198 Topics in Current Chemistry Editorial Board: A. de Meijere KN ...

46 J.P. Glusker
2. Non-intercalative groove binding. The drug lies in one of the grooves in DNA,
following the helical contour of DNA as it binds. Netropsin and distamycin
bind in this way.
3. Covalent bond formation. This occurs with mitomycin C.
The anthracyclines, such as daunomycin and its hydroxy analogue, adriamycin,
are naturally-occurring tetracyclic aminoglycosidic derivatives that contain an
anthraquinone chromophore. The main target of these drugs appears to be
DNA, probably by formation of an intercalation complex. Daunomycin and
adriamycin have a planar chromophore with an amino sugar extending out of
this plane. In the crystal structure of the complex of adriamycin with a self-complementary
hexadeoxynucleotide, the oligonucleotide forms a right-handed
helix with two molecules of adriamycin intercalated in the d(CpG) sequences at
each end, as shown in Fig. 37 [93–95]. Adriamycin and daunomycin are intercalated
in a similar manner with their long axes perpendicular to those of the
base pairs; the 14-hydroxyl group does not significantly affect the orientations
of the chromophore or the amino sugar. The hydroxyl group forms two hydrogen
bonds to an adjacent guanine. The amino sugar lies in the minor groove of
the distorted helix, but does not form bonds to the nucleic acid. Thus ring A
anchors adriamycin in DNA, and the nucleic-acid backbone is distorted by the
interactions formed. Glycosylation of C5 of a thymine residue in an oligonucleotide
does not prevent intercalation [96].
Recently, a bis intercalating derivative of daunomycin has been studied [97].
In this compound the amino groups are joined by a xylyl group. This daunomy-
a
Fig. 37 a – c. Binding of daunomycin to an oligonucleotide [95]: a chemical formula of daunomycin,
showing some interactions in the crystalline state. R 1=CH 3,R 2=CH 3 for daunomycin,
CH 2OH for adriamycin