Comparative studies of UV-induced DNA cleavage by structural isomers of an iodinated DNA ligand
The purpose was to evaluate the importance of the position of the halogen atom in iodinated DNA-binding bibenzimidazoles, with respect to sensitization of UV-A-induced DNA breakage. Three analogues of iodoHoechst 33258, denoted ortho-, meta- and paraiodoHoechst, according to the site of iodine substitution, were synthesized. Plasmid DNA (pBR322) was used to assay UV-A-induced DNA single-strand breaks (ssbs). The location of the sites of strand breakage was determined by DNA sequencing gel analysis, using a [sup 32]P-endlabelled oligoDNA with a single binding site for the ligands. A clear trend in decreasing activity of sensitization of UV-induced DNA ssbs was established: Ortho- > meta-, para- > iodoHoechst 33258. The sequencing gel studies showed that orthoiodoHoechst was distinct from the other three compounds, with respect to the sites of DNA strand breakage and the chemistry of the cleavage reaction. The position of iodine substitution in iodinated bibenzimidazoles determines the location of the carbon-centered radical on the ligand in the minor groove of DNA. DNA strand cleavage is mediated by abstraction of a nearby deoxyribosyl H-atom. Hence, the position of the radical species determines: which deoxyribosyl group is attacked (i.e., site of cleavage relative to the ligand binding site); which H-atom is abstracted, more specifically which of the five deoxyribosyl carbons is involved (i.e., the chemistry of the cleavage reaction), and the stereochemistry of the transition state for the H-atom abstraction (and hence the efficiency or extent of strand breakage). The ortho-compound represents the best example to date of iodinated DNA ligands designed as potential radiation sensitizers, as an extension of the well-established sensitization by halogenated DNA precursors. 30 refs., 3 figs.
- OSTI ID:
- 7100249
- Journal Information:
- International Journal of Radiation Oncology, Biology and Physics; (United States), Vol. 29:3, Issue 3; ISSN 0360-3016
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
BENZIMIDAZOLES
RADIOSENSITIVITY
STRUCTURE-ACTIVITY RELATIONSHIPS
DNA
STRAND BREAKS
IODINATED AROMATIC HYDROCARBONS
ULTRAVIOLET RADIATION
AROMATICS
AZOLES
ELECTROMAGNETIC RADIATION
HALOGENATED AROMATIC HYDROCARBONS
HETEROCYCLIC COMPOUNDS
IMIDAZOLES
NUCLEIC ACIDS
ORGANIC COMPOUNDS
ORGANIC HALOGEN COMPOUNDS
ORGANIC IODINE COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
RADIATIONS
560120* - Radiation Effects on Biochemicals
Cells
& Tissue Culture