The antitumor drug nogalamycin forms two different intercalation complexes with d(GCGT).cntdot.d(ACGC)

Abstract

The structures of the physical complex of d(GCGT).d(ACGC) with the anthracycline antitumor drug nogalamycin were studied in order to determine the sequence specificity and the drug orientation at the symmetric d(C2G3).d(C6G7) binding site of this oligonucleotide. For this purpose, one- and two-dimensional NMR techniques were used in combination with molecular mechanics and molecular dynamics computations. Analysis of the NMR spectra reveals that nogalamycin forms two different intercalation complexes with d(GCGT).d(ACGC). These complexes are called complex I and complex II and are present in a ratio of 0.45:0.55. In both complexes the nogalamycin is intercalated at the d(C2G3).d(C6G7) sequence with the bicyclic and nogalose sugars residing in the major and minor groove, respectively. This results in a buckling of the flanking base pairs and a doubling of the inter-base-pair distances at the intercalation site. In complex I, the aglycon ring of the drug stacks with the C6-G7 bases, and the sugars are directed to the G1.C8 end; while in the case of complex II the anthraquinone ring system is stacked with C2-G3 bases, and the sugars are pointed to the T4.A5 base pair end. The two nogalamycin-d(GCGT).d(ACGC) structures are stabilized by intra- and intermolecular hydrogen bonds, electrostatic interactions, and van der Waals contacts. Comparison of different nogalamycin-oligonucleotide structures reveals a nogalamycin binding specificity to the 3'-side of the cytosine base in cytosine-purine sequences in double-stranded DNA.

Sequence‐Selective Intercalation of Antitumour Bis‐Naphthalimides into DNA

“…1). One of the sugars must project into the major groove of the double helix while the other occludes the minor groove (Fox and Waring, 1986;Egli et al, 1991 ; van Houte et al, 1993). The tracks on the left-hand side of Fig.…”

“…It does not follow that drugs will consistently adopt a common mode of interaction at all possible sites, as Fox and Waring (1986) were forced to conclude in respect of the orientation of nogalamycin bound to DNA and others have since clarified (Searle et al, 1988;Egli et al, 1991 ;van Houte et al, Definitive evidence for bis-intercalation via the major groove of the helix will have to await the determination of a high-resolution structure for an oligonucleotidehis-naphthalimide complex by NMR or X-ray crystallography, as has been achieved for ditercalinium (Williams and Gao, 1992). Efforts to obtain structural data by these means are under way.…”

A Continuous Transition from A-DNA to B-DNA in the 1:1 Complex between Nogalamycin and the Hexamer dCCCGGG

“…DNA footprinting studies have indicated preferential binding at d(CA)⅐d(TG) steps (4). NMR studies using nuclear Overhauser effect data have confirmed that sequences containing more than one potential site can form two different intercalation complexes with roughly equal proportions (5). The x-ray structures of the DNA complexes with nogalamycin and with daunomycin and adriamycin, other anthracycline antibiotics with anti-tumor activities and similar sequence preferences, have utilized modifications to the hexameric sequence d(CGTACG).…”

Differential Poisoning of Topoisomerases by Menogaril and Nogalamycin Dictated by the Minor Groove-Binding Nogalose Sugar

“…As shown in Figure 1, the aglycon ring of nogalamycin intercalates into DNA base pairs while the nogalose and bicyclic amino sugars are positioned in the minor and major grooves of DNA, respectively. Unlike other DNA minor groove binders, such as Ho33342, distamycin and netropsin, which prefer binding to AT-rich DNA (28), nogalamycin prefers binding to GC base pairs (27). However, because of the hook-like structure of intercalated nogalamycin, transient local melting of DNA has been proposed to facilitate nogalamycin binding to the GC base (24,29).…”