Sequence-Specific Trapping of Topoisomerase I by DNA Binding Polyamide−Camptothecin Conjugates

Hairpin pyrrole−imidazole polyamides are synthetic ligands that bind in the minor groove of DNA with affinities and specificities comparable to those of DNA binding proteins. Three polyamide−camptothecin conjugates 1−3 with linkers varying in length between 7, 13, and 18 atoms were synthesized to tr...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2001-09, Vol.123 (36), p.8657-8661
Main Authors: Wang, Clay C. C, Dervan, Peter B
Format: Article
Language:English
Subjects:
Animals
Base Pairing - physiology
Binding Sites - physiology
Camptothecin - chemical synthesis
Camptothecin - metabolism
Cattle
DNA - metabolism
DNA Damage - physiology
DNA Footprinting
DNA Topoisomerases, Type I - metabolism
Nylons - chemical synthesis
Nylons - metabolism
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Summary:Hairpin pyrrole−imidazole polyamides are synthetic ligands that bind in the minor groove of DNA with affinities and specificities comparable to those of DNA binding proteins. Three polyamide−camptothecin conjugates 1−3 with linkers varying in length between 7, 13, and 18 atoms were synthesized to trap the enzyme Topoisomerase I and induce cleavage at predetermined DNA sites. One of these, polyamide−camptothecin conjugate 3 at nanomolar concentration (50 nM) in the presence of Topo I (37 °C), induces DNA cleavage between three and four base pairs from the polyamide binding site in high yield (77%).
ISSN:0002-7863
1520-5126
DOI:10.1021/ja010392p