Anthracyclines and related compounds

The anthracycline antibiotics, which were studied in Section 3 of Chapter 4, also intercalate with DNA. The tetracyclic A-D chromophore of these compounds is oriented with its long axis perpendicular to the long axis of adjacent base pairs at the intercalation site. The daunorubicin-DNA complex is stabilized by the stacking interactions of rings B and C and by hydrogen bonding involving the hydroxyl group at C-9 of ring A, which acts as a donor to N-3 of guanine and as an acceptor from the amino group of the same guanine. Ring D protrudes into the major groove and the amino sugar moiety lies in the minor groove and does not take part in the interaction with DNA, although it is crucial for antitumor activity (see below).

As other antitumor intercalating agents, anthracyclines are topoisomerase II poisons because of the formation of a stable drug-DNA-topoisomerase II ternary complex and consequent inhibition of replication and transcription. The sugar unit is crucial for the stabilization of this complex, and suppression of the C-4 methoxy and C-3' amino groups increases topoisomerase II inhibition.56 The formation of topoisomerase-mediated DNA breaks seem to be too modest to explain the activity of the anthracyclines unless other mechanisms are taken into account (see Chapter 4), but some of these mechanisms are enhanced by anthracycline intercalation and minor groove binding; for instance, intercalation is known to favour DNA propenylation by malondialdehyde.57

In the case of nogalamycin, the presence of two sugar residues at both ends of the chromophore leads to a special way of interaction with DNA, called threading intercalation58 in which one of the sugar units is located at the minor groove and the other at the major groove. The structure of the nogalamycin-DNA complex has been studied by X-ray diffraction.59

Other anthracyclines that act primarily as topoisomerase II catalytic inhibitors, such as aclarubicin, will be mentioned in Section 6.1.

O OH OH

(CH3)2N

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