The crystal structure of the complex formed between the
anthracycline antibiotic 3'-deamino-3'- hydroxy-4'-(O-L-daunosaminyl)-4-demethoxydoxo rubicin (
MEN 10755), an active
disaccharide analogue of
doxorubicin, and the
DNA hexamer d(CGATCG) has been solved to a resolution of 2.1 A.
MEN 10755 exhibits a broad spectrum of antitumor activities, comparable with that of the parent compound, but there are differences in the mechanism of action as it is active in
doxorubicin-resistant
tumors and is more effective in stimulating topoisomerase DNA cleavage. The structure is similar to previously crystallised
anthracycline-
DNA complexes. However, two different binding sites arise from
drug intercalation so that the two halves of the self-complementary duplex are no longer equivalent. In one site both
sugar rings lie in the minor groove. In the other site the second
sugar protrudes out from the
DNA helix and is linked, through hydrogen bonds, to
guanine of a symmetry-related
DNA molecule. This is the first structure of an
anthracycline-
DNA complex where an interaction of the
drug with a second
DNA helix is observed. We discuss the present findings with respect to the relevance of the amino group for
DNA binding and to the potential role played by the second
sugar in the interactions with topoisomerases or other cellular targets.