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 degrees C), induces DNA cleavage between three and four base pairs from the polyamide binding site in high yield (77%).
Wang
C C
CC
Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, California 91125, USA.
Dervan
P B
PB
D000818:Animals; D020029:Base Pairing / Q000502:physiology; D001665:Binding Sites / Q000502:physiology; D002166:Camptothecin / Q000138:chemical synthesis / Q000378:metabolism*; D002417:Cattle; D004247:DNA / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology; D018983:DNA Footprinting; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D009757:Nylons / Q000138:chemical synthesis / Q000378:metabolism*
D009757:Nylons; D004247:DNA; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin