Molecular structure of an anticancer drug-DNA complex: daunomycin plus d(CpGpTpApCpG).

Abstract

The structure of the crystalline daunomycind(CpGpTpApCpG) complex has been solved by x-ray diffraction analysis. The DNA forms a six-base-pair right-handed double helix with two daunomycin molecules intercalated in the d(CpG) sequences. The daunomycin aglycone chromophore is oriented at right angles to the long dimension of the DNA base pairs and the cyclohexene ring rests in the minor groove. Substituents on this ring have hydrogen bonding interactions to the base pairs above and below the intercalation site. These appear to be specific for anthracycline antibiotics. The amino sugar lies in the minor groove of the double helix without bonding to the DNA. The DNA double helix is distorted in a novel manner in accommodating the drug.An important group of antibiotics are those that interact with DNA and have antitumor activity. Daunomycin, an anthracycline antibiotic, has been found to inhibit virus multiplication and shows considerable activity against tumors; it was the first antibiotic to show activity against acute leukemia in man. It has an aglycone chromophore containing four fused rings and an amino sugar (Fig. 1). The closely related antitumor agent adriamycin (14-hydroxydaunomycin) is widely used in treating various solid tumors. These compounds have been the subject of intensive chemical and biological research since their discovery 17 years ago. More than 500 compounds of this type have been synthesized or isolated from nature and tested for activity (1, 2). These agents are believed to act by binding to DNA and inhibiting both DNA replication and transcription. Several studies suggest that the unsaturated chromophore intercalates between DNA base pairs (1, 2). However, the complexity of the molecule makes its mode of interaction with DNA a matter of considerable interest.Here we report the crystal structure of daunomycin with a self-complementary DNA fragment, d(CpGpTpApCpG). The structure has been solved by x-ray diffraction methods. A sixbase-pair fragment of double-helical DNA was found with two molecules of daunomycin bound to it, plus 80 mM spermine, and 30 mM cacodylate buffer (pH 6.5) was equilibrated with 30% (vol/vol) 2-methyl-2,4-pentanediol. After 1 week, attractive bright red-orange, tetragonal, rod-like crystals appeared. Spectroscopic analysis of the dissolved crystal revealed a 1:1 ratio of hexanucleotide to daunomycin. X-ray diffraction studies indicated a tetragonal crystal system with space group P4 212 or P43212, a = b = 27.92 A, c = 52.89 A.The asymmetric unit contained one hexanucleotide and one daunomycin molecule. Intense meridional reflections at 3.3 A along the c axis strongly suggested that the bases were stacked perpendicular to that direction. Three-dimensional data were collected on a Nicolet x-ray diffractometer to a resolution of

Sequence selective binding of ditrisarubicin B to DNA: comparison with daunomycin

“…In the crystal structure of daunomycin complexed to d(CGTACG), drug molecules are intercalated into the CpG steps with the daunosamine ring positioned in the DNA minor groove [4]. The structure is stabilised by several hydrogen bonds.…”

Origins of stereospecificity in DNA damage by anti‐benzo[a]pyrene diol‐epoxides

“…NMR studies [34] and X-ray crystallographic analyses (e.g. [20,35]) show such a preference. These have been reinforced by energy calculations [36], which indicate that increasing the base-pair to base-pair separation from 3.4 to 6.8 A in order to allow intercalation is energetically more favourable for a pyrimidine-3 ' ,5 ' -purine sequence than for other sequences.…”

Two-Dimensional1H and31P NMR Spectra of a Decamer Oligodeoxyribonucleotide Duplex and a Quinoxaline ([MeCys3, MeCys7]TANDEM) Drug Duplex Complex

“…This is apparently accomplished by the phosphate switching from the normal B-DNA conformation ("BI") in which both P-O torsional angles ζ and α are in the g -conformation to the "BII" conformation (ζ = t, α = g -). The 31 P signal of a phosphate in a t, g -BII conformation is predicted to be ~1-1.5 ppm downfield from the g -, g -phosphate in the BI conformation ( 64,70), and we expect to observe a large downfield shift of the 31 …”