Differential effects of camptothecin derivatives on topoisomerase I-mediated DNA structure modification.
The effects of eleven camptothecin derivatives on calf thymus topoisomerase I-mediated cleavage of synthetic DNA duplex have revealed that the A ring of camptothecin is very important for its biochemical activity. Depending on the type, number, and location of substituents, highly active or inactive analogues were obtained. The persistence of CPT-induced topoisomerase I-DNA covalent binary complexes was investigated by using as substrates DNA containing several good topoisomerase I cleavage sites, or else a synthetic DNA duplex of defined structure with a single high-efficiency cleavage site. The ligation kinetics at a given topoisomerase I cleavage site were sometimes quite different in the presence of CPT derivatives whose structures were closely related. Even in the presence of a single CPT analogue, topoisomerase I-DNA covalent binary complexes underwent ligation with different kinetics, presumably reflecting a dependence on DNA sequences flanking the individual topoisomerase I cleavage sites. Individual camptothecin derivatives also exhibited a spectrum of inhibitory potentials in blocking the topoisomerase I-mediated rearrangement of branched, nicked, and gapped DNA duplex substrates; in some cases the potencies of inhibition observed in these assays for individual camptothecin analogues were quite different than those determined for stabilization of the unmodified DNA-topoisomerase I binary complex.
Wang
X
X
Department of Chemistry, University of Virginia, Charlottesville 22901, USA.
Wang
L K
LK
Kingsbury
W D
WD
Johnson
R K
RK
Hecht
S M
SM
D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D004247:DNA / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D011088:DNA Ligases / Q000378:metabolism; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D006868:Hydrolysis / Q000187:drug effects; D009692:Nucleic Acid Heteroduplexes / Q000737:chemistry* / Q000187:drug effects / Q000378:metabolism; D012965:Sodium Chloride / Q000494:pharmacology; D013379:Substrate Specificity / Q000187:drug effects; D059004:Topoisomerase I Inhibitors
D009692:Nucleic Acid Heteroduplexes; D059004:Topoisomerase I Inhibitors; D012965:Sodium Chloride; D004247:DNA; D004264:DNA Topoisomerases, Type I; D011088:DNA Ligases; D002166:Camptothecin