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Vol. 53, Issue 1, 77-87, January 1998

Recognition of Specific Sequences in DNA by a Topoisomerase I Inhibitor Derived from the Antitumor Drug Rebeccamycin

Christian Bailly, Pierre Colson, Claude Houssier, Elisabete Rodrigues-Pereira, Michelle Prudhomme and Michael J. Waring

Laboratoire de Pharmacologie Moléculaire Antitumorale du Centre Oscar Lambret, Institut National de la Santé et de la Recherche Médicale Unité 124, 59045 Lille, France (C.B.), Laboratoire de Chimie Macromoléculaire et Chimie Physique, Université de Liège, Liège 4000, Belgium (P.C., C.H.), Synthèse, Electrosynthèse et Etude de Systèmes à Intérêt Biologique, Université Blaise Pascal, Centre National de la Recherche Scientifique UMR 6504, 63177 Aubière cedex, France (E.R.-P., M.P.) and University of Cambridge, Department of Pharmacology, Cambridge CB2 1QJ, UK (M.J.W.)

We investigated the interaction with DNA of two synthetic derivatives of the antitumor antibiotic rebeccamycin: R-3, which is a potent topoisomerase I inhibitor and contains a methoxyglucose moiety appended to the indolocarbazole chromophore, and its aglycone, R-4. Spectroscopic measurements indicate that R-3 intercalates into DNA and that its carbohydrate domain contributes significantly to reinforce the affinity for DNA. Two complementary ligation assays concur that R-3, but not its aglycone counterpart, exerts a significant effect on the curvature and/or the flexibility of DNA. The sugar moiety may be responsible for preferential binding of R-3 to circular (or bent) DNA molecules as opposed to linear DNA fragments. The sequence selectivity of binding to DNA has been studied thoroughly by footprinting with DNase I and two other nucleases. The glycosylated compound is highly selective for nucleotide sequences containing GpT (ApC) and TpG (CpA) steps. The derivative lacking the sugar moiety on the indolocarbazole chromophore binds at essentially identical sites but with considerably lower affinity, so it seems that the chromophore rather than the carbohydrate is responsible for the preferential binding to sequences surrounding GpT and TpG steps. The influence of the exocyclic substituents present on the bases at the recognition sites (i.e., the 2-amino group of guanine and the 5-methyl group of thymine) was evaluated using two series of modified DNA molecules prepared by polymerase chain reaction containing inosine and/or 2,6-diaminopurine and uridine and/or 5-methylcytosine residues. The introduction of the amino group onto purine residues or the addition of a methyl group to pyrimidine residues suffices to create new drug binding sites. Therefore, unlike most DNA-binding small molecules, the rebeccamycin analogue seems to be highly sensitive to any modification of the exocyclic substituents on the bases in both the major and minor grooves of the double helix. The footprinting profiles with the different DNA fragments bear a remarkable resemblance to those determined for nogalamycin and bisnaphthalimide compounds known to recognize their preferred GpT and TpG sites via intercalation from the major groove. The unique DNA binding characteristics of the rebeccamycin analogue correlate well with its inhibitory effects on topoisomerase I .

Copyright © 1998 by The American Society for Pharmacology and Experimental Therapeutics


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