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 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%).