Sequence‐Selective Intercalation of Antitumour Bis‐Naphthalimides into DNA

FEBS Journal - Tập 240 Số 1 - Trang 195-208 - 1996
Christian Bailly1,2, Miguel F. Braña3, Michael J. Waring1
1Department of Pharmacology, University of Cambridge, England
2Institut de Recherches sur le Cancer, INSERM U124, Lille, France
3Laboratories Knoll S.A., Madrid, Spain

Tóm tắt

LU 79553, a bis‐naphthalimide drug highly active against human solid tumour xenografts, has been shown to bis‐intercalate into DNA with a helix‐unwinding angle of 37°. Footprinting experiments with DNase I reveal that the drug is selective for mixed nucleotide sequences characterised by an alternating purine‐pyrimidine motif, particularly those containing GpT (ApC) and TpG (CpA) steps. Derivatives bearing nitro or amino substituents on the naphthalimide chromophores bind at essentially identical sites. The footprinting profiles on tyrT DNA and on two fragments from pBS bear a remarkable resemblance to those determined for nogalamycin, an antibiotic which binds intercalatively leaving bulky carbohydrate substituents blocking both the major and minor grooves of the helix. Several lines of evidence indicate that the bis‐naphthalimides recognise their preferred binding sites via the unusual expedient of intercalating from the major groove. Footprints on the complementary DNA strands sometimes appear staggered in the 5′ direction. Repositioning the 2–amino group of G · C base pairs, which serves as a critical minor‐groove marker, by substitution with inosine and/or 2,6‐diaminopurine has little effect on the distribution of binding sites for LU 79553. The bisnaphthalimides affect the guanine‐specific reaction with dimethyl sulfate (which reacts with the N7 position of the base located in the major groove) but not reactions with tetrachloropalladinate or methylene blue. Photoactivation of LU 79553–DNA complexes leads to a small amount of strand scission mainly at guanine residues. These observations make a strong case for binding via the major groove of the double helix, in contrast to nearly all common intercalating drugs, which could be important in explaining the unique biological selectivity of bis‐naphthalimides.

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FEBS Journal

Tập 240 Số 1

195-208

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