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Biomedical subjects

In Seok Hong

Publications and source records attributed to In Seok Hong.

9 recordsLinked to original sources
PubMed2006

Radiosensitization by a modified nucleotide that produces DNA interstrand cross-links under hypoxic conditions.

This paper describes the reactivity of a molecule that combines two desirable chemical processes into one molecule for the first time. Interstrand cross-links (ISCs) are an effective family of lesions produced by cytotoxic agents that target DNA. For instance, ISCs are the source of mitomycin C's cytotoxicity. Radiosensitizing agents are molecules that enhance DNA damage produced by ionizing radiation, especially under O2-deficient conditions. Phenyl selenide 1 is the first example of a modified nucleotide that can be incorporated in DNA by polymerases, which produces ISCs when DNA containing it is exposed to gamma-radiolysis under O2-deficient conditions. These experiments suggest that 1 could be useful as a novel type of radiosensitizing agent.

DNA↗
PubMed2006

Oxygen independent DNA interstrand cross-link formation by a nucleotide radical.

A 5-(2'-Deoxyuridinyl)methyl radical (1) was independently generated from three photochemical precursors and is the first example of a DNA radical that forms interstrand cross-links. Oxygen labeling experiments support generation of 1 by all precursors. Interstrand cross-links are produced upon irradiation of DNA containing any of the precursors. Cross-linking occurs via reaction with the opposing 2'-deoxyadenosine and is independent of O(2). The independence of cross-link formation on O(2) is explained by kinetic analysis, which shows that the radical reacts reversibly with O(2). Examination of the effects of glutathione on cross-link formation under anaerobic conditions suggests that adoption of the syn-conformation by 1 is the rate-limiting step in the process. Interstrand cross-link formation is reversible in the presence of a good nucleophile. The stability of the interstrand cross-link suggests that the isolated molecule is a rearrangement product of that formed in solution. The rearrangement is a consequence of the isolation procedure but also occurs slowly in solution. Oxygen independent cross-link formation may be useful for the purposeful damage of DNA in hypoxic tumor cells, where O(2) is deficient.

Base Sequence↗
PubMed2005

DNA interstrand cross-link formation initiated by reaction between singlet oxygen and a modified nucleotide.

DNA is the target of many anti-cancer therapies. These agents damage the biopolymer by oxidation or by alkylation. Interstrand DNA cross-links are believed to be the source of cytotoxicity of anti-tumor agents, such as mitomycin C, which alkylate the biopolymer. In contrast, deoxyguanosine oxidation is the result of reaction between DNA and singlet oxygen, which is the damaging species produced in photodynamic therapy. We have shown that, upon oxidation by singlet oxygen, an analogue of thymidine (2) rearranges to a methide, which forms DNA-DNA interstrand cross-links. This novel process suggests that 2 may be a useful adjuvant in photodynamic therapy.

Cross-Linking Reagents↗
PubMed2005

Efficient DNA interstrand cross-link formation from a nucleotide radical.

5-(2'-Deoxyuridinyl)methyl radical (1) is produced during gamma-irradiation of DNA and other methods of oxidative stress. Independent generation of this reactive intermediate in duplex results in significant levels of DNA interstrand cross-links. Cross-link formation does not require O2 and involves reaction between the nucleotide where the radical is originally generated and the opposing deoxyadenosine. This is the first example in which formation of a nucleotide radical ultimately results in DNA-DNA cross-links. Interstrand DNA cross-links are difficult to repair and are believed to be the source of cytotoxicity of antitumor agents, such as mitomycin C. The efficient formation of DNA cross-links through 1 should provide the impetus for the design of DNA damaging agents that exploit this pathway.

DNA↗
PubMed2004

Mild generation of 5-(2'-deoxyuridinyl)methyl radical from a phenyl selenide precursor.

[reaction: see text] 5-(2'-Deoxyuridinyl)methyl radical (1) resulting from formal hydrogen atom abstraction from the methyl group of thymidine is produced from the respective phenyl selenide precursor (2) via 350 nm photolysis or mild thermolysis (37 degrees C in the presence of glutathione) under aerobic or anaerobic conditions. The mild thermal generation of a nucleoside radical provides an alternative to previously reported photochemical methods, which are not always compatible with nucleic acids.

Deoxyuridine↗
PubMed2004

Evidence for glycosidic bond rotation in a nucleobase peroxyl radical and its effect on tandem lesion formation.

Nucleobase peroxyl radicals are the major reactive intermediates formed in DNA when the biopolymer is exposed to gamma-radiolysis under aerobic conditions. The major reaction pathways for the peroxyl radical (1) derived from 5,6-dihydro-2'-deoxyuridin-6-yl involve pi-bond addition to or hydrogen atom abstraction from the adjacent nucleotides to produce tandem lesions. The ability to independently generate 1 at a defined site in DNA enabled us to probe its reactivity by varying the local DNA structure. The effect of DNA structure variation reveals that 1 reacts from its syn- and anti-conformations in competition with trapping by thiol. These experiments also reveal that tandem lesions will be produced as a mixture of diastereomers, which could impact their biological effects.

DNA↗
PubMed2003

Toward protein-cleaving catalytic drugs: artificial protease selective for myoglobin.

A protein-cleaving catalyst highly selective for a disease-related protein can be used as a catalytic drug. As the first protein-cleaving catalyst selective for a protein substrate, a catalyst for myoglobin (Mb) was designed by attaching the Cu(II) or Co(III) complex of cyclen to a binding site searched by a combinatorial method using peptide nucleic acid monomers as building units. Various linkers were inserted between the catalytic Co(III) center and the binding site of the Mb-cleaving catalyst. Kinetic data revealed catalytic turnover of the Mb cleavage by the Cu(II) or Co(III) complex. MALDI-TOF MS revealed cleavage of the polypeptide backbone of Mb at selected positions. N-Terminal sequencing of the cleavage products identified the cleavage site and provided evidence for the hydrolytic nature of the Mb cleavage. Various chelating ligands were tested as the ligand for the Co(III) center of the Mb-cleaving catalyst. Among the nine chelating ligands examined, only cyclen and its triaza-monooxo analogue manifested catalytic activity.

Binding Sites↗
PubMed2002

Protein-cleaving catalyst selective for protein substrate.

A protein-cleaving catalyst specific for a disease-related protein can be used as a catalytic drug. As the first protein-cleaving catalyst selective for a protein substrate, a catalyst for myoglobin was designed by attaching Cu(II) or Co(III) complex of cyclen to a binding site searched by a combinatorial method using peptide nucleic acid monomers as building units. [reaction: see text]

Base Sequence↗