combination of ground- and excited-state quantum chemistry, classical molecular dynamics, and hybrid QM/MM simulations to rationalize in detail the formation of DNA interstrand cross-links (ICLs) exerted by the noncanonical noncovalent photosensitizer. Unprecedented spatial and temporal resolution of these phenomena is achieved, revealing that the ICL is sequence-specific and that the fastest reactions take place at AT, GC, and GT steps involving either the opposite nucleobases or adjacent Watson-Crick base pairs. The N7 and O6 positions of guanine, the N7 and N3 sites of adenine, the N4 position of cytosine, and the O2 atom of thymine are deemed as the most nucleophile sites and are positively identified to participate in the ICL productions. This work provides a multiscale computational protocol to study DNA reactivity with noncovalent photosensitizers, and contributes to the understanding of therapies based on photoinduced DNA damage at molecular and electronic levels. In addition, we believe the depth understanding of these processes should assist the design of new photosensitizers considering their molecular size, electronic properties, and the observed regioselectivity toward nucleic acids.

Dataset Information

DNA interstrand cross-linking upon irradiation of aryl halide C-nucleotides.

Publications

DNA interstrand cross-linking upon irradiation of aryl halide C-nucleotides.

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