COMPARATIVE-STUDIES OF UV-INDUCED DNA CLEAVAGE BY STRUCTURAL ISOMERS OF AN IODINATED DNA-LIGAND
COMPARATIVE-STUDIES OF UV-INDUCED DNA CLEAVAGE BY STRUCTURAL ISOMERS OF AN IODINATED DNA-LIGAND
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DOI：
10.1016/0360-3016(94)90454-5
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发表时间：
1994-06-15
影响因子：
7
通讯作者：
PARDEE, M
中科院分区：
文献类型：
--
作者：
MARTIN, RF;KELLY, DP;PARDEE, M
目的：为了评估碘化的DNA结合bibenzimidazoles中的卤素原子的位置的重要性，相对于敏化UV-A诱导的DNA breaking.Methods和Materials：三个类似物的iodoHoechst 33258，表示邻，Meta和paraiodoHoechst，根据碘取代的网站，合成。质粒DNA（pBR 322）用于测定UV-A诱导的DNA单链断裂（ssbs）。链断裂的位点的位置通过DNA测序凝胶分析确定，使用P-32-endlabeled oligoDNA与一个单一的结合位点的ligands.Results：一个明确的趋势，在降低活性的紫外线诱导的DNA ssbs的敏化建立：邻- > Meta-，帕拉- > iodoHoechst 33258。测序凝胶的研究表明，orthoiodoHoechst是不同于其他三种化合物，相对于DNA链断裂的网站和化学的裂解reaction.Conclusion：碘取代的碘化bibenzimidazole的位置决定的位置上的碳为中心的自由基的配体在小沟的DNA。DNA链的切割是由附近的脱氧核糖基H原子的提取介导的。因此，自由基种类的位置决定：哪个脱氧核糖基被攻击（即，相对于配体结合位点的切割位点）;哪个H原子被提取，更具体地涉及五个脱氧核糖基碳中的哪一个（即，裂解反应的化学性质），以及H-原子夺取的过渡态的立体化学性质（以及因此链断裂的效率或程度）。邻位化合物代表了迄今为止设计为潜在辐射增敏剂的碘化DNA配体的最佳实例，作为卤代DNA前体的公认增敏的延伸。
Purpose: 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.Methods and Materials: 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 P-32-endlabelled oligoDNA with a single binding site for the ligands.Results: 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.Conclusion: 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.