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X-ray diffraction analyses of the complexes between two anthracycline antitumor
compounds, idarubicin (IDR) and 4-O-demethyl-11-deoxydoxorubicin (ddDOX), with
the DNA hexamer d(CGATCG) provided the detailed three-dimensional molecular
structures at 1.7 A and 1.8 A resolution, respectively. Their structures have
been refined with the constrained refinement procedure to final R-factors of
0.188 (1724 reflections for IDR) and 0.179 (1247 reflections for ddDOX). The
overall structures of both complexes are similar to those of the previously
studied DAU- and DOX-DNA complexes. In both complexes, two IDR (and ddDOX)
molecules bind to the DNA hexamer double helix with the elongated aglycone
chromophore intercalated between the CpG steps at both ends of the helix. The
aglycone chromophore spans the GC Watson-Crick base pairs with its amino sugar
lying in the minor groove where little structural difference is seen, compared
with the daunorubicin-d(CGATCG) and doxorubicin-d(CGATCG) complexes. In
contrast, the missing C4 methoxy of IDR and the missing methyl group at the O4
position of ddDOX result in a different binding surface in the major groove. The
O4 hydroxyl group is capable of receiving and/or donating a hydrogen bond to
proteins that bind to the drug-DNA complex. The missing O11 hydroxyl group in
ring B creates an empty space in the intercalation cavity between the two GC
base pairs, which appears to affect the stacking interactions between the
aglycone and the DNA base pairs. Those structural changes in the major groove of
the drug-DNA complexes due to the modifications of the aglycone chromophore may
be responsible in part for the difference in their biological activities.
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